Microbial Ecology in States of Health and Disease Workshop Summary (2014) / Chapter Skim
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A8 A new vision of immunity: homeostasis of the superorganism--Grard Eberl
A8 A new vision of immunity: homeostasis of the superorganism--Grard Eberl
Pages 224-248
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31 Department of Immunology, Institut Pasteur, Lymphoid Tissue Development Unit, Paris, France 32 CNRS URA1961, Paris, France. Correspondence: G Eberl (gerard.eberl@pasteur.fr)
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Manichaeism describes the cosmological struggle between the good spiritual world of light and the evil material world of darkness, and prescribes how human society should guide this struggle to its resolution by separating good from evil. As esoteric as Manichaeism theology might sound, its dualistic principle seems nevertheless to pervade our usual perception and description of the world, and thereby to shape microbiology and immunology alike.
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. The Superorganism The Role of the Symbiotic Microbiota The human intestine hosts an astronomical 1014 bacteria, roughly 100 times the number of cells in our body, and close to 1,000 distinct species (Backhed et al., 2005)
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of PRRs define the universe of MAMPs that are sensed by the innate immune system (Brown, 2006; Fritz et al., 2006; Kawai and Akira, 2009) , a limited reactivity that is nevertheless expected to provide a broad vision of the microbial world to
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Beyond innate immunity, a virtually unlimited number of receptors are generated by lymphocytes to fill any potential gaps, a diversity suggested to allow vertebrate organisms to host a more complex microbiota (McFall-Ngai, 2007)
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a matter of fact, immunosuppressed individuals are prone to opportunistic infections by ubiquitous and otherwise symbiotic microbes (Slack et al., 2009; Virgin et al., 2009) . It seems, therefore, safe to state that the immune system protects us from microbe invasion.
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. A third proposed POP is disruption of the normal function of the host cell cytoskeleton, as bacterial pathogens and viruses have been shown to exploit the actin network to move within and between cells. During such pathogenic behaviors, MAMPs access forbidden compartments of host tissues and cells.
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. Thus, it is predicted, and testable, that homeostasis of the superorganism not only requires an extensive local crosstalk between symbionts and the immune system, but also a more general systemic effect of microbiota based on invaders or circulating MAMPs. The Continuum Model The continuum model questions the dualistic view of the immune system based on self/non-self discrimination or physiologic versus pathological inflammation (Figure A8-2)
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. For example, most bacteria colonizing the human intestine are members of only two phyla, the Firmicutes and the Bacteroidetes. In addition, containment of the microbiota is enforced by multiple epithelial cell layers, such as in the skin, or thin layers of epithelial cells in the digestive tract and lungs, which produce antibacterial peptides and are protected by mucus produced by Goblet cells.
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Breaches might be generated and microbes might penetrate the forbidden compartments of host tissues and cells. When this happens, the immune system is triggered through PRRs, such as by TLR-5 on the basolateral side of epithelial cells and on phagocytes in the intestinal lamina propria, which activate cascades of proinflammatory pathways (Gewirtz et al., 2001; Uematsu et al., 2006)
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Good includes normal self and mutualistic microbes, whereas evil includes altered self such as dead cells releasing danger signals and pathogenic microbes that alter the antigenic landscape of normal self. In that context, the normal self induces a physiological level of inflammation that contributes to homeostasis through for example containment of the intestinal microbiota, whereas injury and pathogens induce pathological inflammation that leads to "full-blown" inflammation (Sansonetti and Di Santo, 2007)
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However, resistance was re-established by concomitant treatment of mice with LPS, which binds TLR-4 and re-induces the expression of antibacterial peptides. Thus, the symbiotic microbiota pulls the string of immunity and induces the production of antibacterial peptides that contribute to defining an intestinal niche permissive for symbionts, but mostly toxic for potential pathogens such as antibiotic-resistant Enterococcus.
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, and generation of memory lymphocytes and lymphoid tissues (Round and Mazmanian, 2009)
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By contrast, ILFs, present in the adult intestinal lamina propria as hundreds of small B-cell follicles, are not programmed during ontogeny, but induced by colonizing microbiota (Hamada et al., 2002) . Peptidoglycans shed by dividing bacteria are recognized by NOD-1 in epithelial cells, which then upregulate the expression of β-defensin-3 and of the chemokine CCL20.
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Two non-mutually exclusive mechanisms generate and maintain immunological memory: differentiation of long-lived memory lymphocytes during a primary immune response, and latent infection by the microbe or long-lasting antigen depots to uphold specific T- and B-cell activation (Antia et al., 2005; Sprent and Surh, 2002; Welsh et al., 2004; Zinkernagel, 2002) . In another case of herpesvirus infection, cytomegalovirus establishes latency after systemic infection in both mouse and man (Snyder et al., 2008)
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. When specific pathogen-free mutant mice are fed with the symbiont Escherichia coli K-12, live bacteria are recovered from the spleen, and serum IgG are produced against members of the symbiotic microbiota, indicating bacterial leakage into the bloodstream. Similar findings were reported earlier in mice deficient for Myd88 or TLR-4 (Fukata et al., 2005)
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. Wild-type flies harbor an intestinal community dominated by five bacterial species, including Gluconobacter strain EW707 and Acetobacter strain EW911. Mutant flies that show uncontrolled, bacteria-induced nuclear factor-κB activation, due to knockdown of the regulatory Caudal transcription factor, suffer excessive apoptosis of epithelial cells and progressed to death.
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Surprisingly, germfree Myd88-deficient NOD mice develop diabetes to the same extent as germfree or normally colonized Myd88-sufficient NOD mice, indicating a role for the intestinal microbiota in protection from disease progression in the absence of Myd88. A key experiment showed that Myd88-deficient mice develop an altered intestinal microbiota that somehow suppresses the generation of diabetogneic T cells in the pancreatic LN: when NOD newborn mice were raised with Myd88-deficient mothers, disease progression was mitigated.
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The LPS induced TLR-4-mediated production of antibacterial peptides targeting the pathogenic bacteria, an effect normally induced by the symbiotic microbiota. Thus, in patients treated with antibody cocktails, some degree of homeostasis could be restored by complementing the dwarfed microbiota with selected microbiotaderived compounds.
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It is therefore expected that a fine understanding of the crosstalk and equilibrium between microbiota and host, and eventually of the rules that govern the superorganism, should lead to preventive and therapeutic strategies in numbers of ailments that are characterized by disrupted homeostasis. Conclusions The superorganism is discussed here as the association of the mammalian host with its symbiotic microbiota.
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& Yarovinsky, F Gut commensal bacteria direct a protective immune response againstToxoplasma gondii. Cell Host Microbe. 6, 187–196 (2009)
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& Gordon, J.I. Microbial ecology: human gut microbes associ ated with obesity. Nature 444, 1022–1023 (2006)
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& Mazmanian, S.K. The gut microbiota shapes intestinal immune responses during health and disease. Nat.
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Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nat. Immunol. 7,868–874 (2006)
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