ENDING THE WAR METAPHOR

The Changing Agenda for Unraveling the Host-Microbe Relationship

Workshop Summary

Forum on Microbial Threats

Board on Global Health

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu



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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary ENDING THE WAR METAPHOR The Changing Agenda for Unraveling the Host-Microbe Relationship Workshop Summary Forum on Microbial Threats Board on Global Health INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. This project was supported by the American Society for Microbiology; Burroughs Wellcome Fund; Defense Threat Reduction Agency; GlaxoSmithKline; Infectious Disease Society of America; Lawrence Livermore National Laboratory; Merck; Pfizer; Sanofi Pasteur; U.S. Department of Health and Human Services’ National Institutes of Health/National Institute for Allergies and Infectious Disease and Centers for Disease Control and Prevention; U.S. Department of Defense/Global Emerging Infections Surveillance/Walter Reed Army Institute of Research; U.S. Department of Homeland Security; U.S. Department of State; and U.S. Department of Veterans Affairs. The views presented in this report are those of the editors and attributed authors and are not necessarily those of the funding agencies. This report is based on the proceedings of a workshop that was sponsored by the Forum on Microbial Threats. It is prepared in the form of a workshop summary by and in the name of the editors, with the assistance of staff and consultants, as an individually authored document. Sections of the workshop summary not specifically attributed to an individual reflect the views of the editors and not those of the Forum on Microbial Threats. The content of those sections is based on the presentations and the discussions that took place during the workshop. Library of Congress Cataloging-in-Publication Data Ending the war metaphor : the changing agenda for unraveling the host-microbe relationship : workshop summary / Forum on Microbial Threats, Board on Global Health. p. ; cm. Includes bibliographical references. ISBN 0-309-09601-4 (pbk.) 1. Host-parasite relationships—Congresses. 2. Communicable diseases—Transmission—Congresses. 3. Microbiology—Congresses. I. Institute of Medicine (U.S.). Forum on Microbial Threats. [DNLM: 1. Host-Parasite Relations—Congresses. 2. Communicable Diseases, Emerging—microbiology—Congresses. 3. Communicable Diseases, Emerging—prevention & control—Congresses. 4. Drug Resistance, Microbial—Congresses. QX 45 E56 2006] RB153.E53 2006 616.9′041—dc22 2006012949 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2006 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. COVER: A detailed section of a stained glass window 21 × 56″ depicting the natural history of influenza viruses and zoonotic exchange in the emergence of new strains was used to design the front cover. Based on the work done at St. Jude Children’s Research Hospital supported by American Lebanese Syrian Associated Charities (ALSAC) and the National Institute of Allergy and Infectious Diseases (NIAID). Artist: Jenny Hammond, Highgreenleycleugh, Northumberland, England.

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Advising the Nation. Improving Health.

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary FORUM ON MICROBIAL THREATS Stanley M. Lemon (Chair), School of Medicine, University of Texas Medical Branch, Galveston P. Frederick Sparling (Vice-chair), University of North Carolina, Chapel Hill Margaret A. Hamburg (Vice-chair), Nuclear Threat Initiative/Global Health & Security Initiative, Washington, D.C. David Acheson, Center for Food Safety and Applied Nutrition, Food and Drug Administration, Rockville, Maryland Ruth Berkelman, Emory University, Center for Public Health Preparedness and Research, Rollins School of Public Health, Atlanta, Georgia Roger Breeze, Centaur Science Group, Washington, D.C. Steven J. Brickner, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut Joseph Bryan, Office of Medical Services, Department of State, Washington, D.C. Nancy Carter-Foster, Program for Emerging Infections and HIV/AIDS, U.S. Department of State, Washington, D.C. Mark Feinberg, Merck Vaccine Division, Merck & Co., West Point, Pennsylvania J. Patrick Fitch, Lawrence Livermore National Laboratory, Livermore, California S. Elizabeth George, Biological and Chemical Countermeasures Program, Department of Homeland Security, Washington, D.C. Jesse L. Goodman, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland Eduardo Gotuzzo, Instituto de Medicina Tropical–Alexander von Humbolt, Universidad Peruana Cayetano Heredia, Lima, Peru Jo Handelsman, College of Agricultural and Life Sciences, University of Wisconsin, Madison Carole A. Heilman, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland David L. Heymann, Polio Eradication, World Health Organization, Geneva, Switzerland Phil Hosbach, New Products and Immunization Policy, Sanofi Pasteur, Swiftwater, Pennsylvania James M. Hughes, Global Infectious Diseases Program, Emory University, Atlanta, Georgia Stephen Johnston, University of Texas Southwestern Medical Center, Dallas Gerald T. Keusch, Boston University School of Medicine and Boston University School of Public Health, Massachusetts Lonnie King, College of Veterinary Medicine, Michigan State University, East Lansing

