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14.2: Overview of Microbe-Host Interactions - Biology
Normal microbiota are the microorganisms that reside in the bodies of all humans.
Explain the relationship between the normal microbiota and the host upon infection of a pathogen
- The phrase “normal microbiota ” refers to the microorganisms that reside on the surface and deep layers of skin, in the saliva and oral mucosa, in the conjunctiva, and in the gastrointestinal tracts of every human being.
- These microbiota are not harmful to humans some are even beneficial and most help maintain our health.
- Our normal microbiota consists of various bacteria, fungi, and archaea.
- While our bodies are happy to host the array of microbiota that are considered “normal,” the human body does not take a back seat when infection tries to use it as a host.
- Resistance to and recovery from viral infections depends on the interactions that occur between virus and host. The host has a variety of barriers that it uses to prevent infection. One of the first lines of defense is mucus, which has a range of normal microbiota.
- There are a number of other humoral components of the nonspecific immune system as well.
- host: A cell or organism which harbors another organism or biological entity, usually a parasite.
- microorganism: An organism that is too small to be seen by the unaided eye, especially a single-celled organism, such as a bacterium.
- interferon: Any of a group of glycoproteins, produced by the immune system, that prevent viral replication in infected cells.
The phrase “normal microbiota” refers to the microorganisms that reside on the surface and deep layers of skin, in the saliva and oral mucosa, in the conjunctiva, and in the gastrointestinal tracts of every human being. These microorganisms are not harmful to humans in fact, some are even beneficial and all help maintain our health. Our normal microbiota consists of various bacteria, fungi, and archaea. An example of our bacterial microbiota is E. coli . Many people think of E. coli as the bacteria that makes you sick however while it has that capacity, it can also remain dormant and benign in your gastrointestinal tract for your entire life. All humans actually acquire E. coli shortly after birth with the intake of food or water. Other forms of bacteria present in the human gut are necessary for proper digestion of carbohydrates.
Escherichia coli: This is a magnified view of Escherichia coli (or E. coli).
While our bodies are happy to host the array of microbiota that are considered “normal,” the human body does not take a back seat when infection tries to use it as a host. Interestingly, normal microbiota can be key players helping the body fight off infection. Resistance to and recovery from viral infections depends on the interactions that occur between the virus and its host. The host has a variety of defenses that it uses to prevent infection. One of the first lines of defense is mucus, which has a range of normal microbiota that compete with and may even attack invading bacteria and virae.
Once a virus or bacteria makes its way past the skin and mucosa, there may be changes that occur in the host to diminish the invader’s effectiveness. An example of such a change is a fever. There are a number of other humoral components of the nonspecific immune system as well. Specific immune responses are produced by antibodies. Different interferons (IgA, IgG, IgM, etc. ) play roles in defeating viruses located in our membranes. The body does not easily become a host to infection it has a line up of defenses to try to protect you from harm.
Dual systems enable the study of root colonization by filamentous pathogens and symbionts
Dual systems are crop plants whose roots are colonized by filamentous symbiotic microbes (for example, the widely used AM fungus Glomus irregularis) but in addition can also be infected by other biotrophic pathogens. The legume species Medicago truncatula and Lotus japonicus have served as genetic model plants for symbiosis research [4, 8] and a huge genetic resource has been established by the community, rendering these plants prime candidates for systems to study similarities and differences between symbiosis and pathogenicity. Another established monocot system for symbiosis research is rice . It is surprising, however, that not many root pathogen infection systems with clearly distinguishable biotrophic stages exist for these plant species.
In AM fungi colonized roots, the ideal microbial pathogen partner to compare with is a naturally root colonizing filamentous organism with a broad host range. Other than G. irregularis it should be cultivatable, transformable and efficiently traceable in living tissues - for example, by fluorescent proteins. Several filamentous microbes have been employed to unravel the mechanisms involved in root colonization (Table 1). Historically, most research has been carried out using Aphanomyces euteiches , Colletotrichum trifolii  and Verticillium species , and to a major extent using Magnaporthe oryzae . Piriformospora indica colonization of roots and its growth-promoting effects have also been studied in the economically relevant barley , a monocot plant that also establishes interactions with AM fungi .
