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Since RNA viruses and retroviruses all have high mutation rates, why do only a few viruses have the virtue of variability?

Since RNA viruses and retroviruses all have high mutation rates, why do only a few viruses have the virtue of variability?


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We have been taught that it's difficult to make vaccines to influenza, HIV and HCV because they lack the proofreading mechanism, hence have high mutation rates. But most RNA viruses and retroviruses are still antigenically stable, such as measles, rabies, polio, yellow fever, HBV etc. So why do only a few viruses successfully become variable? Is it because their receptors allow flexibility, or their glycoproteins have sophisticated conformations that allow more mutations?


The high mutation rate is only a small part of the reason it's hard to make vaccines against those RNA viruses. The real problem is not that they mutate rapidly, but that they can tolerate high levels of variation in their antigenic regions without losing fitness. Viruses like polio and measles, as you say, have mutation rates easily on a par with influenza or HIV, but when they mutate antigenically significant regions, those new viruses are much less capable of infecting and transmitting between hosts. Vaccines therefore either block the virus replication altogether, or force them into a much weaker form that is much less infectious.

Why do some viruses tolerate antigenic changes better than others? It's not known, but presumably there has been selection for it in those lineages.


Endogenous retrovirus

Endogenous retroviruses (ERVs) are endogenous viral elements in the genome that closely resemble and can be derived from retroviruses. They are abundant in the genomes of jawed vertebrates, and they comprise up to 5–8% of the human genome (lower estimates of

1%). [1] [2] ERVs are a vertically inherited proviral sequence and a subclass of a type of gene called a transposon, which can normally be packaged and moved within the genome to serve a vital role in gene expression and in regulation. [3] [4] ERVs however lack most transposon function, are typically not infectious and are often defective genomic remnants of the retroviral replication cycle. [5] [6] They are distinguished as germline provirus retroelements due to their integration and reverse-transcription into the nuclear genome of the host cell. Researchers have suggested that retroviruses evolved from a type of transposon called a retrotransposon, a Class I element [7] these genes can mutate and instead of moving to another location in the genome they can become exogenous or pathogenic. This means that not all ERVs may have originated as an insertion by a retrovirus but that some may have been the source for the genetic information in the retroviruses they resemble. [8] When integration of viral DNA occurs in the germ-line, it can give rise to an ERV, which can later become fixed in the gene pool of the host population. [1] [9]


Initiation of Infection

To infect a cell, the virus must attach to the cell surface, penetrate into the cell, and become sufficiently uncoated to make its genome accessible to viral or host machinery for transcription or translation.

Attachment

Attachment constitutes specific binding of a virion protein (the anti-receptor) to a constituent of the cell surface (the receptor). The classic example of an anti-receptor is the hemagglutinin of influenza virus (an Orthomyxovirus). The anti-receptors are distributed throughout the surfaces of viruses infecting human and animal cells. Complex viruses such herpes simplex virus (a herpesvirus) may have more than one species of anti-receptor molecule. Mutations in the genes specifying anti-receptors may results in a loss of the capacity to interact with certain receptors. The cellular receptors identified so far are largely glycoproteins, but include sialic acid and heparan sulfate.

Attachment requires ions in concentrations sufficient to reduce electrostatic repulsion but it is largely temperature and energy independent. The susceptibility of a cell is limited by the availability of appropriate receptors and not all cells in an otherwise susceptible organism express receptors. Human kidney cells lack receptors for poliovirus when they reside in the organ, but receptors appear when renal cells are propagated in cell culture. Susceptibility should not be confused with permissiveness. While chick cells are insusceptible to poliovirions because they lack receptors for attachment of the virus, they are fully permissive because they produce infectious virus following transfection with intact viral RNA extracted from poliovirus particles. Attachment of viruses to cells in some instances (e.g., picornaviruses leads to irreversible changes in the structure of the virion. In other instances, if penetration does not ensue, the virus can detach itself and readsorb to a different cell. In the latter category are orthomyxoviruses and some paramyxoviruses which carry a neuraminidase on their surface. These viruses can elute from their receptors by cleaving neuraminic acid from the polysaccharide chains of the receptors.

Penetration

Penetration is an energy-dependent step. It occurs almost instantaneously after attachment and involves one of three mechanisms, i.e., (a) translocation of the virion across the plasma membrane, (b) endocytosis of the virus particle resulting in accumulation of virions inside cytoplasmic vacuoles and (c) fusion of the cellular membrane with the virion envelope. Non-enveloped viruses penetrate by the first two mechanisms. For example, in the course of adsorption of the poliovirus to the cell, the capsid becomes modified and loses its integrity as it is translocated into the cytoplasm. In the case of viruses which penetrate as a consequence of fusion of their envelopes with the plasma membrane (e.g., herpesviruses), the envelope remains in the plasma membrane, whereas the internal constituents spill into the cytoplasm. Fusion of viral envelopes with the plasma membrane requires the interaction of specific viral proteins in the viral envelope with proteins in the cellular membrane.

Uncoating

Uncoating is a general term applied to the events occurring after penetration which set the stage for the viral genome to express its functions. In the case of most viruses, the virion disaggregates, alone or with the aid of cellular components (enzymes) and only the nucleic acid or a nucleic acid-protein complex is all that remains of the virus particle before expression of viral functions. Adenovirus, herpesvirus, and papillomavirus nucleo capsids are transported to the nuclear pore where the viral DNA is released directly into the nucleus. In cells infected with orthomyxoviruses, the particle is taken up into an endocytic vesicle. An ion channel embedded in the viral envelope acidifies the virus particle, alters the structure of the hemagglutinin and enables the fusion of the viral envelope with the membrane of the vesicle and the release of viral ribonucleoprotein (RNP) into the cytoplasm. In the exceptional case of reoviruses, only portions of the capsid are removed, and the viral genome expresses all of its functions even though it is never fully released from the capsid. The poxvirus genome is uncoated in two stages: whereas in the first stage the outer covering is removed by host enzymes, the release of viral DNA from the core appears to require the participation of viral gene products made after infection.


Author summary

Mutations frequently occur in SARS-CoV-2 and the mutant variants, ORF1ab/RdRp 4715L and S protein 614G have been strongly linked to increased infectivity and fatality in other countries. Although increased number of cases in Africa correlated positively with increased deaths, such deaths did not correlate positively with the duo variants, ORF1ab 4715L and S protein 614G in the early part of the outbreak. This could possibly be due to the younger aged population, lower comorbidity and divergent genetic factors.

Citation: Lamptey J, Oyelami FO, Owusu M, Nkrumah B, Idowu PO, Adu-Gyamfi EA, et al. (2021) Genomic and epidemiological characteristics of SARS-CoV-2 in Africa. PLoS Negl Trop Dis 15(4): e0009335. https://doi.org/10.1371/journal.pntd.0009335

Editor: Zvi Bentwich, Ben-Gurion University of the Negev, ISRAEL

Received: October 15, 2020 Accepted: March 26, 2021 Published: April 26, 2021

Copyright: © 2021 Lamptey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are attached to the manuscript and its Supporting Information files.

Funding: This project is part of the EDCTP2 programme supported by the European Union (grant number EDCTP-TMA2015-Career Development Fellowships http://www.edctp.org/projects-2/edctp2-projects/career-development-fellowships/#), and the Centre for Health System Strengthening, Ghana (https://cfhss.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.


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Abstract

Recent studies have uncovered myriad viral sequences that are integrated or 'endogenized' in the genomes of various eukaryotes. Surprisingly, it appears that not just retroviruses but almost all types of viruses can become endogenous. We review how these genomic 'fossils' offer fresh insights into the origin, evolutionary dynamics and structural evolution of viruses, which are giving rise to the burgeoning field of palaeovirology. We also examine the multitude of ways through which endogenous viruses have influenced, for better or worse, the biology of their hosts. We argue that the conflict between hosts and viruses has led to the invention and diversification of molecular arsenals, which, in turn, promote the cellular co-option of endogenous viruses.


Abstract

Recent studies have uncovered myriad viral sequences that are integrated or 'endogenized' in the genomes of various eukaryotes. Surprisingly, it appears that not just retroviruses but almost all types of viruses can become endogenous. We review how these genomic 'fossils' offer fresh insights into the origin, evolutionary dynamics and structural evolution of viruses, which are giving rise to the burgeoning field of palaeovirology. We also examine the multitude of ways through which endogenous viruses have influenced, for better or worse, the biology of their hosts. We argue that the conflict between hosts and viruses has led to the invention and diversification of molecular arsenals, which, in turn, promote the cellular co-option of endogenous viruses.


Emerging Infections: Microbial Threats to Health in the United States (1992)

Emerging infectious diseases are clinically distinct conditions whose incidence in humans has increased. For the purposes of this study, the committee has focused on diseases that have emerged in the United States within the past two decades. Emergence may be due to the introduction of a new agent, to the recognition of an existing disease that has gone undetected, or to a change in the environment that provides an epidemiologic "bridge." (For an example of an emerging disease, see Box 2-1.) Emergence, or, more specifically, reemergence, may also be used to describe the reappearance of a known disease after a decline in incidence. Although an infectious agent plays a role in any emerging infectious disease, other causative factors may be important as well.

BOX 2-1 A Deadly Form of Strep

It was a shock to many when renowned puppeteer Jim Henson died suddenly in May 1990. How could a healthy man in his early 50s be so easily felled by a case of pneumonia? Since his death, attention has focused on a deadly "new" form of streptococcal bacteria. This new bacterium belongs to a category of strep bacteria called "Group A," a subset of organisms familiar to many as the cause of acute pharyngitis (strep throat). The new strep A has been killing otherwise healthy people (like Henson), and doing so in a frighteningly rapid fashion. This was true for a 30-year-old Canadian man who got a splinter in his finger, which later became infected. Within six days he had become so ill that he was admitted to an intensive care unit and placed on a respirator. He died six weeks later of sepsis (disseminated infection) (Goldman, 1991).