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary George Korch, United States Army Medical Research Institute for Infectious Diseases, Ft. Detrick, Maryland Joshua Lederberg, The Rockefeller University, New York Joseph Malone, Department of Defense Global Emerging Infections System, Walter Reed Army Institute of Research, Silver Spring, Maryland Lynn Marks, Medicine Development Center, GlaxoSmithKline, Collegeville, Pennsylvania Stephen S. Morse, Center for Public Health Preparedness, Columbia University, New York Michael T. Osterholm, Center for Infectious Disease Research and Policy, School of Public Health, University of Minnesota, Minneapolis George Poste, Arizona BioDesign Institute, Arizona State University, Tempe David A. Relman, Stanford University, Palo Alto, California Gary A. Roselle, Central Office, Veterans Health Administration, Department of Veterans Affairs, Washington, D.C. Anne Schuchat, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Janet Shoemaker, Office of Public Affairs, American Society for Microbiology, Washington, D.C. Brian Staskawicz, Department of Plant and Microbial Biology, University of California, Berkeley Terence Taylor, International Institute for Strategic Studies, Washington, D.C. Liaisons Enriqueta Bond, Burroughs Wellcome Fund, Research Triangle Park, North Carolina Nancy Carter-Foster, Program for Emerging Infections and HIV/AIDS, U.S. Department of State, Washington, D.C. Edward McSweegan, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland Staff Eileen Choffnes, Forum Director Stacey Knobler, Former Forum Director* Elizabeth Kitchens, Research Associate** Kim Lundberg, Research Associate Allison Mack, Science Writer Muhammad Salaam, Project Assistant Kate Skoczdopole, Research Associate *   Until December 2004 **   Until March 2005

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: John Bailar, University of Chicago, Illinois Ruth Berkelman, Center for Public Health Preparedness and Research, Rollings School of Public Health, Emory University, Atlanta, Georgia Lora Hooper, Center for Immunology, University of Texas Southwestern Medical Center, Dallas Stephen S. Morse, Center for Public Health Preparedness, School of Public Health, Columbia University, New York The review of this report was overseen by Melvin Worth, Scholar-in-Residence, National Academies, who was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Preface The Forum on Emerging Infections was created in 1996 in response to a request from the Centers for Disease Control and Prevention and the National Institutes of Health. It was established by the Institute of Medicine (IOM) to provide structured opportunities for leaders from government, academia, and industry to meet and examine issues of shared concern regarding research, prevention, detection, and management of emerging or reemerging infectious diseases. In pursuing this task, the Forum provides a venue to foster the exchange of information and ideas, identify areas in need of greater attention, clarify policy issues by enhancing knowledge and identifying points of agreement, and inform decision makers about science and policy issues. The Forum seeks to illuminate issues rather than resolve them directly; for this reason, it does not provide advice or recommendations on any specific policy initiative pending before any agency or organization. Rather, its strengths are embodied in the diversity of its membership and the contributions of individual members expressed throughout the activities of the Forum. In September 2003, the Forum changed its name to the Forum on Microbial Threats. ABOUT THE WORKSHOP In the mid-1970s, the U.S. Surgeon General claimed that infectious diseases had been conquered through the development and use of antibiotics and vaccines and that therefore it was time to shift the U.S. government’s attention and resources to the “War on Cancer.” The ensuing years have brought us Legionnaire’s disease, toxic shock syndrome, an awareness of Lyme disease, outbreaks of

