Ending the War Metaphor The Changing Agenda for Unraveling the Host-Microbe Relationship: Workshop Summary (2006) / Chapter Skim
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3 The Ecology of Pathogenesis
3 The Ecology of Pathogenesis
Pages 102-158
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From page 102... ...
The chapter continues with a detailed exploration of a single human pathogen, the bacterium Helicobacter pylori, which is strongly associated with increased risk for peptic ulcer disease and gastric cancer. Martin Blaser considers this example of amphibiosis -- a term coined decades ago by microbial ecologist 102
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From page 103... ...
Balfour Sartor's contribution to this chapter describes bacterial factors and genetically programmed host responses that influence whether the host's response to commensal bacteria is one of coexistence or of aggressive defense via inflammation, as occurs in idiopathic inflammatory bowel disease (IBD) , Crohn's disease, and ulcerative colitis.
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From page 104... ...
The development of pathogens specific to humans was further encouraged by the crowding, defective hygiene, and poor nutrition associated with the transition to living in larger communities. In addition, the domestication of animals has permitted the evolution of infectious diseases such as measles (from canine distemper and rinderpest)
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THE ECOLOGY OF PATHOGENESIS 105 Modern Crisis World War I World War II Reformation Crisis WWII Medieval Crisis religious wars WWI epidemics mass persecutions Dark Age Crisis Period major wars of mass Black Death anarchy and emigration invasions Pestilence of Justinian Carolignian Medieval Great Long Renaissance Renaissance Renaissance Renaissance AD 500 600 800 850 900 950 1100 1200 1300 1400 1500 1600 1700 1800 1900 1971 FIGURE 3-2 Infectious diseases were, and still are, the most common cause of death worldwide. SOURCE: Falkow (2005)
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From page 106... ...
Some infectious diseases -- such as Lyme disease, rabies, and botulism -- occur in humans through accidents of transmissibility, when we are infected by microbes that are specific to other host species. Most potential bioterrorism agents fit this general description.
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Invading microbes without specific mechanisms to avoid the innate immune system are destroyed. Pathogens must possess inherent ways to avoid or subvert these innate host defense mechanisms.
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From page 108... ...
Microbes are very simple creatures, but they can perform the tasks of recognition at their surfaces through either proteins or proteinaceous appendages. The bacterial strain that causes salmonellosis, for example, recognizes specific kinds of cells in the terminal ileum.1 Protein-based adherence mechanisms are also found in viruses; herpesviruses, for example, have proteins on their surfaces that recognize specific receptors on host cells.
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From page 109... ...
Another means to persistence is to breach the tight junctions between epithelial cells or to get inside the cells themselves. Salmonella and Shigella can stimulate human epithelial cells and cause them to extend cytoplasmic ruffles that act to trap the bacteria and literally pull them into the cell.
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From page 110... ...
Humans do not carry the cholera bacterium; its reservoir is probably in marine estuaries. Toxins appear to perform a variety of functions for bacteria, including nutrient acquisition, the breakdown of anatomic barriers, facilitation of exit and transmission, and the modulation of immune function.
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From page 111... ...
Corollaries of Pathogenicity A better understanding of the previously described steps that pathogens must take in order to live successfully in their hosts could result in the search for new ways to protect humans from infectious diseases. Such efforts should also address the following "corollaries" of pathogen behavior, as revealed through microbiological research.
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From page 112... ...
, there are two types of H pylori: one that is associated with gastritis, and another that is associated with peptic ulcer and gastric cancer.
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The mapping of the human genome and of bacterial genomes provides the means to better understand host-microbe relationships. In the context of infectious diseases, it is likely to be just as important to learn about the host as the microbe.
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114 ENDING THE WAR METAPHOR FIGURE 3-3 Illustration of the old rhyme (based on a poem by Jonathan Swift, author of Gulliver's Travels2) , "Big fleas have little fleas upon their backs to bite them, and little fleas have lesser fleas and, so on, ad infinitum." We need to keep that idea in mind today, along with the fact that, in the end, microbes always have the last laugh.