Notably, C. trifolii and M. oryzae are major leaf colonizers in nature however, they can be employed for root infection under laboratory conditions [17, 22]. C. trifolii experiments have helped to extend the role of the DMI3 (DOESN'T MAKE INFECTIONS 3) calcium/calmodulin kinase, a classical symbiosis signaling element, from symbiotic to pathogenic interactions . Infections with C. trifolii showed differential responses between plants that carried either a DMI3 wild-type or a mutated allele.
While C. trifolii and M. oryzae were reported to establish biotrophic stages inside the root, others such as apoplast-colonizing A. euteiches  and Verticillium albo-atrum  lack the potential to form intracellular structures such as the arbuscular feeding structures of AM fungi, thereby complicating the delimitation of their biotrophic stages. Nevertheless, A. euteiches has been successfully employed to identify signaling elements that are shared between symbiotic and pathogen perception mechanisms. An example is NFP (NOD FACTOR PERCEPTION), a lysin motif receptor-like kinase (LysM-RLK) that is integral to perception of lipochitooligosaccharidic symbiosis factors from AM fungi by the plant. Recently, NFP was shown to also affect colonization by the pathogen A. euteiches . Larger sets of LysM-RLK receptor variants can be found in root nodule and AM-forming legumes [23, 24] and non-nodulating but AM-forming rice  compared with non-mycorrhized and non-nodulated Arabidopsis. This enlarged receptor repertoire could correlate with a requirement for higher resolution signal discrimination between pathogens, mycorrhizal fungi and symbiotic bacteria. Further research is required to clarify how specificity in signal perception is achieved.
An overview of SNP interactions in genome-wide association studies
With the recent explosion in high-throughput genotyping technology, the amount and quality of single-nucleotide polymorphism (SNP) data has increased exponentially. Therefore, the identification of SNP interactions that are associated with common diseases is playing an increasing and important role in interpreting the genetic basis of disease susceptibility and in devising new diagnostic tests and treatments. However, because these data sets are large, although they typically have small sample sizes and low signal-to-noise ratios, there has been no major breakthrough despite many efforts, making this a major focus in the field of bioinformatics. In this article, we review the two main aspects of SNP interaction studies in recent years-the simulation and identification of SNP interactions-and then discuss the principles, efficiency and differences between these methods.
Keywords: SNP interactions data simulation detection methods genome-wide association studies.
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4. Interactions between Host and Intestinal Microbiota in C. elegans
As far as we are aware, all the investigations on host-microbe in C. elegans had dealt with only one or few bacterial species till the present year. In 2013, Shapira's research group first characterized the C. elegans natural gut microbial communities by growing germ-free worms in a natural-mimic environment of soil and rotting fruit, with 18 species having been identified. These species include Bacillus sp., Bacillus megaterium/Bacillus sp./Bacillus aryabhattai/Bacillus thuringiensis, Bacillus foraminis/Bacillus asahii, Bacillus nealsonii/Bacillus circulans, Bacillus subtilis, Paenibacillus sp./Paenibacillus lautus/Paenibacillus odorifer, Lysinibacillus fusiformis/Lysinibacillus xylanilyticus/Lysinibacillus sphaericus, Staphylococcus warneri/Staphylococcus pasteuri, Bacillus sp./Bacillus pumilus, Pseudomonas sp./Pseudomonas oleovorans/Pseudomonas stutzeri/P. mendocina/Pseudomonas pseudoalcaligenes, P. aeruginosa/P. mendocina/Pseudomonas alcaligenes, P. oleovorans/P. mendocina/P. pseudoalcaligenes, Pseudomonas trivialis/Pseudomonas poae, Pseudomonas fluorescens/Pseudomonas moraviensis/Pseudomonas koreensis/Pseudomonas putida, Arthrobacter sp., Enterobacter sp./Pasteurella aerogenes, Rahnella aquatilis, and Buttiauxella agrestis/Buttiauxella noackiae. They discovered that members of C. elegans microbiota can enhance the host's pathogenic resistance, although disparate components may employ distinct resistance mechanisms. For the two primary species of the identified bacteria, Bacillus megaterium (BM) and Pseudomonas mendocina (PM), the increase in host's infection resistance supplied by BM is related to the compromised reproduction, while the protection provided by PM is reproduction-independent, by activating the p38-dependent pathway to prime the worm immune system. Considering the p38 pathway is one of the functionally conserved signaling pathways throughout the animal kingdom, this disclosure may indicate that similar interactions might also be present in mammals .