The new strep A bacteria, like all streptococcal organisms, are typically inhaled, but they can also enter the body through a cut or scrape. The infection they provoke once inside the body is especially insidious: its early symptoms are easily mistaken for signs of the flu. In several cases, the bacteria have overwhelmed their host with pneumonia, and in others, with kidney and liver damage before the infected person has sought treatment. So advanced, the infection is extremely difficult to treat. Even if massive doses of penicillin succeed in killing the bacteria, there are no means available to counter the effects of the deadly toxin they produce&mdashwhich actually causes the pneumonia and tissue damage.

Although reports of the first cases of fatal infection with the new strep A appeared in the medical literature in 1989 (Stevens et al., 1989), health problems associated with the streptococcus family of bacteria are not new. In the days before antibiotics, they were responsible for widespread outbreaks of scarlet fever and rheumatic fever. Nor are these bacteria rare. Strep throat is so common an ailment among children that it could almost be considered a rite of passage.

Much about the new strep A remains a mystery. Some scientists&mdashnoting the similarity between the toxin secreted by the new strep A and the toxin once seen with scarlet fever&mdashbelieve that this bacterium is an old microbe making a comeback. Others consider this highly virulent form of strep the result of a recent bacterial mutation.

Whatever its origin, the new strep A deserves attention. Experts strongly encourage people to seek immediate medical care if they become very ill (high fever, sore throat) in a sudden fashion, especially if they have recently suffered a cut or burn.

Although cases of infection with this new, deadly microbe remain quite rare, their increasing incidence in the past two years is cause for concern. A vaccine for streptococcal infections is in development, but researchers estimate that it will not be ready for public use for at least another three years. In the meantime, the Centers for Disease Control is working to track the new strep A more closely, with the hope of learning more about the bacterium and how to stop it.

Table 2-1 is a list of emerging infectious agents, categorized by type of organism. Appendix B provides more detailed information on each of these agents. The committee recognizes that this list is continually expanding, mainly as a result of the growing numbers of immunocompromised individuals. Therefore, it may not contain all organisms that fit the definition above.

Once a new pathogen has been introduced into a human population, its ability to spread becomes a critical factor in emergence. The same is true for agents that are already present in a limited or isolated human population:

TABLE 2-1 Part 1: Examples of Emergent Bacteria, Rickettsiae, and Chlamydiae

Aeromonad gastroenteritis, cellulitis, wound infection, septicemia

Ingestion of contaminated water or food entry of organism through a break in the skin

Immunosuppression improved technology for detection and differentiation

Lyme disease: rash, fever, neurologic and cardiac abnormalities, arthritis

Bite of infective Ixodes tick

Increase in deer and human populations in wooded areas

Campylobacter enteritis: abdominal pain, diarrhea, fever

Ingestion of contaminated food, water, or milk fecal-oral spread from infected person or animal

Increased recognition consumption of uncooked poultry

Chlamydia pneumoniae (TWAR strain)

TWAR infection: fever, myalgias, cough, sore throat, pneumonia

Inhalation of infective organisms possibly by direct contact with secretions of an infected person

Trachoma, genital infections, conjunctivitis infection during pregnancy can result in infant pneumonia

Increased sexual activity changes in sanitation

Colitis: abdominal pain, watery diarrhea, bloody diarrhea

Fecal-oral transmission contact with the organism in the environment

Increased recognition immunosuppression

Ehrlichiosis: febrile illness (fever, headache, nausea, vomiting, myalgia)

Unknown tick is suspected vector

Increased recognition possibly increase in host and vector populations

Hemorrhagic colitis thrombocytopenia hemolytic uremic syndrome

Ingestion of contaminated food, esp. undercooked beef and raw milk

Likely due to the development of a new pathogen

Haemophilus influenzae biogroup aegyptius

Brazilian purpuric fever: purulent conjunctivitis, high fever, vomiting, and purpura

Contact with discharges of infected persons eye flies are suspected vectors

Possibly an increase in virulence due to mutation

Gastritis, peptic ulcer, possibly stomach cancer

Ingestion of contaminated food or water, esp. unpasteurized milk contact with infected pets

Legionnaires' disease: malaise, myalgia, fever, headache, respiratory illness

Air-cooling systems, water supplies

Recognition in an epidemic situation

Listeriosis: meningoencephalitis and/or septicemia

Ingestion of contaminated foods contact with soil contaminated with infected animal feces inhalation of organism

Probably increased awareness, recognition, and reporting

Tuberculosis: cough, weight loss, lung lesions infection can spread to other organ systems

Exposure to sputum droplets (exhaled through a cough or sneeze) of a person with active disease

Abscesses, pneumonia, endocarditis, toxic shock

Contact with the organism in a purulent lesion or on the hands

Recognition in an epidemic situation possibly mutation

Streptococcus pyogenes (Group A)

Scarlet fever, rheumatic fever, toxic shock

Direct contact with infected persons or carriers sometimes ingestion of contaminated foods

Change in virulence of the bacteria possibly mutation

Cholera: severe diarrhea, rapid dehydration

Ingestion of water contaminated with the feces of infected persons ingestion of food exposed to contaminated water

Poor sanitation/hygiene possibly introduced via bilge-water from cargo ships

Cellulitis fatal bacteremia diarrheal illness (occasionally)

Contact of superficial wounds with seawater or with contaminated (raw or undercooked) seafood ingestion (occasionally)

TABLE 2-1 Part 2: Examples of Emergent Viruses

Bovine spongiform encephalopathy (BSE) agent

Bovine spongiform encephalopathy in cows

Ingestion of feed containing infected sheep tissue

Changes in the rendering process

Fever, arthritis, hemorrhagic fever

Bite of infected mosquito

Crimean-Congo hemorrhagic fever

Bite of an infected adult tick

Ecological changes favoring increased human exposure to ticks on sheep and small wild animals

Bite of an infected mosquito (primarily Aedes aegypti)

Poor mosquito control increased urbanization in tropics increased air travel

Filoviruses (Marburg, Ebola)

Fulminant, high-mortality hemorrhagic fever

Direct contact with infected blood, organs, secretions, and semen

Unknown in Europe and the United States, virus-infected monkeys shipped from developing countries via air

Abdominal pain, vomiting, hemorrhagic fever

Inhalation of aerosolized rodent urine and feces

Human invasion of virus ecologic niche

Nausea, vomiting, jaundice chronic infection leads to hepatocellular carcinoma and cirrhosis

Contact with saliva, semen, blood, or vaginal fluids of an infected person mode of transmission to children not known

Probably increased sexual activity and intravenous drug abuse transfusion (before 1978)

Nausea, vomiting, jaundice chronic infection leads to hepatocellular carcinoma and cirrhosis

Exposure (percutaneous) to contaminated blood or plasma sexual transmission

Recognition through molecular virology applications blood transfusion practices following World War II (esp. in Japan)

Fever, abdominal pain, jaundice

Roseola in children, syndrome resembling mononucleosis

Unknown possibly respiratory spread

Human immunodeficiency viruses

HIV disease, including AIDS: severe immune system dysfunction, opportunistic infections

Sexual contact with or exposure to blood or tissues of an infected person vertical transmission

Urbanization changes in lifestyles/mores increased intravenous drug use international travel medical technology (transfusions/transplants)

Same as above, esp. international travel

Skin and mucous membrane lesions (often, warts) strongly linked to cancer of the cervix and penis

Direct contact (sexual contact/contact with contaminated surfaces)

Newly recognized perhaps changes in sexual lifestyle

Erythema infectiosum: erythema on face, rash on trunk aplastic anemia

Contact with respiratory secretions of an infected person vertical transmission

Human T-cell lymphotropic viruses (HTLV-I and HTLV-II)

Vertical transmission through blood/breast milk exposure to contaminated blood products sexual transmission

Increased intravenous drug abuse medical technology (transfusion)

Fever, headache, cough, pneumonia

Airborne (esp. in crowded, enclosed spaces)

Animal-human virus reassortment antigenic shift

Bite of an infective mosquito

Changing agricultural practices

La Crosse and California Group viruses

Bite of an infective mosquito

Increasing interface between human activity and endemic areas discarded tires as mosquito breeding sites

Fever, headache, sore throat, nausea

Contact with urine or feces of infected rodents

Urbanization/conditions favoring infestation by rodents

Fever, conjunctivitis, cough, red blotchy rash

Airborne direct contact with respiratory secretions of infected persons

Deterioration of public health infrastructure supporting immunization

Norwalk and Norwalk-like agents

Gastroenteritis epidemic diarrhea

Most likely fecal-oral alleged vehicles of transmission include drinking and swimming water, and uncooked foods

Acute viral encephalomyelitis

Introduction of infected reservoir host to new areas

Bite of an infective mosquito

Importation of infected mosquitoes and/or animals development (dams, irrigation)

Bite of an infective mosquito

Movement of infected mosquitoes or people

Enteritis diarrhea, vomiting, dehydration, and low-grade fever

Primarily fecal-oral fecal-respiratory transmission can also occur

Venezuelan equine encephalitis

Bite of an infective mosquito

Movement of mosquitoes and amplification hosts (horses)

Fever, headache, muscle pain, nausea, vomiting

Bite of an infective (Aedes aegypti) mosquito

Lack of effective mosquito control and widespread vaccination urbanization in tropics increased air travel

TABLE 2-1 Part 3: Examples of Emergent Protozoans, Helminths, and Fungi

Anisakiasis: abdominal pain, vomiting

Ingestion of larvae-infected fish (undercooked)

Changes in dietary habits (eating of raw fish)

Babesiosis: fever, fatigue, hemolytic anemia

Bite of an Ixodes tick (carried by mice in the presence of deer)

Reforestation increase in deer population changes in outdoor recreational activity

Candidiasis: fungal infections of the gastrointestinal tract, vagina, and oral cavity

Endogenous flora contact with secretions or excretions from infected persons

Immunosuppression medical management (catheters) antibiotic use

Meningitis sometimes infections of the lungs, kidneys, prostate, liver

Cryptosporidiosis: infection of epithelial cells in the gastrointestinal and respiratory tracts

Fecal-oral, person-to-person, waterborne

Development near watershed areas immunosuppression

Giardiasis: infection of the upper small intestine, diarrhea, bloating

Ingestion of fecally contaminated food or water

Inadequate control in some water supply systems immunosuppression international travel

Gastrointestinal illness, diarrhea wasting in immunosuppressed persons

Unknown probably ingestion of fecally contaminated food or water

Bite of an infective Anopheles mosquito

Urbanization changing parasite biology environmental changes drug resistance air travel

Unknown possibly reactivation of latent infection

Strongyloidiasis: rash and cough followed by diarrhea wasting, pulmonary involvement, and death in immunosuppressed persons

Penetration of skin or mucous membrane by larvae (usually from fecally-contaminated soil) oral-anal sexual activities

Immunosuppression international travel

Toxoplasmosis: fever, lymphadenopathy, lymphocytosis

Exposure to feces of cats carrying the protozoan sometimes foodborne

Immunosuppression increase in cats as pets

those agents best adapted to human transmission are likely to be those that will emerge. Introduction of a disease-causing agent into a new host population and dissemination of the agent within the new host species can occur almost simultaneously, but they are more commonly separated by considerable periods of time. Changes in the environment and in human behavior, as well as other factors, may increase the chances that dissemination will occur.

