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Rapporteurs: David A. Relman, Margaret A. Hamburg, Eileen R. Choffnes, and Alison Mack Forum on Microbial Threats Board on Global Health

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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 contracts between the National Academy of Sciences and the U.S. Department of Health and Human Services: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Centers for Disease Control and Prevention, and Food and Drug Administration; U.S. Department of Defense, Department of the Army: Global Emerging Infections Surveillance and Response System, Medical Research and Materiel Command, and Defense Threat Reduction Agency; U.S. Department of Veterans Affairs; U.S. Department of Homeland Security; U.S. Agency for International Develop- ment; Department of Energy: Lawrence Livermore National Laboratory; American Society for Microbiology; Sanofi Pasteur; Burroughs Wellcome Fund; Pfizer; GlaxoSmithKline; Infectious Diseases Society of America; and the Merck Company Foundation. Any opin- ions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-13121-6 International Standard Book Number-10: 0-309-13121-9 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 2009 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: E. coli is a gram-negative, facultatively anaerobic, rod prokaryote. The strains are undergoing conjugation via a pilus (one strain has fimbriae) under ×3,645 magnification. Bacterial conjugation is the ability to transfer DNA between strains of bacteria (via a pilus). It allows a new mutation to spread through an existing population. It is believed that this process led to the spread of toxin synthesis from Shigella to E. coli (O157:H7). E. coli can cause urinary tract infections, traveler’s diarrhea, nosocomial infections, meningitis, peri- tonitis, mastitis, septicemia, and gram-negative pneumonia. It causes a variety of skin and wound infections such as scalded skin syndrome, scarlet fever, erysipelas, and impetigo. SOURCE: Cover art was provided by Dennis Kunkel Microscopy, Inc. The photo of Joshua Lederberg on the spine is courtesy of The Rockefeller University. Suggested citation: IOM (Institute of Medicine). 2009. Microbial evolution and co- adaptation: a tribute to the life and scientific legacies of Joshua Lederberg. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” — Goethe Advising the Nation. Improving Health.

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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. Charles M. Vest 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 Na- tional 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. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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FORUM ON MICROBIAL THREATS DAVID A. RELMAN (Chair), Stanford University, Palo Alto, California MARGARET A. HAMBURG (Vice Chair), Nuclear Threat Initiative/Global Health & Security Initiative, Washington, DC DAVID W. K. ACHESON, Center for Food Safety and Applied Nutrition, Food and Drug Administration, Rockville, Maryland RUTH L. BERKELMAN, Emory University, Center for Public Health Preparedness and Research, Rollins School of Public Health, Atlanta, Georgia ENRIQUETA C. BOND, Burroughs Wellcome Fund, Research Triangle Park, North Carolina ROGER G. BREEZE, Centaur Science Group, Washington, DC STEVEN J. BRICKNER, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut GAIL H. CASSELL, Eli Lilly & Company, Indianapolis, Indiana BILL COLSTON, Lawrence Livermore National Laboratory, Livermore, California RALPH L. ERICKSON, Global Emerging Infections Surveillance and Response System, Department of Defense, Silver Spring, Maryland MARK B. FEINBERG, Merck Vaccine Division, Merck & Co., West Point, Pennsylvania J. PATRICK FITCH, National Biodefense Analysis and Countermeasures Center, Frederick, Maryland DARRELL R. GALLOWAY, Medical S&T Division, Defense Threat Reduction Agency, Fort Belvoir, Virginia S. ELIZABETH GEORGE, Biological and Chemical Countermeasures Program, Department of Homeland Security, Washington, DC 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 IOM Forums and Roundtables do not issue, review, or approve individual documents. The responsibil- ity for the published workshop summary rests with the workshop rapporteur(s) and the institution. v

