Ending the War Metaphor The Changing Agenda for Unraveling the Host-Microbe Relationship: Workshop Summary (2006) / Chapter Skim
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4 The Host Response to Pathogens
4 The Host Response to Pathogens
Pages 159-174
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From page 159... ...
She describes the structure and function of these rare and specialized regions of the intestinal epithelium and their vital role in the development of mucosal immunity; particular attention is paid to the role of M cells, which transport pathogens and antigens from the lumen to the lymphoid tissue. Understanding the molecular means by which M cells fulfill their gatekeeping role could inform the design of mucosal vaccines to prevent infection by pathogens such as human immunodeficiency virus (HIV)
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From page 160... ...
Specialized epithelial cells survey the contents of the gut and report it to a highly developed mucosal immune recognition system that resides in adjacent lymphoid cells -- and, remarkably, this occurs without provoking all-out war in the form of chronic intestinal inflammation. The following essay recounts several recent discoveries that show how these specialized intestinal epithelial cells accomplish this critical balancing act.
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From page 161... ...
Because the epithelial cells in these immune induction sites are associated with underlying collections of lymphoid cells known as lymphoid follicles, they are known as the follicleassociated epithelium (FAE)
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From page 162... ...
M cells appear to make their luminal surfaces readily accessible to microbes, which are then endocytosed and delivered to dendritic cells that lie just beneath the epithelial surface. The dendritic cells rapidly capture antigens and pathogens from the M cells and migrate to nearby deposits of T or B cells where the antigens are presented.
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From page 163... ...
, which is only about 30 nm thick. The absorptive epithelial cells that cover the intestinal mucosa bear a thick glycoprotein coat (as shown on the right)
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From page 164... ...
It achieves this structure through the action of gut proteases, which process the folded reoviral surface protein on the native virion into this infectious form. Because we are interested in mucosal immunity, we wanted to determine an immune response that could protect M cells from attachment of the virus and prevent reinfection of the mucosa.
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From page 165... ...
Our current hypothesis is that IgA interacts specifically or nonspecifically with gut microbes, then brings them back to be sampled or promotes further sampling by the organized mucosal lymphoid tissues.
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From page 166... ...
Because we know that dendritic cells can enter M-cell pockets, and we know that dendritic cells are involved in antigen capture, these observations suggest to us that TLR2 binding sets off a signaling cascade that alerts the underlying dendritic cells to prepare for subsequent antigen delivery by M cells. Antigen Transfer in the FAE Another effect we observed following exposure of the FAE to peptidoglycan was a dramatic increase in the rate of transcytosis of particles across the epithelium.
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From page 167... ...
Mucosal immune responses clearly require extra signals, such as ligands recognized by TLRs, enterotoxins, and probably others yet unknown; such information is being used to boost the effectiveness of mucosal vaccines. However, much more needs to be learned about how these signals work and how they might be manipulated to promote human health.
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From page 168... ...
DNA microarrays, in particular, permit one to examine human genomewide RNA transcript abundance patterns during the course of an infectious disease. Although this effort is in its early days, the resulting data reveal previously unappreciated sterotyped patterns, suggesting choreography and great complexity.
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From page 169... ...
However, the source of variability is often difficult to resolve due to confounding, biologically important parameters such as time and dose. Based on the "30,000-foot view" of host transcriptional response that we obtained from these primate model hosts, we now suspect that, although the set of host responses to all microbes is largely conserved, disease -- a specific host response to pathogens -- acquires its agent-specific features when conserved responses are triggered at a time point, or at a location within the host, or to a magnitude, that is not usually seen when the same responses are triggered by commensals.
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From page 170... ...
Using broad range archaeal rDNA PCR, we detected archaeal sequences only at sites with moderate or severe disease. The relative abundance of the archaeal sequences was significantly higher in severe disease than in lesser degrees of disease, and decreased in association with favorable responses to treatment (scaling and root planing)
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From page 171... ...
In comparison, among individuals with hematologic malignancies, there was a high degree of variability in these patterns. Individuals with fever and systemic infection caused by different known microbial agents displayed an intermediate degree of variability in their bloodassociated transcript abundance patterns (between that associated with health and cancer)
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From page 172... ...
. Similarly, detailed analysis of the in vivo responses of nonhuman primates to the five systemic infectious agents described earlier reveals significant numbers of genes with transcript abundance patterns that distinguish otherwise similar responses of macaques infected with smallpox from those infected with monkeypox, and a similar general finding when any two of the infections are compared to each other.
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From page 173... ...
Future Inquiries A prerequisite to answering some of the questions that I have raised in the above discussion is the generation of more complete time- and anatomic sitedependent profiles of genomewide transcript abundance in humans with natural infectious disease of various kinds, as well as during various states of health. To be most useful, such data sets should include analyses from patients infected by closely related microbial pathogens (by taxonomy or by virulence mechanism)
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From page 174... ...
2001. Collaboration of epithelial cells with organized mu cosal immune lymphoid tissues.
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