Ending the War Metaphor The Changing Agenda for Unraveling the Host-Microbe Relationship: Workshop Summary (2006) / Chapter Skim
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Summary and Assessment
Summary and Assessment
Pages 1-34
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Stewart told a White House gathering of health officers that "it was time to close the book on infectious diseases and shift all national attention (and dollars) to what he termed `the New Dimensions' of health: chronic diseases" (Garrett, 1994; Stewart, 1967)
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Finally, participants examined the prospects for manipulating host-microbe relationships to promote health and mitigate disease. The workshop's primary goal of replacing the war metaphor for infectious disease intervention represents an expansion of the Forum's focus on microbial threats to health.
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THE RISE AND FALL OF THE WAR METAPHOR More than a century of research, sparked by the germ theory of disease and rooted in historic notions of contagion that long precede Pasteur and Koch's 19thcentury research and intellectual synthesis, underlies current knowledge of microbe-host interactions (Lederberg, 2000)
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and reemergent (e.g., influenza) infectious diseases; lethal outbreaks of Ebola, hantavirus, and other such exotic viruses; and a new appreciation for the associations of various chronic diseases with prior microbial infections, as noted above.
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The microbe-host interaction is influenced by the interlocking domains of the determinants of the emergence of infection: genetic and biological factors; physical environmental factors; ecological factors; and social, political, and economic factors.
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. A broader view, reflected in many workshop presentations and discussions, considers how pathogens coexist within host-microbial communities and places infectious disease within an ecological context.
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. The complexity of the human gut microbiota has been studied using culturebased assays and, more recently, a variety of molecular methods.
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Identifying the host genes targeted by gut microbes and the mechanisms by which they manipulate host gene expression could lead to novel approaches for preventing and controlling a variety of diseases and promoting human health. To explore such host-microbe interactions at a molecular level, researchers have introduced genetically mutable components of the human intestinal microbiota into germ-free animals (Bäckhed et al., 2004; Hooper et al., 1998, 2001, 2002; Rawls et al., 2004; Xu and Gordon, 2003)
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IT'S A SMALL UNIVERSE: INSIGHTS FROM OTHER HOST-MICROBE SYSTEMS The host-microbe environment of the human gut is complex, compelling, and likely to yield important scientific and medical insights, but the same can be said for microbial communities in plants, insects, and the soil (dubbed "nature's GI tract" by presenter Jeffrey Gordon) that have received considerably less attention.
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. Thus, while it is not surprising that studies of plants and their associated microbial communities have added considerably to knowledge of host-microbe relationships, these findings have not been widely appreciated nor have they been well integrated with current understanding of the human gut microbiota.
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. Conserved cellular defense responses in plants may also be analogous to certain innate immune responses to pathogens in vertebrates and insects, suggesting that these defense pathways are highly conserved and may be inherited from a common ancestor (Baker et al., 1997)
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and others -- including Jared Diamond in his Pulitzer Prize-winning book Guns, Germs, and Steel (Diamond, 1999) -- have observed, the advent of infectious disease adapted to humans is a relatively recent phenomenon, made possible by the existence of large host populations in close contact with one another and abetted by poor hygiene, malnutrition, and the opportunity for zoonotic transmission afforded by animal domestication (Falkow, 2005; McNeill, 1976)
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Further support for this notion was provided by presenter Maria DomínguezBello (see Chapter 3) , whose studies of indigenous American Indians determined that the presence of multiple intestinal parasites was not correlated with reduced lean body mass in this population.
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. Such conditions highlight the inadequacy of the war metaphor, with its "us versus them" paradigm for pathogenesis.
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. Host Recognition of Microbe-Associated Molecular Patterns PRRs are a broad class of host molecules that activate innate immune responses upon encountering certain conserved molecules and structures4 common to pathogenic bacteria, viruses, and fungi (but not, apparently, to multicellular parasites)
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Knowledge of the diverse microbial signatures recognized by PRRs has expanded rapidly, but recent findings indicate that there is much more to be learned about the various means by which hosts detect the microbes in their midst. For example, presenter David Relman raised the question of whether mammalian hosts recognize endogenous archaea, since these organisms do not display any of the known molecular patterns recognized by PRRs (Relman, 2005)
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. Similarly, knowing how certain pathogens exploit immune induction sites in order to gain entry to a protected niche within their hosts could lead to novel preventive strategies against a variety of microbial threats, including Salmonella, Shigella, poliovirus, and reoviruses (Neutra and Kraehenbuhl, 1994)
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Such variability -- which is thought to result from pathogen-specific mechanisms that co-opt, subvert, or modify the stereotypical host response to microbial stimuli -- could be exploited for diagnostic purposes. Some promising initial efforts toward this goal were described, including the use of host transcriptional patterns to identify infants with Kawasaki syndrome, which in its symptomatology resembles several other pediatric infectious diseases (Relman, 2005)
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digestion in pigs. The pig study was intended to shed light on the larger question of whether gut function in mammals -- and especially humans -- could be modified by altering the structure of the endogenous microbial community (Stahl, 2005)
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. However, despite far-reaching health claims associated with daily consumption of foods containing live bacterial cultures, the biological effects of such products have been demonstrated only under extremely limited 5Verocytotoxigenic E
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. Synbiotics, according to presenter Lorenzo Morelli, are defined as "mixtures of probiotics and prebiotics that beneficially affect the host by improving the survival and implantation of live microbial dietary supplements in the GI tract of the host" (Andersson et al., 2001)
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Immune Regulation by Probiotics: Evidence and Application Do probiotic bacteria actually regulate the mucosal immune response? This central question was approached through a series of related queries posed by presenter Suzanne Cunningham-Rundles.
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· Commensal bacteria influence the priming of the immune response, probably through the action of T regulatory cells. · Oral consumption of probiotic bacteria can have a therapeutic effect by improving gut flora richness and barrier function and by down-regulating inflammation.
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Although this situation is expected to change, workshop participants noted, there is little incentive for manufacturers of probiotics currently marketed as dietary supplements to develop them as biotherapeutics, given the rigors and expense of the associated review and regulation process. This situation confuses many consumers, who struggle to understand the vague health claims associated with probiotics and other dietary supplements, and who may (especially if they are ill)
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, that encourage an integrated and cooperative research effort by human and animal health communities on infectious disease threats. It was recognized that these goals would be furthered by engaging the plant research community and that the collaborative research agenda on infectious disease should incorporate host-microbe ecology.
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to environmental change. Indeed, it was observed, the collection of this data could be viewed as an extension of the human genome project to encompass the "organismal metagenome." In addition to advancing understanding of the etiology and epidemiology of infectious disease, this project may shed light on microbial influence on a host of chronic disorders, including GI conditions, allergy, asthma, diabetes, and obesity.
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At best, the war metaphor is a limiting mental shortcut that distracts from abundant opportunities to improve human and animal health. At worst, it represents a dangerous influence on disease control practices that have accelerated the development of antimicrobial resistance among human and animal pathogens, and perhaps also increased virulence in some pathogens.
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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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Presentation at the Fo rum 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. D'Souza AL, Rajkumar C, Cooke J, Bulpitt CJ.
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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. Greenberg EP.
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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., Insti tute of Medicine, Forum on Microbial Threats.
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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. Relman DA, Loutit JS, Schmidt TM, Falkow S, Tompkins LS.
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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. Staskawicz BJ.
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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. Woolhouse M, Dye C
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