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JAMES M. HUGHES, Global Infectious Diseases Program, Emory University, Atlanta, Georgia STEPHEN A. JOHNSTON, Arizona BioDesign Institute, Arizona State University, Tempe GERALD T. KEUSCH, Boston University School of Medicine and Boston University School of Public Health, Massachusetts RIMA F. KHABBAZ, National Center for Preparedness, Detection, and Control of Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia LONNIE J. KING, Center for Zoonotic, Vectorborne, and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia GEORGE W. KORCH, U.S. Army Medical Research Institute for Infectious Diseases, Fort Detrick, Maryland STANLEY M. LEMON, School of Medicine, University of Texas Medical Branch, Galveston EDWARD McSWEEGAN, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 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 JOHN C. POTTAGE, JR., GlaxoSmithKline, Collegeville, Pennsylvania GARY A. ROSELLE, Central Office, Veterans Health Administration, Department of Veterans Affairs, Washington, DC JANET SHOEMAKER, Office of Public Affairs, American Society for Microbiology, Washington, DC P. FREDERICK SPARLING, University of North Carolina, Chapel Hill BRIAN J. STASKAWICZ, Department of Plant and Microbial Biology, University of California, Berkeley TERENCE TAYLOR, International Council for the Life Sciences, Washington, DC MURRAY TROSTLE, U.S. Agency for International Development, Washington, DC Staff EILEEN CHOFFNES, Director KATE SKOCZDOPOLE, Senior Program Associate SARAH BRONKO, Research Associate KENISHA PETERS, Senior Program Assistant ALISON MACK, Science Writer vi

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BOARD ON GLOBAL HEALTH Margaret Hamburg (Chair), Consultant, Nuclear Threat Initiative, Washington, DC George Alleyne, Director Emeritus, Pan American Health Organization, Washington, DC Donald Berwick, Clinical Professor of Pediatrics and Health Care Policy, Harvard Medical School, and President and Chief Executive Officer, Institute of Healthcare Improvement, Boston, Massachusetts Jo Ivey Boufford (IOM Foreign Secretary), President, New York Academy of Medicine, New York David R. Challoner, Vice President for Health Affairs, Emeritus, University of Florida, Gainesville Ciro de Quadros, Albert B. Sabin Vaccine Institute, Washington, DC Sue Goldie, Associate Professor of Health Decision Science, Department of Health Policy and Management, Center for Risk Analysis, Harvard University School of Public Health, Boston, Massachusetts Richard Guerrant, Thomas H. Hunter Professor of International Medicine and Director, Center for Global Health, University of Virginia School of Medicine, Charlottesville Gerald T. Keusch, Assistant Provost for Global Health, Boston University School of Medicine, and Associate Dean for Global Health, Boston University School of Public Health, Massachusetts Jeffrey Koplan, Vice President for Academic Health Affairs, Emory University, Atlanta, Georgia Sheila Leatherman, Research Professor, University of North Carolina School of Public Health, Chapel Hill Michael Merson, Director, Duke Global Health Institute, Duke University, Durham, North Carolina Mark L. Rosenberg, Executive Director, Task Force for Child Survival and Development, Emory University, Decatur, Georgia Philip Russell, Professor Emeritus, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland Staff Patrick Kelley, Director Allison Brantley, Senior Program Assistant IOM boards do not review or approve individual reports and are not asked to endorse conclusions and recommendations. The responsibility for the content of the report rests with the authors and the institution. vii

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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, evi- dence, 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: Martin J. Blaser, New York University School of Medicine Steven J. Brickner, Pfizer Global Research and Development, Pfizer, Inc. James M. Hughes, Hubert Department of Global Health and Rollins School of Public Health, Emory University Although the reviewers listed above have provided many constructive com- ments and suggestions, they were not asked to endorse the final draft of the report before its release. The review of this report was overseen by Dr. Melvin Worth. Appointed by the Institute of Medicine, he 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. ix