For familiar, "old" agents, whose spread has been successfully controlled, reemergence is often the result of lapses in public health measures owing to complacency, changes in human behavior that increase person-to-person transmission of an infectious agent, or changes in the ways humans interact with their environment. The return of dengue fever into areas of South and Central America where previously Ae. aegypti had been eradicated and the resurgence of yellow fever in Nigeria, where more than 400 persons were estimated to have died between April 1 and July 14, 1991 (Centers for Disease Control, unpublished data, 1992), reflect the operation of these mechanisms.

THE CONCEPT OF EMERGENCE

Although specific agents are usually associated with individual diseases, historically it is the diseases that usually have been recognized first. With improved techniques for the identification of microbes, however, this situation is changing. The causative agents for many newly emergent diseases are often discovered virtually simultaneously with (or in some cases before) their associated disease syndromes. For this reason, the term emerging microbial threat as used in this report includes both the agent and the disease.

It is important to understand the difference between infection and disease. Infection implies that an agent, such as a virus, has taken up residence in a host and is multiplying within that host&mdashperhaps with no outward signs of disease. Thus, it is possible to be infected with an agent but not have the disease commonly associated with that agent (although disease may develop at a later time).

In discussions about the emergence of "new" diseases, considerable debate has centered on the relative importance of de novo evolution of agents versus the transfer of existing agents to new host populations (so-called microbial traffic). It is sometimes presumed that the appearance of a novel, disease-causing microorganism results from a change in its genetic properties. This is sometimes the case, but there are many instances in which emergence is due to changes in the environment or in human ecology. In fact, environmental changes probably account for most emerging diseases.

For example, despite the fact that many viruses have naturally high rates of mutation, the significance of new variants as a source of new viral

diseases has been hard to demonstrate, and there appear to be relatively few documented examples in nature. Influenza is probably the best example of a virus for which the importance of new variants (i.e., antigenic drift) can clearly be shown. Variants of the hepatitis B virus also have been shown recently to cause disease. However, cases like these are greatly outnumbered by instances of new diseases or outbreaks resulting from microbial traffic between species. Cross-species transfer of infectious agents is often the result of human activities.

The evolution of viruses is constrained by their requirement for being maintained in a host. It would therefore seem that new variants of nonviral pathogens, such as bacteria, would be more common than new forms of viral pathogens since nonviral organisms are less constrained by host requirements. However, most nonviral pathogens usually show a clonal origin (Selander and Musser, 1990 Musser et al., 1991 Tibayrenc et al., 1991a,b). That is, they appear to be derived from a single ancestor, suggesting that the evolution of a successful new pathogen is a relatively rare event. When it does occur, the new microbe probably originates in a single geographic area and is disseminated through channels of microbial traffic. One implication of this model is that the control of ''new" diseases may be more likely if the new variant is identified early (e.g., by worldwide infectious disease surveillance) and steps are taken to prevent its further dissemination.

It is likely that emerging pathogens generally are not newly evolved. Rather, it appears that they already exist in nature. Some may have existed in isolated human populations for some time others, including many of the most novel, are well established in animals. Infections in animals that are transmissable to humans are termed zoonoses. As discussed in Chapter 1, throughout history rodents have been particularly important natural reservoirs of many infectious diseases.

The significance of zoonoses in the emergence of human infections cannot be overstated. The introduction of viruses into human populations, for example, is often the result of human activities, such as agriculture, that cause changes in natural environments. These changes may place humans in contact with infected animals or with arthropod vectors of animal diseases, thereby increasing the chances of human infection. Argentine hemorrhagic fever, a natural infection of rodents, emerged as a result of an agricultural practice placing humans in close proximity to the rodents. Marburg, Machupo, Hantaan, and Rift Valley fever viruses are also of zoonotic origin, as, arguably, is human immunodeficiency virus (HIV). Yellow fever, whose natural cycle of infection takes place in a jungle habitat and involves monkeys and mosquitoes in tropical areas of Africa and South America, is probably an ancient zoonosis. Jungle yellow fever occurs when humans interpose themselves in the natural cycle and are bitten by infected mosquitoes. Yet there is also urban yellow fever, in which the same virus is transmitted among

humans by other mosquitoes (e.g., Aedes aegypti) that have adapted to living in cities. It is generally believed that the movement of people through the slave trade and maritime commerce disseminated yellow fever, dengue, and chikungunya viruses, as well as Ae. aegypti , from Africa to other tropical areas. Ae. aegypti is still widespread in many urban areas of the southeastern United States, although the last yellow fever epidemic in a major U.S. city was in New Orleans in 1905.

Although the odds are low that a randomly chosen organism will become a successful human pathogen, the great variety of microorganisms in nature increases those odds. For example, field sampling and disease surveillance efforts have now identified more than 520 arthropod-borne viruses, or arboviruses (Karabatsos, 1985). The disease potential of most of these viruses is unknown, but nearly 100 have been shown to cause human disease (Benenson, 1990). In spite of the demise of the Rockefeller Foundation arbovirus program in 1971, and although only a few laboratories are actively searching for new pathogens in animals and arthropods, new viruses are being discovered every year (see Box 2-2).

One example of a recently discovered zoonotic virus is Guanarito, the cause of Venezuelan hemorrhagic fever. In the fall of 1989, an outbreak of an unusually severe and sometimes fatal disease was detected in the state of Portuguesa in central Venezuela. Patients presented for treatment with prolonged fever, headache, arthralgia, diarrhea, cough, sore throat, prostration, leucopenia, thrombocytopenia, and hemorrhagic manifestations. Physicians in the region initially diagnosed the disease as dengue hemorrhagic fever (DHF). During one period, from early May 1990 through late March 1991, 104 cases of the disease were recorded. Slightly more than a quarter of these patients, most of them adults, died (Salas et al., 1991).

All of the cases of the DHF-like illness occurred in the Municipio of Guanarito in Portuguesa State, or in adjoining areas in Barinas State. The Municipio of Guanarito, population 20,000, is located in the central plains of Venezuela, a major food-producing region. The outbreak was confined to the municipio's roughly 12,000 rural inhabitants, who either farm or raise cattle (Salas et al., 1991).

In the fall of 1990, a virologist from the Venezuelan Ministry of Health sent serum samples from several patients who were suspected to have DHF to the Yale Arbovirus Research Unit (YARU) at Yale University School of Medicine. No virus could be isolated after routine culture of the sera in mosquito cells (the standard method for recovery of dengue viruses).

In early 1991, a member of the YARU staff visited Venezuela while on a trip to South America collecting dengue virus isolates for an ongoing research project. In Caracas, the YARU staff member was given spleen cultures from two fatal cases of suspected DHF from the Guanarito area. Upon inoculation into newborn mice and Vero (monkey kidney) cell cultures at

BOX 2-2 Arboviruses

Worldwide, in 1930, only six viruses were known to be maintained in cycles between animal hosts and arthropod vectors like mosquitoes, gnats, and ticks (Karabatsos, 1985). Only one of the recognized arboviruses (arthropod-borne viruses), yellow fever virus, caused disease in humans. The other five viruses were responsible for epizootics and major economic losses in domestic animals: bluetongue in sheep and cattle, Nairobi sheep disease, Louping ill in sheep, vesicular stomatitis in cattle, and African swine fever.

Later in the same decade, there was an explosion of newly emerged arthropod-borne diseases in North America. Western and eastern equine encephalomyelitis viruses caused major outbreaks with high case fatality rates in both equines and humans. St. Louis encephalitis virus was associated with more than 1,000 cases and 201 deaths in residents of Missouri. Subsequent research demonstrated that each of these viruses was maintained in a cycle dependent on mosquitoes and birds. When any of the viruses invaded the human population, an epidemic often ensued.

Since the 1930s, 86 additional arboviruses have been found in North America. Fortunately, only a few, such as the California encephalitis complex, Colorado tick fever, and the dengue fever viruses, have been consistently associated with human disease. However, all 86 viruses are distributed widely, and many have thus far been shown to cause only inapparent infections in humans. A shift in the virulence of the viruses or in human susceptibility could potentially alter the present equilibrium. Some experts warn that the arboviruses are "viruses looking for a human disease."

The threat of arboviral disease is not limited to North America. The 1985 International Catalogue of Arboviruses (Karabatsos, 1985) identified 504 arboviruses worldwide, 124 of which have been associated with a disease. It is of continuing concern that nonindigenous viruses might be introduced into the United States through travel and trade.

The rate of discovery of arboviruses reflects the intensity of the worldwide search by the Rockefeller Foundation, government agencies, and universities from 1950 to 1980. There has been a significant decrease in activity for such programs in recent years, as seen in the table below. Yet all the while, new arboviruses continue to be found whenever and wherever a search is made.

YARU, these samples subsequently yielded two isolates of a previously unknown arenavirus, a family of viruses generally thought to be rodent-borne. The organism was distinct from Lassa, Junin, and Machupo viruses, the other arenaviruses that are known to cause severe hemorrhagic illnesses in humans. The new agent has since been designated the Guanarito virus, and its associated disease has been labeled Venezuelan hemorrhagic fever (Salas et al., 1991).