Exploring human host–microbiome interactions in health and disease—how to not get lost in translation
A meeting report on the 7th Wellcome Trust conference on Exploring Human Host–Microbiome Interactions in Health and Disease, held at Hinxton, UK, 5–7 December 2018.
The meeting titled Exploring Human Host–Microbiome Interactions in Health and Disease was held in December 2018 for the seventh time in Hinxton, Cambridge, UK. The Scientific Programme Committee once again did an outstanding job in selecting excellent keynote, invited and abstract speakers. The meeting started with a keynote lecture by John Cryan (University College Cork, Ireland) on the link between the gut microbiome, stress and brain development. The various routes of communication between the gut and brain include the vagus nerve, the immune system, tryptophan metabolism, the enteric nervous system and microbial metabolites such as short-chain fatty acids (SCFAs). These mechanisms also impinge on neuroendocrine function at multiple levels. Multifactorial modes of interaction between the microbiome and human physiological functions were a key aspect addressed at this meeting for different human body sites. This is a crucial factor to consider when translating the increased knowledge about the human microbiome into tangible human health applications. It also represents a key difference in comparison with classic approaches in medicine, where single molecules or compounds are typically selected to target single pathways in attempts to treat diseases or alleviate symptoms.
Most studies in humans are still focused on (gut) microbiome comparisons of healthy and diseased or unbalanced conditions. Such comparisons (generally by 16S amplicon sequencing) have suggested that the gut microbiota is altered in a variety of conditions such as obesity, schizophrenia, autism and Parkinson’s disease, but these relationships are—until now—mainly associations, without substantiation of real causality. Studies in animal models have the power to reveal causal relations. They have thus been key in delineating that neurodevelopment and the programming of an appropriate stress response are dependent on the microbiota. For example, Cryan presented data from an animal model that mice delivered through C-section behaved differently in acute stress situations compared with vaginal-birth controls. This opens up possibilities for studying the impact of prebiotics and probiotics and other microbiome interventions. A more extreme situation is when all microbes are eliminated, such as in germfree mice, and this model is thus increasingly being applied to study causal links between the microbiome and social behaviour. Yet, also for mice maintained in conventional nonsterile conditions, interesting causal links can be established. For instance, Cryan presented novel data showing that oral supplementation of a mixture of the three principle SCFA microbiome metabolites (acetate, propionate and butyrate) alleviated psychosocial stress-induced behaviour. In addition, SCFAs exhibited behavioral-test-specific antidepressant and anxiolytic effects, which were not present when mice had undergone psychosocial stress without impacting on the microbiome.
Yet, mice are not men. A paramount example is Lactobacillus rhamnosus (JB-1), which has been shown to reduce stress-related behaviour and corticosterone release and alter central expression of GABA receptors in anxious mouse models. Based on these mouse experiments, this L. rhamnosus strain was one of the first strains shown to be highly promising as a psychobiotic—that is, a live microorganism with a potential mental health benefit. In humans, however, this strain failed to modulate stress or cognitive performance in healthy male subjects. Thus, translating psychobiotic- and microbiota-related animal data to a healthy human population remains challenging, owing to the physiological, microbiota, immunological and social differences between humans and the stress-susceptible mouse models.