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Preface The Forum on Emerging Infections was created by the Institute of Medicine (IOM) in 1996 in response to a request from the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH). The purpose of the Forum is to provide 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; for this reason, it does not provide advice or recommendations on any specific policy initiative pending before any agency or organization. Its value derives instead from the diversity of its membership and from the contributions that individual members make throughout the activities of the Forum. In September 2003, the Forum changed its name to the Forum on Microbial Threats. ABOUT THE WORKSHOP To a great extent, the Forum on Microbial Threats (hereinafter, the Forum) owes its very existence to the life and legacies of the late Dr. Joshua Lederberg. Along with the late Robert Shope and Stanley C. Oaks, Jr., Lederberg orga- nized and co-chaired the 1992 Institute of Medicine study, Emerging Infections: Microbial Threats to Health in the United States. The Emerging Infections report xi

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xii PREFACE helped to define the factors and dynamic relationships that lead to the emergence of infectious diseases. Its recommendations addressed both the recognition of and interventions against emerging infections as well as identified major unmet challenges in responding to infectious disease outbreaks and monitoring the prevalence of endemic diseases. This report ultimately led to the Forum’s creation in 1996. As the first chair of the Forum, 1996-2001, Lederberg was instrumen- tal in establishing it as a venue for the discussion and scrutiny of critical and sometimes contentiousscientific and policy issues of shared concern related to research on and the prevention, detection, and management of infectious diseases and dangerous pathogens. Lederberg’s long shadow may readily be appreciated in the Forum’s 2005 workshop, Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship. Its central theme was derived from a comprehen- sive essay that he published several years earlier in Science entitled “Infectious History.” Under the heading, “Evolving Metaphors of Infection: Teach War No More,” Lederberg argued that “[w]e should think of each host and its parasites as a superorganism with the respective genomes yoked into a chimera of sorts.” Thus began a discussion that developed the concept of the microbiome—a term Lederberg coined to denote the collective genome of an indigenous microbial community—as a forefront of scientific inquiry. Having reviewed the shortcomings and consequences of the war metaphor of infection Lederberg suggested, in the same essay, a “paradigm shift” in the way we collectively identify and think about the microbial world around us, replacing notions of aggression and conflict with a more ecologically—and evolutionarily—informed view of the dynamic relationships among and between microbes, hosts, and their environments. This perspective recognized the par- ticipation of every eukaryotic organism—moreover, every eukaryotic cell—in partnerships with microbes and microbial communities, and acknowledged that microbes and their hosts are ultimately dependent upon one another for survival. It also encouraged the exploration and exploitation of these ecological relation- ships in order to increase agricultural productivity and to improve animal, human, and environmental health. More than a century of research, sparked by the germ theory of disease, underlies our current appreciation of microbe-host-environment interactions. Our “war” on infectious microbes has restricted the spread of several pathogens and drastically reduced the burden of human disease, but the tide of the human conquest shows many signs of turning. Over the past 30 years, 37 new human pathogens have been identified as disease threats, and an estimated 12 percent of known human pathogens have been recognized as either emerging or reemerg- ing.1 Due in large part to the HIV/AIDS pandemic, the number of deaths in the 1 Merell, D. S., and S. Falkow. 2004. Frontal and stealth attack strategies in microbial pathogenesis. Nature 430(6996):250-256.