Venezuelan health officials are now attempting to determine the risk factors, geographic distribution, and clinical spectrum of Guanarito virus infection and to update the incidence data on it. Studies are currently in progress at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) to develop an animal model for the disease and to evaluate possible therapeutic agents. In October 1991, scientists from YARU visited Venezuela to initiate a study to identify positively the rodent reservoir(s) of Guanarito virus.

Rodents have been implicated in a number of zoonotic infections, but the zoonotic pool also includes marine animals, such as seals, porpoises, and dolphins, which like humans are susceptible to outbreaks of infectious disease. Most such occurrences pass unnoticed, either because they occur far from shore or because the number of animals affected is too small to draw attention to the possibility of infectious disease. Occasionally, however, marine epidemics do attract attention, usually when large numbers of dead carcasses suddenly appear on a popular beach.

The most recent major epizootic, reported initially in harbor seals living in the waters off Europe and the United Kingdom, began in April 1988. Thousands of the animals died. The hardest-hit area was along Britain's East Anglian coast, where more than half of the native seal population is estimated to have died. The outbreak peaked in August and tapered off through late 1989. Few dead seals have since been reported in this area.

It now appears that the same or a similar disease was present in Siberian seals somewhat earlier than the European epizootic (Grachev et al., 1989). The disease was also found in porpoises (Kennedy et al., 1988) and in dolphins (M. Domingo et al., 1990). Extensive study of the European outbreak resulted in the isolation of the causative agent, a virus, which is similar to measles, canine distemper, and rinderpest viruses.

Occasionally, marine viruses cause disease in terrestrial mammals or humans. For example, a strain of influenza A virus (H7N7) led to epidemic outbreaks in seals in 1980 and caused conjunctivitis in humans who handled the affected seals (Webster et al., 1981). It has been suggested that vesicular exanthema of swine, a serious viral disease caused by a calicivirus, was introduced into pigs through feed that contained material from sea lions. Many caliciviruses of terrestrial mammals may have been introduced from marine sources (Smith and Boyt, 1990). Among human viruses, hepatitis E

virus (the enterically transmitted non-A, non-B hepatitis that is usually waterborne and is widespread in tropical areas including parts of South America) has tentatively been classified as a calicivirus (Reyes et al., 1990).

There are also a number of established diseases whose link to an infectious agent has only recently been discovered. In addition to peptic ulcer, mentioned in Chapter 1, other diseases with a newfound link to a microbe include cervical cancer (associated with human papillomaviruses) and human T cell lymphotropic virus (HTLV)-I-associated myelopathy or tropical spastic paraparesis (resulting from infection with HTLV). Diseases for which possible links to infectious agents are under investigation include rheumatoid arthritis (parvovirus B19, HTLV-I) atherosclerosis (cytomegalovirus [CMV], herpes simplex virus [HSV]-1 and HSV-2, or Chlamydia pneumoniae) and insulin-dependent diabetes mellitus (coxsackievirus B5). Several of these examples are discussed later in this chapter.

Rather than categorize emerging microbial threats by type of agent&mdashviral, bacterial, protozoal, helminthic, or fungal&mdashthis report classifies emerging threats according to the factors related to their emergence:

Human demographics and behavior

Economic development and land use

International travel and commerce

Microbial adaptation and change

Breakdown of public health measures

The classification draws attention to the specific forces that shape infectious disease emergence (see Figure 2-1). These forces (i.e., factors in emergence) operate on different elements in the process of emergence. Some of the factors influence the acquisition of an emerging microbe by humans and other animals others primarily affect the microbe's spread among populations. Although it is a difficult, if not impossible, task to predict the emergence of "new" infectious diseases/agents, it is helpful to understand the factors that facilitate the emergence and spread of infectious diseases in general. We must focus on what we do know: the infectious disease that will emerge or reemerge is likely to do so through one or more of the "facilitative pathways" diagrammed in Figure 2-1. An awareness of this system of pathways constitutes the first step to reasoned prevention and control of infectious diseases.

Many of the diseases addressed in this report have emerged because of a combination of factors. This is not surprising, given the often complex interactions of microbes, their human and animal hosts, and the environment. As much as possible, however, the committee has attempted to illustrate specific causes of emergence with diseases or agents whose emergence is primarily due to that one factor.

FIGURE 2-1 Schematic of infectious disease emergence.

HUMAN DEMOGRAPHICS AND BEHAVIOR

In the complex set of interactions that result in disease emergence, the human element&mdashpopulation growth, density, and distribution immunosuppression and behavior&mdashplays a critical role. Increases in the size, density, and distribution of human populations can facilitate the spread of infectious agents changes in the distribution of populations can bring people into contact with new pathogenic organisms or with vectors that transmit those organisms. Immunosuppression, a by-product of aging, the use of certain medications, diseases, or other factors, often permits infection by microorganisms that are not normally pathogenic in humans. Individual behavior, particularly sexual activity and the use of illegal drugs, contributes to the transmission of a number of diseases that have a major health impact on this and other countries.

Population Growth, Density, and Distribution

Until recently, most of the world's population lived in rural areas. In 1800, for example, less than 1.7 percent of people lived in urban communities. By 1970, however, more than a third of the world's people lived in urban settings. By the year 2000, that fraction is expected to rise to one-half (Dentler, 1977).

Not only are more people choosing to live in urban areas, but the size and density of many cities are also increasing, in part because of the overall population growth rate&mdasheach year the population of the world grows by approximately 70 million. High birth rates in many cities contribute to urbanization. By the end of the century, there will be 425 cities with a million or more inhabitants, an increase of 200 cities since 1985 (United Nations, 1985 World Resources Institute, 1986). Twenty-five cities are expected to have populations that exceed 11 million (Last and Wallace, 1992).

In many parts of the world, urban population growth has been accompanied by overcrowding, poor hygiene, inadequate sanitation (including wastewater disposal), and insufficient supplies of clean water. Urban development, with its attendant construction, emergence of slum areas and shanty towns, and infrastructure needs (e.g., water treatment and waste disposal facilities), has also caused ecological damage. These factors have created conditions under which certain disease-causing organisms and the vectors that carry them have thrived. The dengue viruses and their primary mosquito vector, Ae. aegypti, are one such example.

DENGUE

There are four distinct serotypes of dengue virus, each of which can cause a spectrum of illnesses ranging from mild fever and general malaise (dengue fever) to shock and fatal hemorrhagic disease (dengue hemorrhagic fever/dengue shock syndrome [DHF/DSS]). Dengue typically is a disease of young children, although older children and adults can be affected. Dengue viruses are transmitted to humans by Ae. aegypti mosquitoes.

Although dengue fever has plagued tropical populations for hundreds of years, the more severe form of the disease, DHF/DSS, is relatively new. The first recognized epidemic of DHF/DSS occurred in Manila in 1953 (Hammon et al., 1960). Dengue fever is usually the result of primary infection with one of the four dengue virus serotypes. DHF/DSS occurs in people who have been infected with two or more serotypes. The global spread and mixing of dengue serotypes have been made possible by the movement of infected individuals from one area to another.

Over the past 15 years, outbreaks of dengue fever have become increasingly numerous and severe, especially in urban centers in the tropics. At the

same time, epidemics of DHF/DSS have spread from Asia to the Americas. In the early 1980s, the disease arrived in Cuba, where it killed 158 Cubans in a major outbreak in 1981. The most recent epidemic took place in Venezuela in 1990 more than 3,100 cases of severe hemorrhagic disease were recorded, as well as 73 deaths (Gubler, 1991). There are currently endemic foci of DHF/DSS in the Caribbean and on the Yucatan Peninsula of Mexico.

Although the disease is concentrated in a small number of areas, worldwide incidence rates for DHF/DSS have skyrocketed. Since its appearance in 1956, there have been an average of 29,803 cases of DHF/DSS reported per year. Between 1986 and 1990, the average number of reported cases per year was more than 267,692 (Gubler, 1991). In Southeast Asia, DHF/DSS ranks as one of the leading causes of hospitalization and death among children.

Although the reasons for the increase in dengue activity and the changing disease pattern are not fully understood, the consequences of increased urbanization, densely populated areas, and poor sanitation play a significant role. These conditions favor the growth of mosquito populations. Dengue virus, which is short-lived in the human host, is best maintained in densely populated areas in which Ae. aegypti is abundant and susceptible individuals are concentrated. The lack of effective mosquito control in many tropical urban centers&mdasha by-product of economic and political problems as well as indifference&mdashhas undoubtedly contributed to the dramatic rise in dengue infection worldwide.

The United States experienced dengue fever outbreaks in 1922 and 1945 (Langone, 1990). No cases of DHF/DSS have been reported to date, but imported cases of dengue fever occur annually in U.S. citizens who have returned from travel abroad. In 1990, for instance, 24 confirmed cases of imported dengue were reported to the Centers for Disease Control (CDC) (Centers for Disease Control, 1991c). Although Ae. aegypti and Ae. albopictus (a secondary vector) have become firmly established in much of the southeastern United States, epidemics of DHF/DSS, such as those seen in Cuba and Venezuela, are unlikely. The United States is less vulnerable because its standard of living is higher, houses are more likely to be screened, and discarded tires (see Box 2-3) and other containers that can breed Aedes are much less common than in many cities in the tropics. At present, the only effective way to limit the spread of dengue is to attack its principal vector, Ae. aegypti. Government-supported pesticide application programs, and efforts of private citizens to eliminate mosquito breeding sites (i.e., source reduction) near their homes, have been shown to work. The success of such source reduction efforts rests on public education programs.

Like the yellow fever vaccine, a reasonably priced dengue vaccine will be an important adjunct to vector control in stemming the spread of urban epidemics. Dengue vaccine development, however, has been complicated

BOX 2-3 Environmental Eyesore or Mosquito Nursery?

Both! Discarded tires are an eyesore to most, but to some mosquitoes they offer an ideal location to deposit their eggs. Aedes aegypti and Ae. albopictus, both vectors of diseases such as dengue fever, viral encephalitis, and yellow fever, prefer to lay their eggs in water that collects in containers. Discarded tires, which hold water no matter in what position they land and which do not typically harbor predators like fish or frogs, are perfect incubators for the eggs of these mosquitoes. And each year, the United States throws away a quarter of a billion tires and imports several million (mostly from Japan) to be retreaded and resold.