Effective translation from bench to bedside can be facilitated by a better understanding of the microbiome and probiotic and prebiotic mechanisms of action responsible for the observed health benefits. In his talk, Jack Gilbert (University of California San Diego, USA) encouraged the field to move from identifying correlations towards a more mechanistic understanding of the relationships between the human microbiome and disease through intervention trials. Recent developments in sequencing, metabolomics, proteomics and bioinformatics in combination with longitudinal sampling and multiple molecular perspectives have paved the way for microbiome-wide association studies (MWASs). Such MWASs, although highly complex in nature (Fig. 1), allow us to link the whole microbiome as a complex and dynamic system, with various aspects of health and disease, as well as treatment efficacy, and to identify targets for novel clinical interventions. This was also nicely illustrated by Paul Wilmes (University of Luxembourg, Luxembourg) in his talk on systems ecology and integrated multi-omics of human–microbiome interactions to identify key molecular transactions. However, proving causation and sufficiency remains a challenge that requires evidence from microbially mediated human intervention studies in classic diseases. A well-known example of such studies includes reports of successful treatment of Clostridium difficile infections through fecal microbiota transplants, for which now various follow-up trials are ongoing with more defined fecal microbial strain mixtures or formulations. More recently, Gilbert described how adjusting a patient’s diet before gut surgery could lead to a more healthy and robust microbial response to surgery-related stress factors and better surgery outcomes through the reduced presence of collagen-degrading microbes. Currently, according to ClinicalTrials.gov, more than 650 clinical trials ongoing globally involve the microbiome as a biomarker or treatment option.
Driven by major advances in sequencing, metabolomics, proteomics and bioinformatics, an increasing number of microbiome-wide association studies (MWAS) aim to take complex and large data set analyses of the microbiome with longitudinal sampling and multiple molecular perspectives, and associate these with markers for health and disease. As discussed in the keynote debate led by Jack Gilbert and moderated by Colin Hill, it is time to cease merely measuring. It is crucial that the microbiome field moves towards more detailed functional and mechanistic studies. Various examples presented at the Wellcome Trust meeting have shown that the field is ready for the next steps in the translation of microbiome knowledge indeed, one could assert that microbiome research is as beautiful (and as complex) as modern art. (a) and (b) show typical Principal Component Analyses (PCAs), which are often used to visualize complex, multidimensional microbiome data. (c) represents a typical heat map-based way of visualizing complex microbiome correlation data, with different colors representing correlation coefficients, microbiome operational taxonomic units (OTUs) and groups of subjects. More details can be found in the original paper (figure taken from Fig. 1, Claesson et al., Nature 488, 178-184)
Translation of the potential of microbiome studies is also supported by the emerging evidence that microbiota members can have a profound impact on therapy efficacy and pharmacodynamics of various drugs. Laurence Zitvogel (Gustave Roussy, France) gave a convincing talk on the pathways through which the gastrointestinal microbiota and microbial factors can impact colon cancer immunotherapy and immunosurveillance. Accumulating data show that antibiotic administration can negatively alter the course of cancer immunotherapy, whereas specific microorganisms can promote positive therapy outcomes. Zitvogel described how cell-death inducers and gut microbiota members both play a role in facilitating immunogenic cell death in the ileum, which promotes immune responses against proximal colon cancer. Importantly, natural adjuvants from gut commensal microorganisms are crucial for stimulating the anticancer responses of the immune system. In particular, recent unpublished data from the Zitvogel group show that particular microbe-associated molecular patterns (MAMPs) and damage-associated molecular patterns (DAMPs) present in the ileum are highly relevant during oxaliplatin-induced death of ileal intestinal epithelial cells.
While certain microbiota can influence pharmacological treatment efficacy, there is an increasing understanding that regularly administered drugs can in turn also alter the microbiota composition. Nassos Typas (European Molecular Biology Laboratory, Germany) described a high-throughput microbiomics system that was developed as a collaborative effort of several European Molecular Biology Laboratories to screen for the interactions between representative gut bacteria and pharmacological compounds and xenobiotics. More than 1000 commercially available non-antibiotic drugs have been tested, and 24% of pharmacological compounds with human targets have been demonstrated to have an inhibitory effect on at least one of the 40 tested bacterial strains. Future research should focus on the mechanisms through which non-antibiotic drugs might promote antibiotic resistance and on determining how gut bacteria can influence the bioavailability of regularly administered drugs.