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xiii PREFACE United States attributable to infection, having fallen steadily since the turn of the century, began to increase in the early 1980s. Infectious diseases continue to cause high morbidity and mortality throughout the world, particularly in develop- ing countries. In 2001, infectious diseases accounted for an estimated 26 percent of deaths worldwide. Clearly, a reconsideration of our interactions with pathogenic microbes is warranted, and it must be based on a better understanding of host-microbe rela- tionships in general. Estimates indicate that 90 to 99 percent of the approximately 1014 cells that comprise a healthy human body belong to the complex microbiota that share our space. Only a small fraction of the roughly several thousand bacte- rial species that inhabit our bodies cause illness; very little is known about the other nonpathogenic bacteria, or even about microbes that in most cases cause chronic, subclinical disease in humans, and that only occasionally produce ill- ness and death. Research into our own microbial ecology and that of our fellow eukaryotes, including plants, appears certain to reveal new strategies for prevent- ing and treating a broad spectrum of infectious disease. Dr. Lederberg’s death on February 2, 2008, marked the departure of a central figure of modern science. It is in his honor that the Forum convened this public workshop on May 20 and 21, 2008, to examine Dr. Lederberg’s scientific and policy contributions to the marketplace of ideas in the life sciences, medicine, and public policy. The agenda for this workshop demonstrates the extent to which conceptual and technological developments have, within a few short years, advanced our collective understanding of microbial genetics, microbial communi- ties, and microbe-host-environment interactions. Through invited presentations and discussions, participants explored a range of topics related to microbial evo- lution and co-adaptation, including methods for characterizing microbial diver- sity; model systems for investigating the ecology of host-microbe interactions and microbial communities at the molecular level; microbial evolution and the emergence of virulence; the phenomenon of antibiotic resistance and opportuni- ties for mitigating its public health impact; and an exploration of current trends in infectious disease emergence as a means to anticipate the appearance of future novel pathogens. As Adel Mahmoud, first co-chair of the Forum observed, “Joshua believed very strongly in the work of this Forum. He had great confidence in the ability of scientists and researchers to continue to solve some of the riddles that still con- front science in the fight against infectious diseases. By remembering him with this tribute, we are also remembering the many things that his life and career can teach all of us. I hope that every time we meet at this Forum, Joshua Lederberg will be an inspiration and a reminder that our work can truly change the world, just as his life and career certainly did.” It is to Josh’s life and living legacies that we dedicate this volume.

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xiv PREFACE ACKNOWLEDGMENTS The Forum on Microbial Threats and the IOM wish to express their grati- tude to the individuals and organizations who, through their participation in this workshop, provided invaluable information and advice to the Forum. A full list of presenters may be found in Appendix A. The Forum is deeply 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 Dr. Eileen Choffnes, director of the Forum; Kate Skoczdopole, senior program associate; Sarah Bronko, research associate; and Kenisha Peters, senior program assistant, for dedicating much effort and time to developing this workshop’s agenda and for their thoughtful and insightful approach and skill in planning for the workshop and in translating the workshop’s proceedings and discussion into this workshop summary. We would also like to thank the following IOM staff and consultants for their valuable contributions to this activity: Alison Mack, Bronwyn Schrecker Jamrok, Jackie Turner, Michael Hayes, and Florence Poillon. Finally, the Forum wishes to recognize the sponsors that supported this activity: U.S. Department of Health and Human Services: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Centers for Disease Control and Prevention, and Food and Drug Administration; U.S. Department of Defense: Global Emerging Infections Surveillance and Response System, Walter Reed Army Institute of Research, U.S. Army Medical and Materiel Command, and the Defense Threat Reduction Agency; U.S. Department of Veterans Affairs; U.S. Department of Homeland Security; U.S. Agency for International Develop- ment; U.S. Department of Energy: Lawrence Livermore National Laboratory; American Society for Microbiology; Sanofi Pasteur; Burroughs Wellcome Fund; Pfizer; GlaxoSmithKline; Infectious Diseases Society of America; and the Merck Company Foundation. David A. Relman, Chair Margaret A. Hamburg, Vice Chair Forum on Microbial Threats

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Contents Workshop Overview 1 Appendix WO-1 Infectious History, 53 Joshua Lederberg, Ph.D. Workshop Overview References, 71 1 The Life and Legacies of Joshua Lederberg 76 Overview, 76 Reflections on the Career of Joshua Lederberg, 77 David A. Hamburg, M.D. Joshua Lederberg Remembered, 80 Stephen S. Morse, Ph.D. The Life and Impact of a Legend—Joshua Lederberg, 88 Adel Mahmoud, M.D., Ph.D. References, 94 2 Microbial Ecology and Ecosystems 95 Overview, 95 War and Peace: Humans and Their Microbiome, 101 David A. Relman, M.D. Deciphering the Complex Molecular Dialogue of Symbiosis: Esperanto or Polyglot?, 110 Margaret McFall-Ngai, Ph.D. References, 118 xv