Not only do the mosquitoes find homes in discarded tires, but they also find transportation. When old tires are transported around the country by truck, mosquito eggs often go with them. Eggs then hatch hundreds of miles from where they were laid, and populations of adult mosquitoes can establish themselves in areas they might never have reached. Ae. albopictus actually "hitchhiked" to the United States in 1985 from Japan in a shipment of used tires. Already, this species has established itself as a resident.

Tires are not the only human-made accommodations favored by mosquitoes. Any container that holds water&mdashan empty beer or soda can, a bucket, or flowerpot&mdashthat is left outside during the warm spring and summer months is an attractive egg-laying site for a female mosquito. Some mosquitoes will even breed indoors in a moist container in a basement, garage, or shed if given the opportunity. This is in part why aerial spraying of pesticides is not an effective way to control mosquitoes the insects usually lurk (and lay their eggs) in damp hiding places that the chemicals cannot reach.

Thus, as innocuous as they may seem to many, discarded items like old tires and empty aluminum cans may play a role in the initiation and spread of mosquito-borne disease. Eliminating human-made breeding sites is a simple, logical way to reduce the chances of such disease.

by the dengue virus's four serotypes. Scientists do not expect that a vaccine will be available in the next 5 to 10 years.

Immunosuppression

Immunosuppression, a weakening of the immune system, can be caused by a number of factors, including the following:

Immunosuppressive medications for transplantation, therapy of malignancy (chemotherapy), or treatment of autoimmune disease

Other concurrent infections

Immunosuppression can result in disease in an individual who otherwise would have been able to fend off illness. Infections caused by typically nonthreatening organisms that take advantage of a person's weakened state are called opportunistic infections.

Although opportunistic infections have received a great deal of attention over the past decade with the onset of the HIV disease pandemic, they are not new. During the pandemics of influenza in the early part of this century, it was well understood that both the very young (who have immature immune systems) and the elderly (who have waning immune defenses and, often, concurrent disease) were in the greatest danger of succumbing to this viral disease. New medical treatments and technologies&mdashfor example, therapy for collagen-vascular diseases like rheumatoid arthritis and vasculitis, cancer chemotherapy, and organ transplantation&mdashhave created additional openings for opportunistic pathogens.

There is good reason to believe that opportunistic infections will continue to threaten human health. The mean age of the U.S. population continues to rise. More and more people are surviving into their eighties and nineties, when previously non-life-threatening infections become common killers. Suboptimal prenatal care for women of lower socioeconomic status, which often results in premature and disease-prone infants, will likely continue to be the norm. The number of people with AIDS will continue to grow as those who became infected years ago develop full-blown disease. The HIV-infected population serves as a particularly important point of surveillance for emerging opportunistic infections because of its size and because the immunosuppression that characterizes the disease is comprehensive.

In many cases, knowledge of the type and extent of a person's immune dysfunction makes it possible to predict the kinds of infections that person is likely to acquire. When immune deficiency is acute and general in nature, however, any number of infections are apt to result, often simultaneously and often with astounding intensity. Such is the case for people with HIV disease. It is not surprising that opportunistic infections account for 90 percent of all HIV disease-related deaths (Double Helix, 1990).

Opportunistic, infections are often caused by naturally occurring organisms that reside in most individuals. These organisms typically are kept in check by a healthy immune system, and many of them&mdashfor example, certain types of digestion-aiding bacteria in the intestine&mdashare actually beneficial to normal body function. Disturbances in the integrity of the gastrointestinal tract, often the result of chemotherapy or radiation therapy, can introduce intestinal bacteria into the bloodstream, which can ultimately lead to life-threatening infection. Prolonged therapy with antibiotics can suppress the normal, resident bacteria that tend to keep fungal organisms like Candida in check, and the fungi can initiate a potentially dangerous infection.

The definition of an opportunistic infection should also include those infections caused by organisms that are normally pathogenic in healthy hosts but that are more common or induce more severe infections in the immune-impaired host. For example, although a nonimmune, healthy person who comes into contact with varicella virus might develop, and recover from, chickenpox, a person with an impaired immune system has a good chance of dying from the infection.

''Reactivated" infections, another type of opportunistic infection, occur in people who were previously infected with an organism that the body was able to suppress but not eliminate completely. When the immune systems of these individuals weaken, the circulating organism has a chance to cause disease again, or, in many cases, for the first time. For example, an estimated 80 percent of Americans are infected with cytomegalovirus (CMV), a herpesvirus (National Institute of Allergy and Infectious Diseases, 1991b). The virus typically does not produce serious illness in healthy adults, but for transplant recipients, who receive immunosuppressive drugs to keep them from rejecting foreign tissue, CMV can be a life-threatening complication.

Tuberculosis (TB) is another example of an infection that can be reactivated during immunosuppression. The causative agent of TB, Mycobacterium tuberculosis, usually persists in the body long after primary infection. Although infection with this bacterium in a previously unexposed person is usually self-limiting, reactivated TB, which can occur years later, can cause life-threatening lung disease. In recent years, TB has stricken HIV-infected individuals with alarming severity, causing a rapidly disseminated disease involving organs throughout the body.

After declining steadily since the 1950s, the incidence of TB in the United States has recently begun to climb. Since 1986, reported cases have increased 16 percent (see Figure 2-2) (Snider and Roper, 1992). This trend is largely attributable to cases of TB among those infected with HIV. TB is also occurring with greater frequency among immigrants and refugees, substance abusers, the homeless, the medically underserved, and the elderly. The majority of the increase has been among racial and ethnic minorities (especially blacks and Hispanics), children and young adults, and immigrants and refugees.

FIGURE 2-2 Incidence of tuberculosis, 1980 to 1990.

SOURCE: Center for Prevention Services, Centers for Disease Control.

The TB incidence rate among people infected with HIV is nearly 500 times the rate for the general population. In contrast to some fungal and other bacterial infections that occur only in the late stages of HIV disease, TB is a sentinel disease for HIV infection and tends to occur prior to other opportunistic infections, often before individuals realize they are HIV seropositive. In healthy individuals, pulmonary tuberculosis can be diagnosed and treated with relative ease (the cure rate is approximately 95 percent). In immunocom-promised persons, however, the disease is often disseminated throughout the body, making it much more difficult to diagnose and treat.

Sexual Activity and Substance Abuse

The HIV disease pandemic is the most devastating outbreak of a sexually transmitted disease since the emergence of syphilis almost 500 years ago in Western Europe. Syphilis, a bacterial disease, spread rapidly during the late fifteenth and early sixteenth centuries, quickly reaching a prevalence of 20 percent in many urban areas (Hirsch, 1885). Scholars believe that the disease was disseminated by the sexual activities of soldiers, and heterosexual promiscuity was, and continues to be, the primary mechanism by which the infection is spread. The incidence of syphilis in the United States fell dramatically earlier in this century with the introduction of penicillin. Between 1985 and 1990, however, incidence almost doubled, most notably among

heterosexuals who use crack cocaine (Centers for Disease Control, 1992f). A number of factors are associated with this rise, including multiple-partner sex to procure drugs, especially crack cocaine inadequate health care among groups at risk and declining educational levels among lower socioeconomic populations (Centers for Disease Control, 1991g).

The origin of HIV, the lentivirus (a member of the retrovirus family) that causes HIV disease and acquired immunodeficiency syndrome (AIDS), is not known. Viruses closely related to HIV have been present for hundreds, if not hundreds of thousands, of years in African nonhuman primates. Similar comparisons of human and nonhuman lentivirus isolates strongly suggest that HIV-2, the variant of HIV found primarily in persons from West Africa, may have infected humans following cross-species transmission from nonhuman primates (Gao et al., in press). This transmission could have occurred through bites of infected monkeys that were kept as pets, captured by trappers, or transported to other countries. Nucleotide sequence analyses show that HIV-2 and some isolates of simian immunodeficiency virus (SIV), an HIV-like virus, belong in the same subgroup there are no data at present placing an SIV isolate from monkeys in the same subgroup as HIV-1. However, an SIV virus belonging to the same subgroup as HIV-1 has been isolated from chimpanzees. Yet if HIV-1-like viruses are present in nonhuman primates, it is possible that both HIV-1 and HIV-2 were occasionally, but infrequently, transmitted to humans and persisted in remote areas or in isolated individuals or populations for centuries. Although the earliest documented case of HIV infection was obtained from a serum sample collected in central Africa in 1959 (Garry, 1990), the country or continent in which the HIV disease epidemic began is not known. What is clear is that HIV and SIV arose through natural evolutionary processes.

The HIV disease pandemic initially escaped detection because of the disease's long incubation period (the time from infection to onset of life-threatening disease). After reservoirs of infection had been established in African and Western countries, HIV spread to all parts of the globe. In Africa, it is believed that HIV was transported by the movement of infected individuals from isolated rural communities to rapidly expanding cities. This urbanization was accompanied by changes in sexual behavior, which played a major role in the transmission of HIV among (primarily) heterosexual populations in Africa (Quinn et al., 1986). Preexisting infection with other sexually transmitted microorganisms, especially those that cause genital ulcers and local genital tract inflammation, probably facilitated heterosexual transmission of HIV (Hillman et al., 1989).

The early spread of HIV, particularly in the United States and Europe, was largely the result of high-risk sexual practices of some male homosexuals, and it was in this population that most of the early cases were seen. Within a short period, however, another major group of HIV-infected individuals

emerged: intravenous substance abusers. The introduction of crack cocaine in the United States in the mid-1980s added another component to the complex epidemiology of HIV infection. Many persons who abuse crack cocaine use sex as a currency to support their habit. The result has been a striking rise in heterosexually transmitted syphilis, chancroid, and HIV infection. Although in the United States, HIV infection occurs predominately in male homosexuals and intravenous substance abusers, the rate of infection among non-substance-abusing heterosexuals is increasing.