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary hantavirus throughout the southwestern United States, SARS, and of course, HIV. The discovery that infection with Helicobacter pylori is associated with peptic ulcer and gastric cancer has led to an increasing search for the infectious nature of other “noninfectious” diseases such as atherosclerosis. Infectious diseases remain the leading causes of death and morbidity on our planet. For these reasons, the IOM’s Forum on Microbial Threats hosted a public workshop: “Ending the War Metaphor: The Future Agenda for Unraveling the Host-Microbe Relationship.” Through invited presentations and discussion, this workshop aimed to inform the Forum, the public, and policymakers of the dynamic host-microbe-environment relationships and to explore the issues that must be resolved to better prepare and protect the global community from infectious disease threats. Resistance in microbes—bacterial, viral, or protozoan—to therapeutics is not surprising or new. It is, however, an increasing challenge as drug resistance accumulates and accelerates, even as the drugs for combating infections are reduced in power and number. Today some strains of bacterial and viral infections are treatable with only a single drug, some no longer have effective treatments. The disease burden from multidrug-resistant strains of tuberculosis, malaria, hepatitis, and HIV is growing in both developed and developing countries. The challenges of resistance are compounded by growing concerns about the possible use of biological weapons leading to large-scale disease outbreak or exposure. The ability to respond effectively to such exposures could be significantly compromised by the introduction of drug-resistant pathogens. The use of prophylactic drugs or therapies on large populations may also contribute to the development of drug resistance and thus increase both the immediate and longer-term challenges of treating infectious diseases. With such evidence of a dwindling armamentarium to wage our wars against infectious diseases, it has been suggested that a paradigm shift is warranted in how we address the threats posed by pathogens. In an attempt for the Forum to understand how such a new lens might be devised through which the challenges of disease should be viewed, the presentations and discussions of the workshop were structured to explore the existing knowledge and unanswered questions indicated by (but not limited to) the following topics: host-pathogen interactions: defining the concepts of pathogenicity, virulence, colonization, commensalism, and symbiosis; the ecology of host-microbe interactions; understanding the dynamic relationships of host-microbe interactions; novel approaches for mitigating or minimizing the development of antimicrobial resistance; and challenges and opportunities for developing a new paradigm to replace the “war metaphor” of the host-microbial relationship.

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary The issues pertaining to these topical areas were addressed through invited presentations and subsequent discussions that highlighted the complexity and incompleteness of our appreciation of the dynamic interplay between a host and its associated microbial flora and fauna, and identified areas for research collaborations within and between the clinical medicine, veterinary medicine, and plant pathology communities. ACKNOWLEDGMENTS The Forum on Microbial Threats and the IOM wish to express their warmest appreciation to the individuals and organizations who gave valuable time to provide information and advice to the Forum through their participation in the workshop. A full list of presenters can be found in Appendix A. The Forum is indebted to the IOM staff who contributed during the course of the workshop and the production of this workshop summary. On behalf of the Forum, we gratefully acknowledge the efforts led by Eileen Choffnes, director of the Forum, Kim Lundberg, research associate, and Kate Skoczdopole, research associate, who dedicated much effort and time to developing this workshop’s agenda, and for their thoughtful and insightful approach and skill in translating the workshop proceedings and discussion into this workshop summary. We would also like to thank our science writer, Alison Mack, for her thoughtful and insightful approach and skill in translating the workshop proceedings and discussion into this workshop summary. Finally, the Forum also thanks sponsors that supported this activity. Financial support for this project was provided by the American Society for Microbiology; Burroughs Wellcome Fund; Defense Threat Reduction Agency; GlaxoSmithKline; Infectious Disease Society of America; Lawrence Livermore National Laboratory; Merck; Pfizer; Sanofi Pasteur; U.S. Department of Health and Human Services’ National Institutes of Health/National Institute for Allergies and Infectious Disease and Centers for Disease Control and Prevention; U.S. Department of Defense/Global Emerging Infections Surveillance/Walter Reed Army Institute of Research; U.S. Department of Homeland Security; U.S. Department of State; and U.S. Department of Veterans Affairs. The views presented in this workshop summary are those of the editors and workshop participants and are not necessarily those of the funding organizations. Stanley M. Lemon, Chair P. Frederick Sparling, Vice-chair Margaret Hamburg, Vice-chair Forum on Microbial Threats