In addition to the impact of gut microbiota on exogenously administered compounds, resident microorganisms also play an important role in the metabolism of endogenous host signaling molecules. In her talk, Susan Joyce (University College Cork, Ireland) emphasized the importance of gut microbial enzymes for generating the range and variety of bile acids and salts. These bile moieties engage in local and systemic cross-talk with the host processes linked to health or disease. Consequently, metabolic (e.g. bile moieties, hormones and cytokines) and microbial markers can serve as read-outs for the health status of the host. Susan Joyce presented data from a patient cohort with inflammatory bowel diseases (IBDs), in which secondary bile acids generated by the host microbiota were linked to bile acid diarrhea and incidence of Crohn’s disease. These results demonstrate both marker correlations and a mechanistic understanding of how microbial activity can influence the host health status through alteration of host signaling molecules.
In the final part of the meeting, Julie Segre (National Human Genome Research Institute, USA) once again emphasized that humans are ecosystems constantly undergoing beneficial and potentially harmful microbe–host interactions. She used the complexity of the human skin microbiome as an example of the various multi-kingdom functional interactions that involve not only bacteria but also fungi and viruses. Interestingly, the presented longitudinal data demonstrated that skin microbial communities were specific for individuals and largely stable over months and even years of sampling. These findings are highly relevant for studies in which microbiome alterations in disease are explored and suggest that both disease development and therapeutic outcomes might be highly individualized from the microbiome perspective. In addition, Julie Segre presented data on how host genetics can define skin microbial communities, which adds another layer to the complexity of microbe–host interactions. For example, drastically increased eukaryotic viral colonization was detected in patients with the dedicator of cytokinesis-8 (DOCK8) primary immune deficiency. Hundreds of previously undescribed human papillomavirus genomes were detected in these patients through deep metagenomic sequencing, shedding light on the ‘microbial dark matter’ of the human microbiome.
In the future, sequencing and culturing data should be combined with translational microbiome approaches for a thorough characterization of how the microbiota can shape host health and disease. Detailed knowledge on the causative links between microbiota composition and functionality, and host physiology and genetics, will pave the way for personalized and precision medicine.
2014-2017 NSF BCS Female Sociality, Dispersal, and Comparative Microbial Community Composition in wild chimpanzees (Pan troglodytes). (PI) K. Langergraber (co-PI)
2009-2017 National Science Foundation Human Origins Moving in New Directions (HOMINID). “Microbes, diet, and hominin evolution: comparative and metagenomic approaches.” PI: S Leigh Co-PIs: RM Stumpf, B White, K Nelson, A Salyers
2011-2014 National Institute of Health. Wilson, BA, Stumpf, RM, Yildirim, S., "Dynamics of Normal Pigtailed Macaque Vaginal and Intestinal Microbiota," University of Washington subaward.
2012-2014 U.S. Fish and Wildlife Department. “Sexually transmitted diseases and African ape conservation.” PIs: J. Rushmore, S. Altizer, and R.M. Stumpf.
2009-2011 Leakey Foundation. “Social and Sexual Development in Adolescent Chimpanzees of Kanyawara.” PI
2013-2014 University of Illinois Research Board. PI. RM Stumpf “Sexual conflict in wild chimpanzees”
2008-2013 National Science Foundation. "Comparative Primate Microbial Ecology." PI: RM Stumpf, Co-PIs: A Salyers, S Leigh, B Wilson
2010-2011 US Fish and Wildlife Department. “Close-contact pathogens, sexually transmitted diseases, and African ape conservation.” PIs: J Rushmore, S Altizer, and RM Stumpf
2008-2011 Wenner Gren Foundation for Anthropological Research. "Female Social and Sexual Development in Wild Chimpanzees." PI
2008-2011 National Science Foundation Doctoral Dissertation Improvement Grant. “The Effects of Deforestation on Reproductive Fitness in Female Red Colobus (Piliocolobus tephrosceles) in Kibale National Park, Uganda.” K Milich, RM Stumpf
2008-2009 University of Illinois, Inclusive Illinois. “Study of classroom climate in relation to issues of diversity.” J Keller, RM Stumpf and B Farnell
2008-2009 Center for Advanced Study Fellowship
2006-2007 Critical Research Initiatives Grant. "Evolutionary Medicine and Women’s Sexual Health." Co-PI
1998-2001 National Science Foundation Doctoral Dissertation Improvement Grant. "Reproductive Strategies of Female West African Chimpanzees."