The fact that HIV first established itself in the United States mainly among gay men has both negative and positive repercussions. On the negative side, rapid emergence was facilitated among those individuals who engaged in anal intercourse with multiple partners. On the positive side, unusual diseases related to HIV infection initially occurred in a specific subpopulation, and that specificity probably hastened recognition of the syndrome and its infectious nature. Had the first cases of AIDS occurred in a more diverse population, it is likely that discovery of the exact nature of the problem would have been slowed. Once the disease was recognized as a new entity with the potential for epidemic spread, the biomedical research community began a concerted effort to identify the etiologic agent. Collaborations were established between health care workers, who provided blood samples from patients, and researchers, who in turn isolated and defined properties of the virus so that blood tests could be generated and the development of drugs and vaccines could begin.

Unfortunately, the U.S. political sector was not as responsive to the crisis and by its slow response may have contributed to the explosive growth of the epidemic. A major reason for this hesitancy appeared to be the antipathy of some federal officials to the behaviors of those persons initially affected by HIV disease: gay men and substance abusers. In some instances, federal officials thwarted efforts to curtail the epidemic. For example, former Surgeon General C. Everett Koop has stated, "Even though the Centers for Disease Control commissioned the first AIDS task force as early as June 1981, I, as Surgeon General, was not allowed to speak about AIDS publicly until the second Reagan term. Whenever I spoke on a health issue at a press conference or on a network morning TV show, the government public affairs people told the media in advance that I would not answer questions on AIDS, and I was not to be asked any questions on the subject. I have never understood why these peculiar restraints were placed on me. And although I have sought the explanation, I still don't know the answer" (Koop, 1991).

More detrimental, however, was the government's continued resistance to proposed sex education programs designed to interrupt transmission of HIV (Koop, 1991). The federal government's recent revocation of funding for an approved five-year study of teenage sexual behavior (Marshall,

1991) indicates the continuing controversy and ambivalence that surrounds many aspects of the nation's response to HIV disease.

To date, no drug has been developed that can prevent or cure HIV infection, and it is not likely that a vaccine will be available soon. In many areas of the world, particularly Eastern Europe, India, and Southeast Asia, the numbers of cases of the disease are escalating rapidly. In Africa, the demographics of the pandemic are changing, with HIV-infected individuals moving away from cities and back to rural areas (R. M. Anderson et al., 1991). In Africa, Latin America, the Caribbean, and North America, HIV is infecting increasingly larger numbers of heterosexuals, intravenous substance abusers, and children (Centers for Disease Control, 1991a). In 1989, HIV disease passed heart disease to become the second leading cause of death in U.S. males aged 25 to 44, behind accidental and unintended injury (Centers for Disease Control, 1991e). Estimates now place the total number of adults worldwide who have developed HIV disease at more than 1 million and those who are infected with HIV at 10 million. The World Health Organization (WHO) estimates that as many as 40 million people could be infected with HIV by the year 2000 (World Health Organization, 1991).

TECHNOLOGY AND INDUSTRY

Notwithstanding all of their benefits, technology and industry may directly or indirectly cause the emergence of infectious diseases. Modern medicine has created situations that are ideally suited for the emergence of infectious agents. The food and agriculture industries work continually to prevent the introduction of pathogenic organisms into our food supply, but they are not always successful. Waterborne pathogens are controlled by the careful treatment and disinfection of drinking water, but breakdowns do occur and sometimes result in the spread of infectious disease.

Modern Medicine

Generally, people who enter the hospital expect that their health will be improved by the treatment they receive. For at least 1 out of 20 patients, however, this is not the case. Each year, an estimated 2 million individuals in the United States (about 5 percent of the total number hospitalized) suffer nosocomial infections&mdashviral, bacterial, protozoan, and fungal infections that were not present or incubating at the time of hospital admission (Fuchs, 1979 Wenzel, 1988 Martone, 1990). The rates of nosocomial infections in developing countries may be 5 to 10 times higher (Wenzel, 1987).

The health and financial impacts of nosocomial infections in this country are staggering. More than 20,000 deaths annually are attributed to hospital-acquired

infections, and patients who recover from these infections typically require 10 extra days of hospital care (Fuchs, 1979 Wenzel, 1988). Every year, hospital-acquired infections account for between $5 billion and $10 billion in additional medical-related expenses, most of which are due to excess hospital stays (Wenzel, 1987 Schaechter et al., 1989 Martone, 1990).

Although hospital sanitation has improved markedly since the late nineteenth century, when carbolic acid was first used as an antiseptic during surgery, nosocomial infections continue to challenge efforts to control them (Fuchs, 1979). Medical advances and antimicrobial resistance are at the heart of the struggle.

In February 1991, the CDC's Hospital Infections Division looked at 10-year trends in nosocomial infections using data collected through the National Nosocomial Infections Surveillance System (NNISS). The 1980s saw a tripling of the incidence of bacteremias (Ross, 1990) and a shift in the organisms that are most prevalent as the causes of nosocomial infections, from those that are generally susceptible to antimicrobials (e.g., Proteus mirabilis, Escherichia coli, and Klebsiella pneumoniae) to those that tend to be more refractory to treatment (e.g., Enterobacter, Pseudomonas, Enterococcus, and Candida species) (Schaberg et al., 1991). In addition, there appears to have been a significant increase in both the prevalence and variety of viral and fungal pathogens found to be causes of nosocomial infections (Ross, 1990). All of these observations implicate the hospital setting as a prime site for the emergence of microbial threats to health.

Many of the factors that increase the risk of infection in a hospital are inherent to any health care setting. Not only are persons with serious infections frequently admitted to hospitals, thus providing an intrahospital source of pathogenic organisms, but the proportion of people with increased susceptibility to infections is also greater in a hospital than in the general population. In addition, because health care institutions are not completely isolated from the community (employees, visitors, food, and supplies enter daily), patients are exposed to the same pathogens that circulate in the surrounding locale. Thus, nosocomial infections can be transmitted from staff to patients, from visitors to patients, and from patients to other patients. Infections can also be acquired from contaminated surfaces, such as floors, examining tables, or improperly sterilized instruments, and from the patient's own normal microbial flora, especially during invasive procedures.

Antimicrobial resistance, a problem in the treatment of many bacterial diseases, has particular relevance in the hospital setting. By their very nature, hospitals are filled with people who have increased susceptibility to infection. Also by nature, hospitals tend to use large quantities of antibiotics. (About a third of hospitalized patients receive such agents [Shapiro et al., 1979].) The combination of an immunologically vulnerable population and the widespread use of antibiotics is potentially risky, since the selective

pressure exerted on microbes by the constant challenge of antimicrobial compounds favors the survival of organisms that are resistant to these drugs (Holmberg et al., 1987).

An organism's development of drug resistance through selective pressure usually begins with exposure to an antimicrobial drug. Antimicrobial drugs and other compounds designed to combat human pathogens work by killing or inhibiting the growth of susceptible microorganisms. Because of genetic variability, however, not every bacterium, virus, protozoan, helminth, or fungus is naturally susceptible to these drugs. The result is that the drugs leave untouched a small number of resistant microbes, effectively "selecting for" those organisms that can survive attack by the drugs. These resistant organisms pose a potentially serious threat to health. Although the role of selective pressure in antimicrobial resistance is clear, additional studies (using appropriate epidemiological and molecular biological methodologies) are needed to identify and investigate the risk factors that promote transmission of resistant pathogens in the hospital setting.

Many standard hospital procedures facilitate patient acquisition of nosocomial infections. The use of conventional medical devices is responsible for the greatest share of such infections: several hundred thousand cases of device-related disease occur each year. The most common of these (and the most frequent of all nosocomial infections) is urinary tract infection (UTI) (Harding et al., 1991). The great majority of hospital-acquired UTIs are the result of catheterization. In some cases, infection results from nonsterile insertion of the catheter more frequently, however, it is the entry with the catheter of normal body bacteria (e.g., E. coli and Staphylococcus species, which are usually kept out of the bladder by the mucosal barriers of the urinary tract) that cause infection. Other devices, such as endotracheal tubes and mechanical ventilators, can cause infection in a similar fashion.

Pneumonia is the second most common hospital-acquired illness and the leading cause of death from nosocomial infection. Infections related to surgical wounds are the third most common type. Skin provides one of the body's natural defenses against microbial invasion, and it is also home to usually harmless staphylococcal bacteria. When the skin is broken, however, as happens during surgery or intravenous catheterization, staphylococci (including antibiotic-resistant hospital strains) can gain access to deeper tissues and cause infection. Bloodstream infections, the fourth most common type of nosocomial condition, occur when microbes make their way deep into the body&mdashtypically with the help of medical devices or the use of invasive procedures&mdashand enter the bloodstream. On rare occasions, bloodstream infections, including transfusion-induced yersiniosis and HIV infection, can also result from the use of contaminated blood products (see Box 2-4) (Cover and Aber, 1989 Martone, 1990).

BOX 2-4 How Safe Is the Blood Supply?

Many of the 4 million people who receive a blood transfusion in the United States each year have concerns about contracting a communicable disease in the process. Like organs and other tissues that are transplanted, blood is a biological product that can host disease-causing microorganisms. Fortunately, however, blood that is donated today goes through a battery of tests designed to ensure that it is free of contamination by infectious agents. The American Red Cross (ARC) now tests donor blood for syphilis, hepatitis B and C, human T-lymphotrophic virus types 1 and 2 (HTLV-I and HTLV-II), HIV-1, and, recently, HIV-2 as well. HIV-2 currently ranks as the primary cause of HIV disease only in West Africa yet as of September 1991, 31 people in the United States had been diagnosed with HIV-2 infection, making the virus a potential threat to the safety of the blood supply in this country (Johnston, 1991).

The Department of Defense (DOD) and the American Association of Blood Banks (AABB) recently took steps to protect the blood supply from contamination with another microorganism, the leishmania parasite. Found primarily in Africa and Asia, the parasite was found late last year in the blood of more than two dozen soldiers returning from the Persian Gulf War. Both the DOD and the AABB, as well as the ARC, plan to refuse donations until at least 1993 from all individuals&mdashmainly members of the U.S. armed services&mdashwho have traveled to the Middle East since August 1990.