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xvi CONTENTS 3 Pathogen Evolution 121 Overview, 121 Bacterial Pathogenicity: An Historical and Experimental Perspective, 126 Stanley Falkow, Ph.D. Evolution of Bacterial-Host Interactions: Virulence and the Immune Overresponse, 137 Elisa Margolis and Bruce R. Levin, Ph.D. References, 152 4 Antibiotic Resistance: Origins and Countermeasures 158 Overview, 158 Antibiotic Resistance and the Future of Antibiotics, 160 Julian Davies, Ph.D. Microbial Drug Resistance: An Old Problem in Need of New Solutions, 173 Stanley N. Cohen, M.D. Expanding the Microbial Universe: Metagenomics and Microbial Community Dynamics, 180 Jo Handelsman, Ph.D. References, 188 5 Infectious Disease Emergence: Past, Present, and Future 193 Overview, 193 Emerging Infections: Condemned to Repeat?, 195 Stephen S. Morse, Ph.D. Ecological Origins of Novel Human Pathogens, 208 Mark Woolhouse, Ph.D., and Eleanor Gaunt, B.Sc. Genomic Evolvability and the Origin of Novelty: Studying the Past, Interpreting the Present, and Predicting the Future, 230 Jonathan A. Eisen, Ph.D. Can We Predict Future Trends in Disease Emergence?, 252 Peter Daszak, Ph.D. References, 266 Appendixes A Agenda 273 B Acronyms 277 C Glossary 280 D Forum Member Biographies 287

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Tables, Figures, and Boxes TABLES WO-1 An Infectious Disease Timeline, 58 3-1 Some Examples of Virulence Resulting from an Immune Overresponse, 142 4-1 Reports on Antibiotic Resistance Genes Isolated from the Environment, 163 4-2 Mechanisms of Resistance, 2008, 164 4-3 Phylogeny of Cultured and Uncultured Bacteria from Third Instar Gypsy Moth Midguts Feeding on an Artificial Diet, 183 5-1 New Opportunities for Pathogens: Ecological Changes, 200 5-2 Numbers of Pathogen Species by Taxonomic Category, 212 5-3 Dates of First Reports of Human Infection with Novel Pathogen Species, 213 5-4 List of Human Pathogens Which Have Successfully Crossed the Species Barrier and Proved Capable of Epidemic Spread and, in Some Cases, Endemic Persistence in Human Populations, 225 5-5 BLAST Search Results as They Were Seen in 1997 Using the MutS-like Protein from Helicobacter pylori as a Query, 234 xvii

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xviii TABLES, FIGURES, AND BOXES FIGURES WO-1 Newly emerging, reemerging or resurging, and deliberately emerging diseases, 12 WO-2 Temporal profiles of the most abundant level 3 taxonomic groups, 20 WO-3 Six genotypes of Leptospirillum group II bacteria were detected in the Richmond Mine (Iron Mountain, CA), 24 WO-4 Virus-host associations in AMD biofilms, 25 WO-5 The symbiotic continuum, 26 WO-6 Symbiotic relationship between plants and bacteria, 27 WO-7 The “winnowing,” 29 WO-8 Comparison of pathogenesis of infection associated with Salmonella typhimurium versus S. typhi (human restricted), 35 WO-9 The relationship between antibiotic resistance development in Shigella dysentery isolates in Japan and the introduction of antimicrobial therapy between 1950 and 1965, 38 WO-10 Deaths resulting from infectious diseases decreased markedly in the United States during most of the twentieth century, 42 WO-11 Global examples of emerging and reemerging infectious diseases, 43 WO-12 The convergence model, 45 WO-13 While known human pathogens are dominated by bacterial species, the vast majority of novel pathogen species are viruses, 47 WO-14 Global distribution of relative risk of an EID event, 50 WO-15 Longer life, 57 2-1 Domain Bacteria, 103 2-2 Bacterial diversity in human colonic tissue and stool, 104 2-3 Site-specific distributions of bacterial phyla in healthy humans, 105 2-4 Representations of bacterial diversity, 106 2-5 Individualized responses to the same antibiotic, 108 2-6 The squid-vibrio association, 114 2-7 The series of events that characterize the trajectory of the symbiosis, 115 2-8 Some symbiosis characteristics shared among the mouse, zebrafish, and squid, 116 2-9 The language of symbiosis, 117 3-1 Pathogenic bacteria interfere with or manipulate for their own benefit the normal function(s) of the host cell, 128 3-2 Salmonella infection, 129 3-3 Microarray-based negative selection strategy, 130 3-4 Time-dependent selection of persistence genes, 131