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pylori populations are not clearly delineated (Figure 3-4A)
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showed that all or essentially all modern H pylori populations derive from five ancestral populations.
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H pylori colonization is mostly acquired early in life (Oliveira et al., 1994; Pérez-Pérez et al., 2003)
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B: An integrated view of host-microbial interactions in the human body, constituting the metabolome. In this model, our indigenous microbes are as much a part of human physiology as is a recognized human organ, such as the liver.
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As this continues, gastric acidity is reduced, H pylori populations decline, and as they decline, host responses diminish.
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Organisms have been selected that signal specific host cells to produce effectors that abrogate the stress. Such a model represents an equilibrium relationship, but since both hosts and their H
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Because all developed countries were formerly developing countries, the prevalence of colonization should have shifted downward () over the course of development, and much evidence supports this hypothesis.
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pylori could be a risk factor for development of gastric cancer. On the basis of both epidemiologic and animal challenge studies, it is now clear that colonization by H
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pylori and gastric cancer is greater than the relationship with ulcer disease. Differences Among H
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From page 124... ...
pylori colonization leads to gastric cancer risk is that the organism induces a variety of host responses that are affected by strain, host, or cofactor differences; there is evidence that each of these factors affects cancer risk (Blaser et al., 1995b; El-Omar et al., 2000; Machado et al., 2003)
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Adenocarcinoma FIGURE 3-9 Potential pathways by which H pylori colonization increases risk of gastric cancer.
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H pylori Strain Type and Risk of Disease by Location The data suggest that in relation to diseases of the lower stomach and esophagus, such as ulcer disease and gastric cancer, carrying a cag-positive strain increases risk of disease (Blaser, 1999)
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H pylori colonization initiates a multidecade sequence of events leading to atrophic gastritis and ultimately to gastric cancer.
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. Nishi and colleagues examined plasma ghrelin levels by whether subjects were H
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pylori Genotypes Within an Individual Host There now is extensive evidence that H pylori populations within a host are changing over the course of colonization (Israel et al., 2001; Kuipers et al., 2000)
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H pylori populations in each host are varied and continue to diversify over the course of the colonization of that host.
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These concepts help explain the pathogenesis of chronic immune-mediated intestinal inflammation such as the idiopathic IBD, Crohn's disease, and ulcerative colitis, as well as differential host responses to enteric microbial pathogens. Normal Host Responses The normal host with appropriate regulated immune responses develops tolerance when confronted with commensal bacteria (Figure 3-12A)
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IFN TH3 TH1 ( ) IL-10 IL-12 TR1 M B IBD-Susceptible Host: Induction of Pathogenic Immune Responses Luminal Antigens, Adjuvants Leaky mucosal IgG barrier Impaired mucosal Dysregulated defenses, immune bacterial clearance IL-1 response TNF IFN TNF IL-12 IL-23 Loss of TH1 TH2 Tolerance FIGURE 3-12 Induction of homeostatic or pathogenic immune responses by commensal bacteria.
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From page 133... ...
Pathogenic Mucosal Immune Responses to Bacteria in Genetically Susceptible Hosts Hosts with a variety of genetic defects in mucosal barrier function, immune regulation, or bacterial killing can develop chronic relapsing intestinal inflammation when confronted with the same microbial environment present in normal hosts (Figure 3-12B)
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The onset of histologically detectible colitis is preceded by colonic secretion of IL-12 p40 and enteric-specific IFN secretion by CD4+ T cells (Kim et al., Role of Commensal Enteric Bacteria in the Pathogenesis of Chronic Intestinal Inflammation No bacteria Resident bacteria Mice IL-2KO IL-10KO TCR KO CD 3 26TG Macrophage No immune SAMP1/Yit (?