Many of the efforts made by blood banks to improve the safety of the blood supply have been tremendously successful. Thirty years ago, nearly one in three people who received a blood transfusion contracted some form of hepatitis today, that risk has dropped to less than 1 in 100 (Russell, 1991). The chances of contracting HIV from a blood transfusion are considerably less than in the early 1980s, when AIDS was first identified. Prior to 1985, when testing for HIV in donor blood became widespread, more than 4,300 persons were infected by the virus through blood transfusions. From 1985 through December 1991, only 20 people have acquired HIV through transfusions (Centers for Disease Control, 1992e). The risk of HIV infection from a blood transfusion has been estimated at from 1 in 40,000 to 1 in 150,000 per unit of blood transfused, depending on the region from which the blood originated (Russell, 1991).

Safeguards against microorganism-contaminated blood unfortunately are not foolproof. As a result, doctors have become much more conservative about using transfusions. Most encourage patients to contribute their own blood prior to surgery whenever possible, and many doctors have sought new alternatives to transfusions altogether. Automated cell salvage techniques that can be used either during or after surgery to recover, cleanse, and return lost blood are one such alternative. Until the search for an effective blood substitute is successful (several companies appear to be close to developing a safe product), protecting the blood supply and its users from infectious disease remains a top priority.

Complex invasive procedures, such as tissue or organ transplantation, can also lead to nosocomial infection. The immunosuppressive drugs used to prevent the rejection of the foreign tissue or organ have the undesirable side effect of weakening the body's immune system. Often, these infections do not involve hospital microbes but pathogens from the donor tissue or pathogens that are already present in the recipient. Extensive testing of foreign tissue prior to transplantation guards against transmission of most such microbes. Latent agents, however, like the "slow" virus that causes Creutzfeld-Jacob disease, are extremely difficult to detect and may be inadvertently transferred to the transplant recipient in the seemingly normal tissue of the donor. Cases of HIV infection, hepatitis C, and CMV infection resulting from organ transplantation have all been documented, as have cases of Creutzfeld-Jacob, a degenerative brain disease, in recipients of transplanted corneas and human growth hormone (Lorber, 1988 Pereira et al., 1991).

HEALTH CARE DELIVERY

Changes in health care delivery over the past 20 years undoubtedly have had an impact on nosocomial infection rates. Rising health care costs play a key role. One cost-conscious health care strategy that appears to be contributing to the rise in cases of nosocomial infection is so-called industrial management in hospitals. Industrial management is intended both to maximize the ratio of patients to nurses and to maintain pools of health care workers&mdashparticularly nurses&mdashwho can rotate frequently between two or more units of an institution. From the hospital's perspective, maximizing the ratio of patients to nurses is desirable because it decreases health care costs. At the same time, the practice can increase disease transmission by reducing the time available for proper sanitation and increasing the number of infected patients to whom a nurse is exposed.

Exacerbating the potential disease-producing quality of these problems is the increasing bidirectional transfer of patients between acute care and chronic care hospitals. The mixing of patients from acute care facilities (who tend to be severely ill) with residents of chronic care hospitals (who tend to have decreased immune function owing to aging or chronic illness, or both) is potentially risky. Compared with hospital-based programs, infection control programs in many long-term care facilities are rudimentary, at best. Unlike hospital-based programs, there are no standardized criteria for defining nosocomial infections in long-term care facilities in addition, adequate studies designed to assess the efficacy of their surveillance and control measures have not been conducted. This state of affairs contrasts sharply with such efforts in acute care hospitals, which have received for more attention and federal funding.

The problem is likely to grow even more serious with time, given the Agency for Health Care Policy and Research's estimates that 43 percent of all those who turned 65 years old in 1990 will enter a nursing home at some point in their lives (Agency for Health Care Policy and Research, 1990).

In sum, hospitals and long-term care facilities can no longer be viewed as isolated epidemiological units but must be seen as part of a network of patient care facilities. This network makes it possible for nosocomial and community-acquired infections to be rapidly and widely spread.

PREVENTION OF NOSOCOMIAL INFECTIONS

Studies show, surprisingly, that even under the most sanitary of conditions, only about a third to a half of all hospital-acquired infections are preventable (Schaechter et al., 1989 Martone, 1990). Several factors "stack the deck" against infection control efforts. Little can be done to eliminate most of these risk factors, which include age (newborns and the elderly have limited immunity), severity of illness (related to length of stay, also a risk factor), and underlying diseases (latent infections or immune deficiencies) (Freeman and McGowan, 1978). Increased attempts at prevention for high-risk patients may be the only weapon against infection in these circumstances.

Two recent approaches to controlling hospital-acquired infections have been remarkably successful: CDC's 1987 "Universal Blood and Body Fluid Precautions" and hepatitis B vaccination. Under the universal precautions, blood and certain body fluids of all patients are considered potential sources of HIV, hepatitis B virus (HBV), and other blood-borne pathogens. The guidelines are a revision of a 1983 document that recommended special precautions (use of gloves and other protective barriers, and careful handling and disposal of needles and other sharp instruments) for blood and body fluids of patients known or suspected to be infected with blood-borne pathogens. The hepatitis B vaccine was licensed in 1982.

Statistics demonstrate the impact of these two infection control measures. A recent study by the Hepatitis Branch at CDC documented a 75 percent decrease in cases of hepatitis B among health care workers in four sentinel counties between 1982 and 1988 (Alter et al., 1990). The study's authors surmised that the decrease in cases was "probably a direct result of immunization with hepatitis B vaccine and of wider implementation of universal blood precautions" (Alter et al., 1990).

Although the hepatitis B story clearly can be counted as a victory for hospital infection control, new microbial threats are likely to surface in the future. Health care institutions are prime breeding grounds for new and more virulent strains of organisms and may well represent one of the most

important sites of surveillance for new pathogens that will emerge to jeopardize health in the future.

Food Processing and Handling

The potential for foods to be involved in the emergence or reemergence of microbial threats to humans is great, in large part because there are many points in the food chain at which food safety can be compromised. This chain of events begins wherever crops or animals are raised it proceeds through a complex system of manufacturing, distribution, and retailing and ends with the use of a food product by the consumer. Changes in any of a number of aspects of the farm-to-consumer chain, or inattention to food safety in general, can result in outbreaks of food-borne illness.

Although food containing viruses or parasites can cause illness (as can chemical contamination), the majority of individual cases of food-borne disease of known etiology in the United States are caused by bacteria. However, in more than half of the outbreaks of food-borne illness, the exact cause is unknown (Bean and Griffin, 1990). Although in many cases the lack of an exact cause reflects an incomplete investigation, at least some proportion of those outbreaks are likely to be the result of as yet unidentified food-borne pathogens.

There has been a substantial increase in our knowledge of food-borne diseases during the past 20 years, as reflected in an approximate tripling of the list of known food-borne pathogens. An important component of this increase in understanding is a better scientific grasp of the factors that allow microorganisms, and bacteria in particular, to cause human disease. Because of better methods of identifying food-borne pathogens, it has become clear that only certain strains of a bacterial species may cause food-borne illness.

For example, Escherichia coli is part of the natural intestinal flora of humans its presence in a water sample has been used as evidence of fecal contamination by other pathogenic microorganisms. The majority of isolates of E. coli pose no threat to humans as food-borne pathogens. Researchers, however, have identified five distinct groups of E. coli that cause enteric disease. Based on the mechanism of pathogenesis of each group, they are designated enteroinvasive, enterotoxigenic, enteropathogenic, enteroadherent, and enterohemorrhagic E. coli (Archer and Young, 1988). The ability to detect these pathogenic isolates has been greatly enhanced by diagnostic tests that identify specific virulence-related genes or gene products such as toxins, adhesins, and cell-surface markers.

Improved epidemiologic surveillance has also played an important role in identifying microorganisms that cause food-borne disease. This was the

case for four outbreaks of human listeriosis, a bacterial infection that occurred in the United States, Canada, and Switzerland in the early to mid-1980s. Careful monitoring of disease incidence data by medical facilities allowed these epidemics to be detected, even though the actual number of cases was relatively low. Subsequent epidemiologic investigations implicated cole slaw (Schlech et al., 1983), milk (Fleming et al., 1985), and soft cheeses (Office of Federal Public Health, Switzerland, 1988 Linnan et al., 1988) as the vehicle of infection. Of particular concern is that listeriosis, caused by Listeria monocytogenes, is most often diagnosed in pregnant women or their newborns and in immunosuppressed individuals, in whom it can be fatal. The CDC has recently published recommendations for the prevention of food-borne listeriosis for those at high risk (immunocompromised individuals, pregnant women, and the elderly) the recommendations cite additional foods to avoid (Centers for Disease Control, 1992h).

AGRICULTURAL CONDITIONS AND PRACTICES

Any change in the conditions or practices associated with the production of agricultural commodities can affect the safety of the food supply. A virtually uncontrollable factor, like the weather, can have a substantial impact. For example, drought can make grains more susceptible to mycotoxin-producing fungi, and toxic fungal metabolites, such as aflatoxin, can threaten the health of both humans and livestock. This particular risk has been substantially lessened by an ongoing U.S. Department of Agriculture (USDA) program that monitors the status of major agricultural commodities. Once identified, contaminated grain is destroyed.

New agricultural procedures can also have unanticipated microbiological effects. For example, the introduction of feedlots and large-scale poultry rearing and processing facilities has been implicated in the increasing incidence of human pathogens, such as Salmonella, in domestic animals over the past 30 years. The use of antibiotics to enhance the growth of and prevent illness in domestic animals has been questioned because of its potential role in the development and dissemination of antibiotic resistance (Cohen and Tauxe, 1986 Institute of Medicine, 1989). Approximately half the tonnage of antibiotics produced in the United States is used in the raising of animals for human consumption. Thus, concerns about the selection of antibiotic-resistant strains of bacteria and their passage into the human population as a result of this excessive use of antibiotics are realistic (Institute of Medicine, 1989). It is conceivable that surveillance of feedlot animals for the development of resistant organisms might be a means of early warning for the emergence of newly drug-resistant pathogens.