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Contents     SUMMARY AND ASSESSMENT   1 1   MICROBIAL COMMUNITIES OF THE GUT   35      The Role of the Indigenous Microbiota in Zebrafish Gastrointestinal Tract Development, Karen Guillemin   36      Host-Bacterial Mutualism in the Human Intestine, Fredrik Bäckhed, Ruth E. Ley, Justin L. Sonnenburg, Daniel A. Peterson, Jeffrey I. Gordon   41      Activities of Human Colonic Microbes, Abigail A. Salyers   52 2   BEYOND THE GUT: INSIGHTS FROM OTHER HOST-MICROBE SYSTEMS   80      It Takes a Village: Role of Indigenous Microbial Communities in Infectious Disease, Christina Matta and Jo Handelsman   81      The Molecular Basis of Bacterial Innate Immunity in Arabidopsis thaliana, Brian Staskawicz   91 3   THE ECOLOGY OF PATHOGENESIS   102      The Zen of Pathogenicity, Stanley Falkow   103

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary      Pathogenicity and Symbiosis: Human Gastric Colonization by Helicobacter pylori as a Model System of Amphibiosis, Martin J. Blaser   115      Induction of Pathogenic Immune Responses in Susceptible Hosts by Commensal Enteric Bacteria, R. Balfour Sartor   131      How Do Changes in Microecology Affect the Human Host?, María G. Domínguez-Bello   140 4   THE HOST RESPONSE TO PATHOGENS   159      The Intestinal Epithelium: An Interactive Barrier Between Host and Microbe, Marian Neutra   160      How the Host “Sees” and Responds to Pathogens, David A. Relman   167 5   ADDRESSING COMPLEXITY IN MICROBIAL AND HOST COMMUNITIES   175      DNA Microarrays as Salivary Diagnostic Tools for Characterizing the Oral Cavity’s Microbial Community, Laura M. Smoot, James C. Smoot, Hauke Smidt, Peter A. Noble, Martin Könneke, Z.A. McMurry, and David A. Stahl   176      Population Biology of Multiple Hosts and Multiple Pathogens, Mark E.J. Woolhouse and Sonya Gowtage-Sequeira   185      Host Range and Emerging and Reemerging Pathogens, Mark E.J. Woolhouse and Sonya Gowtage-Sequeira   192 6   MANIPULATING HOST-MICROBE INTERACTIONS: PROBIOTIC RESEARCH AND REGULATIONS   207      Molecular Analysis of Probiotic-Host Interactions in the Gastrointestinal Tract, Michiel Kleerebezem   209      Role of Probiotics in Modulation of Host Immune Response, Susanna Cunningham-Rundles, Siv Ahrne, John Peoples, Francesca Tatad, Mohamed Mohamed, and Mirjana Nesin   220      Regulating Pre- and Probiotics: A U.S. FDA Perspective, Julienne Vaillancourt   229      From Research in Microbiology to Guidelines, Lorenzo Morelli and Elena Bessi   237

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary     APPENDIXES     A   AGENDA   261 B   ACRONYMS   265 C   FORUM MEMBER BIOGRAPHIES   268

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Tables and Figures TABLES 1-1   Comparison of the Glycoside Hydrolase and Polysaccharide Lyases in the Human, Mouse, and B thetaiotaomicron Genomes,   63 1-2   Effects of the Microbiota on Host Biology, Defined by Comparing Germ-Free (GF) and Conventionally-Raised (CONV-R) Rodents,   69 1-3   Six Ways Environmental Engineers Improve Bioreactor Efficiency,   73 3-1   Genes Associated with IBD and Experimental Colitis,   138 5-1   Counts of All, Emerging or Reemerging and Zoonotic Species of Human Pathogens and Comparison of the Relative Risks of Emergence for Zoonotic and Nonzoonotic Species for Each of the Major Pathogen Groups,   186 5-2   Main Categories of Drivers Associated with Emergence and Reemergence of Human Pathogens,   194 6-1   Overview of Genome Sequences of Food-Grade Bacteria,   213 6-2   Functional Classification of Predicted ivi Gene Functions in L. plantarum and Pathogenic Bacteria,   216 6-3   Lactobacillus Species Recovered and Genetically Identified from Biopsies of Seven Adults,   242 6-4   Host Specificity of the Lactobacillus Species,   244