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xix TABLES, FIGURES, AND BOXES 3-5 Response to Salmonella infection, 133 3-6 Response to Salmonella infection in 129sv mice following immunization, 134 3-7 The decline of many infectious diseases in industrialized countries (A) has been accompanied by an increase in immune disorders (B), United States, 1950 to 2000, 136 3-8 The artist’s conception of the infection process and the host’s immune response and overresponse, 139 4-1 Major classes of antimicrobials and the year of their discovery, 161 4-2 Integron mechanism of gene capture, 165 4-3 Concentration dependence of transcription modulation by antibiotics, 167 4-4 The road to anthrax toxicity, 176 4-5 Diagrammatic representation of the site of chromosomal insertion of a lentiviral GSV, 177 4-6 Detection of quorum-sensing activity and signal exchange in the guts of cabbage white butterfly larvae, 184 4-7 Mortality of cabbage white butterfly larvae fed P. aeruginosa strains and the quorum-sensing analog indole inhibitor, 185 4-8 Gypsy moth larvae reared on antibiotics are not susceptible to Bt, 186 4-9 Restoration of B. thuringiensis toxicity by an Enterobacter spp. after elimination of the detectable gut flora and B. thuringiensis activity by antibiotics, 187 5-1 Leading causes of death in young adults, United States, 1987-2005, 197 5-2 Global examples of emerging and reemerging infectious diseases, 199 5-3 A deer mouse (Peromyscus maniculatus), natural host for the Sin Nombre (Hantavirus pulmonary syndrome) virus, with her young, 202 5-4 Hantaviruses of the Americas, 203 5-5 Influenza pandemic 1918 at Camp Funston, Kansas, 205 5-6 World map indicating points of origin of the first reported human cases of disease caused by 51 novel pathogen species since 1980, 214 5-7 Counts of recently discovered human pathogens species associated with various categories of non-human animal reservoirs, 217 5-8 The pathogen pyramid, 219

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xx TABLES, FIGURES, AND BOXES 5-9 Analysis of Andes virus outbreaks, 223 5-10 Phylogenetic prediction of gene function, 236 5-11 Phylogenetic tree of methyl-accepting chemotactic protein (MCP) homologs in completed genomes, 240 5-12 Phylogenetic profile analysis of sporulation in Carboxydothermus hydrogenoformans, 243 5-13 There is significant variation in the rate of evolution among endosymbionts, with the highest rates tending to be found in those that lack homologs of mismatch repair genes, 245 5-14 Phylogenetic trees of putative proteins encoded by single sequence reads of DNA isolated from symbiont-containing tissue of the glassy- winged sharpshooter, 249 5-15 The diversity of Bacterial and Archaeal species for which complete genomes are available is still poor, 250 5-16 The rate of globalization has accelerated to the point where we are connected as never before via globalized travel and trade networks, 254 5-17 Economic impacts of selected emerging infectious diseases, 255 5-18 WNV is most likely to be spread by airplane, 256 5-19 Predicted risk of H5N1 avian influenza introduction from countries that have had H5N1 outbreaks, 258 5-20 Species chain for Nipah virus in Malaysia, 260 5-21 Global richness map of the geographic origins of EID events from 1940 to 2004, 262 5-22 Global distribution of the relative risk of an EID event, 265 BOxES WO-1 Joshua Lederberg: An Extraordinary Life, 4 WO-2 Host-Restriction Versus Virulence in Bordetella spp., 36 WO-3 Factors in Emergence, 44 WO-4 The Microbial World Wide Web, 69 1-1 Traits That Could Be the Foundation of Selection in Unfamiliar Genomic Settings, 92