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. We conclude from these gnotobiotic studies that normal luminal bacteria can induce and perpetuate chronic T cell-mediated colitis and gastroduodenitis and associated extraintestinal inflammation such as peripheral arthritis in genetically susceptible hosts.
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. Finally, luminal bacteria can induce both detrimental and protective responses, with epithelial activation of NFB by commensal bacteria being predominantly beneficial.
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. These results indicate that certain commensal bacterial species can selectively induce disease in hosts with different genetic backgrounds and cause different phenotypes of disease in a single genetically susceptible host.
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It is quite interesting, and potentially important, to note that the genes studied to date fall into several categories relating to either epithelial barrier function or response to bacteria. The first gene implicated in Crohn's disease, NOD2/CARD 15, is an intracellular bacterial sensor whose leucine-rich repeat (LRR)
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From page 139... ...
Commensal bacteria provide the constant antigenic and adjuvant stimuli that perpetuate chronic intestinal inflammation in susceptible hosts, but induce homeostatic signals in normal hosts. Thus, we hypothesize that the inflammatory bowel diseases are the result of an overly aggressive cellmediated immune response to a relatively small subset of commensal bacteria in a genetically susceptible host.
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Modern practices have become arms of microbial mass destruction, to which, of course, many infectious disease agents have succumbed. Yet, as infectious diseases disappear in modern societies, autoimmune disorders and obesity are increasing.
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. Ribosomal DNA sequence data has recently revealed that gastrointestinal bacterial communities in cattle appear to be dominated by Firmicutes, particularly those related to the genus Clostridium (Nelson et al., 2003; Tajima et al., 2001a; Whitford et al., 1998)
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142 fermenta Similar gastric lysozyme acids DIET host. Bacteria the of Amino nutrition the for Gas Liquid biomass and products source humans.
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. Host immunity and indigenous microbes may protect against the assault of primary pathogens through what is known as colonization resistance, while host immunity acts specifically against invaders.
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144 microbes other of cell B germinal center effect bacterial lymphocytes patch unknown present cells maturing the Dendritic cells to Peyer's cell B showing Dendritic antigens cell cell T lymphocyte bacteria, epithelial IgA indigenous Intestinal Intraepithelial parasites? by targeted immune ?
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The "intelligent" use of antimicrobials by man, outside the pace of evolution, lacks selectivity. Although the fight against infectious diseases has increased human well-being and life expectancy, nature's trade-off imposes a cost to this success: new diseases as a consequence of microbiome alterations.
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. Developing countries still fall in the descendent region of the bimodal curve in Figure 3-17, suffering from primary pathogens, but perhaps keeping their normal microbiota less altered than modern societies.
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Host responses to microbes, either immune (adaptive, innate) or endocrine (leptin, ghrelin)
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Journal of Infectious Diseases 161(4)
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Presentation at the Forum on Microbial Threats Workshop Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship, Washington, D.C., Institute of Medicine, Forum on Microbial Threats. Blaser MJ, Atherton JC.
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2000. Interleukin-1 polymorphisms associated with increased risk of gastric cancer.
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Journal of Infectious Diseases 153(4)
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2004. Dual-association of gnotobiotic IL-10-/- mice with two nonpathogenic commensal bacterial species accelerates colitis [abstract]
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Journal of Infectious Diseases 181(1)
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pylori cagA status and risk of peptic ulcer disease. American Journal of Epidemiology 155(11)
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1997. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection.
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From page 156... ...
Presentation at the Forum on Microbial Threats Workshop Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship, Washington, D.C., Institute of Medicine, Forum on Microbial Threats. Sartor RB, Hoentjen F
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From page 157... ...
1995. Helicobacter pylori picB, a homologue of the Bordetella pertussis toxin secretion protein, is required for induction of IL-8 in gastric epithelial cells.
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From page 158... ...
2004. Helicobacter pylori infection and gastric atrophy: Risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia.
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