Broad-based societal events indirectly related to agriculture may also affect food safety. Recent concerns about bovine spongiform encephalopathy

(BSE) illustrate this point. In 1980, in England, the combination of increasing fuel prices and tighter restrictions on the use of organic solvents for lipid extraction led to changes in the processing of offal, the viscera and trimmings of butchered animals that are a major component of animal feed. The new methods do not appear to inactivate sufficiently the BSE agent, and increased incidence of BSE in domestic animals has been linked to offal. There is considerable controversy, at least in England, about whether the BSE agent may also infect humans (Dealer and Lacey, 1990, 1991 K. C. Taylor, 1991). To date, however, no human infections have been detected.

In addition to modifications of traditional farming methods, the introduction of new types of agriculture can have an impact on the emergence of microbial threats. Aquaculture and mariculture, for example, are rapidly becoming important methods of producing fish and seafood. Yet there has been relatively little effort to understand the potential microbial impact of this new technology. As aquaculture and mariculture farmers attempt to increase their yields of freshwater and marine animals, the stresses of overcrowding and overfeeding create ideal conditions for Aeromonas hydrophila, a common fish pathogen found in fresh and estuarine waters (Plumb, 1975 Hazen et al., 1978). Increasingly, A. hydrophila, A. veronii (biovariant sobria), A. caviae, A. jandaei, A. trota, A. schubertii, and A. veronii (biovariant veronii ) are being implicated as causes of nosocomial, wound, waterborne, and food-borne infections in humans (Daily et al., 1981 Buchanan and Palumbo, 1985 Hickman-Brenner et al., 1987, 1988 Janda and Duffey, 1988 Carnahan et al., 1989 Carnahan and Joseph, 1991 Joseph et al., 1991 Samuel Joseph, Professor, Department of Microbiology, University of Maryland, personal communication, 1992). These bacterial infections are being found in immunocompromised individuals and those in otherwise poor health (W. A. Davis et al., 1978). Although there are a number of potential sources of infection with Aeromonas species, aquaculture and mariculture are probably the most common sources, since the incidence of these organisms in the products of these agricultural methods approaches 100 percent.

The use of human and animal fecal material to enrich pond cultures in parts of China and India raises additional concerns about the safety of some imported aquaculture products (Ward, 1989). Such practices may enhance the spread of pathogens transmitted by an oral-fecal route. In the Calcutta region of India, where this method of enrichment is used to raise prawns, a high incidence of non-O1 Vibrio cholerae contamination has been reported (Nair et al., 1991).

FOOD PROCESSING AND PRESERVATION TECHNOLOGIES

The application of new food processing and preservation technologies can have unexpected effects on the microbial safety of foods. Something

as simple as a change in packaging can be important. For example, plastic overwraps for packages of fresh mushrooms were introduced in 1967 because they enhanced the keeping-quality of this highly perishable food. It was soon discovered, however, that the respiratory rate of mushrooms is so rapid that, even with a semipermeable plastic film, the oxygen in the pack is quickly depleted. This produces an anaerobic environment perfectly suited to Clostridium botulinum, the neurotoxin-producing bacterium that causes botulism (Sugiyama and Yang, 1975). The problem was remedied by punching two holes in the plastic film, which allowed sufficient oxygen transfer to prevent the growth of anaerobes and still permitted enough carbon dioxide accumulation to retard spoilage (Kautter et al., 1978).

Another example comes from China. It appears that the transportation of brined mushrooms in plastic bags in that country provided conditions favorable to the growth of S. aureus (Hardt-English et al., 1990). The resulting presence of staphylococcal enterotoxin brought a halt (which is still in force) in November 1989 to the importation of Chinese mushrooms into the United States.

New food preservation methods, such as modified atmosphere packaging (MAP), are being used with more frequency as U.S. consumers demonstrate a preference for fresh food products that have a minimum of processing and preservatives. MAP uses combinations of gases to suppress aerobic spoilage bacteria that create unpleasant odors and flavors (Seideman and Durland, 1984). Unfortunately, these gases may not discourage, and may even encourage, the growth of other pathogenic microorganisms that are not detectable by smell or taste (Post et al., 1985 Hintlian and Hotchkiss, 1986, 1987 Berrang et al., 1989 Ingham et al., 1990 Wimpfheimer et al., 1990 Hart et al., 1991).

One technology for ridding foods of microbial contaminants is ionizing irradiation. This approach was used for many years to sterilize medical equipment and supplies at low doses, it can eliminate or control pathogenic bacteria, fungi, protozoa, and helminths in foods (Thayer, 1990). The technology is also highly effective for insect disinfestations. Ionizing irradiation to pasteurize or sterilize foods has been recommended as an effective tool for the control of food-borne diseases (Joint Expert Committee on Food Irradiation, 1980 Council for Agricultural Science and Technology, 1986 Thayer, 1990). It has been approved for various applications in more than 30 countries this includes, recently, approval for eliminating insects from fruits, Trichinella spiralis from infected pork, and Salmonella from raw poultry. One of the unique characteristics of irradiation is that the appearance of foods processed in this way is not altered. Much of the controversy over the use of irradiation is the result of the misconception that treated foods are radioactive. Extensive research has unequivocally demonstrated

that there is no induction of radiation in foods that are treated with isotope sources of 60 Co or 137 Cs, x-ray sources of up to 5 million electron volts (MeV), or accelerated electron beam sources of less than 10 MeV (Koch and Eisenhower, 1967 Becker, 1983). It should be noted, however, that irradiation is not a panacea. In dairy products, which contain lipids sensitive to oxidation, for example, taste is affected. Furthermore, the technique is generally considered much less effective for inactivating viruses, compared with its effectiveness with bacteria and other more complex pathogens (e.g., fungi).

DEMOGRAPHICS

There are several important, ongoing demographic changes in the United States that will have direct and indirect effects on the emergence of new food-borne microbial diseases. Foremost is the fact that, at least through the early twenty-first century, the population increasingly will be composed of the elderly, a group particularly susceptible to food-borne pathogens.

Population expansion and the accompanying demands on infrastructure can also affect the safety of the food supply. For example, when estuarine areas are developed for residential or recreational purposes, water treatment capacity often lags behind requirements imposed by the population increase. In some cases, potentially dangerous viral and bacterial pathogens are released into the water from sewage effluent and storm-drain runoff, where they are concentrated by shellfish and subsequently harvested and consumed, often with minimal processing. The closing of shellfish beds because of the presence of these pathogens has become a major public health and economic issue in a number of coastal regions. The problem is compounded by poaching from closed beds. Methods for testing water for human enteric viruses (e.g., hepatitis A and C, Norwalk virus, and caliciviruses) currently are inadequate (Institute of Medicine, 1991b).

CONSUMER ATTITUDES AND BEHAVIOR

In general, particularly in the developed world, the public expects its food supply to be safe. To a great extent this expectation has been met through the safe manufacturing and distribution of prepared foods. The extent of training that individuals receive in proper food handling and preparation is declining. Owing to changes in family structure and the roles of women, home economics courses are being deemphasized in schools, and the use of convenience foods and dining out is increasing. With these changes, assumptions about food safety may lead to complacency. Consumer inattention to appropriate steps for maintaining food safety in the home can easily overwhelm safeguards built into food production and processing.


Biology 202 - Chapter 27 - Viruses

Because they can't reproduce by themselves (without a host), viruses are not considered living.

Nor do viruses have cells: they're very small, much smaller than the cells of living things, and are basically just packages of nucleic acid and protein.

A nucleic acid genome made of DNA or RNA, tucked inside of the capsid

Replicated in the host cell's cytoplasm

Filamentous/ helical - Filamentous capsids are named after their linear, thin, thread-like appearance.

Head-tail -These capsids are kind of a hybrid between the filamentous and icosahedral shapes. They basically consist of an icosahedral head attached to a filamentous tail.

they "borrow" a patch from the host membranes on their way out of the cell.

Mimivirus does not has a virion 750nm in diameter -->
was originally misidentified as a bacterium

Mimivirus genome contains 9 genes necessary for translation

suggests these viruses may have once been autonomous

Viral genome tricks host cell into making viruses

Cell with a virus is often damaged by infection

Viruses can only reproduce inside cells

Outside, they are metabolically inert virions

Negative-strand virus - genome is complementary to the viral mRNA

E. coli-infecting viruses are the best studied

must infect a host cell in order to reproduce.

Penetration or injection
--T4 pierces cell wall to inject viral genome

Synthesis
--Phage takes over the cell's replication and protein synthesis enzymes to synthesize viral components

Assembly
--Assembly of components

Release
--Mature virus particles are released through enzyme that lyses host or budding through host cell wall

Integrate: virus copies it's nucleic acid into host cell genome

Integration allows a virus to be replicated along with the host cell's DNA as the host divides

Integrated genome called prophage

cell containing a prophage called lysogen

People resistant to HIV infection have a mutation in the CCR5 gene (CCR5-Δ32)

Over time, HIV infection causes a massive drop in the total number of CD4 cells from about 1000 cells per ul of blood to less than 200 ul, -->resulting in immunodeficiency.

Host may ultimately die from a variety of opportunistic infections
Do not normally cause disease

-Test for presence of antibody against HIV

-Further testing confirms HIV-positive status

Spread of AIDS:
-Carriers have no clinical symptoms but are infectious

-Infection continues throughout latent period

-Viral gp120 attaches to CD4 protein on macrophages and CD4+ cells

-Coreceptors like CCR5 affect likelihood of entry

Entry through fusion pore: virus enters

Replication:
-Reverse transcriptase converts virus RNA to double-stranded DNA

-Mutations common in process

-DNA is incorporated into host

-Variable period of dormancy

Assembly:
-Making many copies of virus

-DNA, and maturation of HIV proteins

Reverse transcriptase inhibitors
-AZT - 1st drug licensed for clinical use
Selective for HIV

Protease inhibitors:
-Target a protease that cleaves a polyprotein into the smaller proteins necessary for viral replication and assembly

Blocking viral entry:
-Fusion inhibitor blocks the fusion of the viral envelope with the plasma membrane of a target cell