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary FIGURES S-1   The Convergence Model,   5 1-1   Important events in zebrafish development,   37 1-2   Representation of the diversity of bacteria in the human intestine,   44 1-3   Taxon richness estimates for bacteria in the human GI tract,   46 1-4   Lessons about adaptive foraging for glycans obtained from B. thetaiotaomicron,   48 1-5   The flow of contents through the small intestine and colon,   54 1-6   Flow of antibiotic resistance genes (hypothetical),   60 2-1   Ferdinand Julius Cohn (1828–1898), Heinrich Anton De Bary (1832–1888), and Robert Koch (1843–1910),   83 2-2   Schematic depiction of the first strategies to select in vivo for promoters that are induced by plant (left panel) or animal (right panel) hosts,   86 2-3   A rice plant (left) and Arabidopsis thaliana (right), a model plant for host-pathogen interactions,   92 2-4   Phenotypes of bacterial disease resistance,   95 2-5   Arabidopsis disease resistance genes,   96 2-6   Representative protein motifs found in immune receptors of plants and animals,   97 2-7   Model for RPS2-mediated innate immunity,   98 2-8   Model of RPS2-mediated immunity in Arabidopsis,   99 3-1   Host macrophage engulfing the plague bacillus (Yersinia pestis),   104 3-2   Infectious diseases were, and still are, the most common cause of death worldwide,   105 3-3   Illustration of the old rhyme (based on a poem by Jonathan Swift, author of Gulliver’s Travels), “Big fleas have little fleas upon their backs to bite them, and little fleas have lesser fleas and, so on, ad infinitum.”,   114 3-4   Modern and ancient H. pylori populations,   116 3-5   Who are we?,   118 3-6   Schematic of the natural history of H. pylori populations and host characteristics in colonized individuals over their lifetime,   119 3-7   Equilibrium relationships between coevolved persistent microbes and their hosts,   120 3-8   Prevalence of H. pylori in human populations in developing and developed countries,   121 3-9   Potential pathways by which H. pylori colonization increases risk of gastric cancer,   125

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary 3-10   Proposed reciprocal relationship between adenocarcinomas of the stomach and esophagus,   127 3-11   Schematic of H. pylori variation in a single host,   130 3-12   Induction of homeostatic or pathogenic immune responses by commensal bacteria,   132 3-13   Immune activation and chronic intestinal inflammation depends on the presence of commensal luminal bacteria in multiple animal models,   134 3-14   Interaction of genetic, environmental, and microbial factors in the pathogenesis of IBD,   136 3-15   Fate of dietary products in the rumen, providing microbial products and biomass for the nutrition of the host,   142 3-16   Model of modulation of adaptive and innate immunity by indigenous bacteria, showing the unknown effect of other microbes on mucosal immunity,   144 3-17   Evolution of human societies and their diseases,   146 3-18   Host-microbial interactions shape health and disease,   147 4-1   The follicle-associated epithelium and MALT: a close collaboration,   161 4-2   Reovirus has access to carbohydrate receptors on M cells,   163 4-3   The “backpack” hybridoma tumor protocol,   165 4-4   Variation in gene expression in health and disease,   171 5-1   Phylogenetic tree generated from small subunit rRNA sequences of oral microorganisms,   178 5-2   Description of the MAGIChip DNA oligonucleotide microarray technology used in the Stahl Laboratory,   182 5-3   Numbers of species of zoonotic pathogens associated with different types of nonhuman host,   197 5-4   Relationship between breadth of host range and the fraction of pathogen species regarded as emerging or reemerging,   198 5-5   Expected relationship between outbreak size and two key epidemiologic parameters,   201 6-1   Schematic representation of pure culture genomics in relation to GI tract behavior, and corresponding molecular analyses of host responses,   212 6-2   Response of CD8+ naive (CD45RA+) and CD8+ memory (CD45 RO+) cord blood T cells to bacterial antigens,   226 6-3   Intracellular cytokine response of cord blood monocytes from term infants to bacterial antigens,   227

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary 6-4   Differential response of T cells (CD3+) and natural killer (NK) subpopulations defined as NK (CD3−CD56+), NK bright (CD3−CD56+bright), and NKT (CD56+CD3+) lymphocytes from HIV-positive children to bacterial antigens,   228 6-5   Stages of premarket review and regulation for live biotherapeutics,   235 6-6   Guidelines for the evaluation of probiotics for food use,   249

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