2011 Excellence in Undergraduate Teaching, Department of Anthropology
2016 Promoted to Full Professor with Distinction
2016 University Scholar
2016-2017 Guggenheim Fellow
2010-2011 Irwin C. Gunsalus Scholar
2008-2009 Center for Advanced Study Fellowship
2004 Harvard University Certificate of Distinction in Teaching
2004, 2005, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016 Teachers Ranked as Excellent by their Students, Center for Teaching Excellence, University of Illinois
2005 Arnold O. Beckman Research Award
2004 President's Award for Outstanding Dissertation, SUNY - Stony Brook
Helicobacter pylori colonizes the surface of gastric epithelial cells and is generally considered a non-invasive bacterium, but in vitro observations have demonstrated that it can enter host epithelial and immune cells (Weir et al., 2010). The bacterium infects over 50% of the population worldwide and a relationship with MS has been reported (Jaruvongvanich et al., 2016) however, its potential role in the disease is unclear and controversial.
In agreement with the hygiene hypothesis, which assumes that infections during childhood are essential for preventing autoimmune conditions later in life, immunity to Helicobacter pylori seems to protect against the development of MS. Indeed, meta-analyses have shown that the bacterial presence and MS are negatively correlated in western countries (Jaruvongvanich et al., 2016 Yao et al., 2016). Concerning Asian countries, antibodies against Helicobacter pylori antigens were more prevalent in aquaporin 4 antibody-positive NMOSD patients, but negative in MS patients (Yoshimura et al., 2013). Furthermore, Helicobacter pylori infection seems to exert some protective role against EAE, inhibiting both Th1 and Th17 responses and reducing the severity of the disease (Cook et al., 2015).
Helicobacter pylori can evade pathogen recognition by the innate immune system by manipulating PRRs (such as TLR4, which recognizes LPS), thereby using the immune system to induce an anti-inflammatory response (Efthymiou et al., 2017). In addition, Helicobacter antigens can also inhibit activation of the adaptive immune system by suppressing Th1/Th17 cell responses by FoxP3(+) regulatory T cells (Salama et al., 2013). These findings support a protective role of this gram-positive bacterium in autoimmune diseases such as MS.
While these data do not suggest any link between the bacteria and MS susceptibility, a previous report showed a high frequency of acute Helicobacter pylori infection in 44 relapsing–remitting MS patients in stable phase (Gavalas et al., 2015). Instead, we showed a lack of humoral responses against the Helicobacter pylori HP986 protein, previously associated with peptic ulcer and gastric carcinoma, in a cohort of 119 MS patients from Sardinia (80.5% relapsing–remitting in acute phase) (Cossu et al., 2012).
In a recent seroprevalence study performed in Greece, antibodies against to the vacuolating cytotoxin A antigen of Helicobacter pylori, a virulence factor involved in gastric injury, were detected more frequently in secondary progressive MS patients compare to healthy controls, suggesting that antigen recognition by serum antibodies differed not only between patients and controls, but also amongst patients with relapsing–remitting and secondary progressive MS (Efthymiou et al., 2017).
Persistent bacterial infection may cause a loss of self-tolerance due to the constant release of bacterial antigens able to stimulate the release of pro-inflammatory cytokines from immune cells. Helicobacter pylori can exert these effects not only locally, but also directly via the CNS with modulation of the brain–gut axis (Kountouras et al., 2015).
In natural environments, plants are exposed to diverse microbiota that they interact with in complex ways. While plant–pathogen interactions have been intensely studied to understand defense mechanisms in plants, many microbes and microbial communities can have substantial beneficial effects on their plant host. Such beneficial effects include improved acquisition of nutrients, accelerated growth, resilience against pathogens, and improved resistance against abiotic stress conditions such as heat, drought, and salinity. However, the beneficial effects of bacterial strains or consortia on their host are often cultivar and species specific, posing an obstacle to their general application. Remarkably, many of the signals that trigger plant immune responses are molecularly highly similar and often identical in pathogenic and beneficial microbes. Thus, it is unclear what determines the outcome of a particular microbe–host interaction and which factors enable plants to distinguish beneficials from pathogens. To unravel the complex network of genetic, microbial, and metabolic interactions, including the signaling events mediating microbe–host interactions, comprehensive quantitative systems biology approaches will be needed.