Legionella pneumophila: Pathogenesis and Immunity

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2 Legionella pneumophila: Pathogenesis and Immunity

3 INFECTIOUS DISEASES AND PATHOGENESIS Series Editors: Mauro Bendinelli, University of Pisa Herman Friedman, University of South Florida College of Medicine Recent volumes in this series: IN VIVO MODELS OF HIV DISEASE AND CONTROL Edited by Herman Friedman, Steven Specter, and Mauro Bendinelli INFECTIOUS DISEASES AND SUBSTANCE ABUSE Edited by Herman Friedman, Catherine Newton, and Thomas W. Klein CHLAMYDIA PNEUMONIAE INFECTION AND DISEASE Infection and Disease Edited by Herman Friedman, Yoshimasa Yamamoto, and Mauro Bendinelli DNA TUMOR VIRUSES Oncogenic Mechanisms Edited by Giuseppe Barbanti-Brodano, Mauro Bendinelli, and Herman Friedman ENTERIC INFECTIONS AND IMMUNITY Edited by Lois J. Paradise, Mauro Bendinelli, and Herman Friedman HELICOBACTER PYLORI INFECTION AND IMMUNITY Edited by Yoshimasa Yamamoto, Herman Friedman, and Paul S. Hoffman HERPESVIRUSES AND IMMUNITY Edited by Peter G. Medveczky, Herman Friedman, and Mauro Bendinelli HUMAN RETROVIRAL INFECTIONS Immunological and Therapeutic Control Edited by Kenneth E. Ugen, Mauro Bendinelli, and Herman Friedman MICROORGANISMS AND AUTOIMMUNE DISEASES Edited by Herman Friedman, Noel R. Rose, and Mauro Bendinelli LEGIONELLA PNEUMOPHILA: PATHOGENESIS AND IMMUNITY Edited by Paul Hoffman, Herman Friedman, and Mauro Bendinelli A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information, please contact the publisher.

4 Legionella pneumophila: Pathogenesis and Immunity Paul Hoffman Department of Microbiology Medicine, Division of Infectious Diseases and International Health, UVA Health System, University of Virginia, Charlottesville, VA, USA Herman Friedman College of Medicine, University of South Florida, Tampa, FL, USA Mauro Bendinelli University of Pisa, Italy

5 Paul Hoffman University of Virginia, Charlottesville, VA, USA Herman Friedman University of South Florida, Tampa, FL, USA Mauro Bendinelli University of Pisa, Pisa Italy ISBN-13: e-isbn-13: Library of Congress Control Number: Springer Science Business Media, LLC All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Printed on acid-free paper springer.com

6 Dedication We dedicate this book to the memory of Dr. Herman Friedman, editor and friend, who passed away on August 25, As scholar, scientist and teacher, he contributed broadly to the disciplines of medical microbiology and immunology, but he will be best remembered for his books, mentorship of young scientists and for his seminal contributions to our knowledge of the immunobiology of Legionnaires disease.

7 Contents Preface and Introduction xiii Contributors xvii 1. Legionella pneumophila Pathogenesis: Lessons Learned from Genomics CHRISTEL CAZALET and CARMEN BUCHRIESER 1. Genomics of Legionella pneumophila General Features and Organization of the L. pneumophila Genomes Host Pathogen Interaction Specific Features of the L. pneumophila Genomes Eukaryotic-Like Proteins Putative Virulence Factors as Deduced Prom Sequence Analysis Secretion Machineries Presence of Particular Many and a Wide Variety Metabolism as Deduced from the Genome Sequence Clues to Adaptation Regulation and Signal Transduction Comparative Genomics of Legionella pneumophila The Specific Gene Complements of L. pneumophila Paris, Lens and Philadelphia Genomic and Pathogenicity Islands Plasmids of Legionella Variability at the Gene Level Comparative Genomics Legionella, Coxiella and Other Intracellular Pathogens Genome Comparison of Legionella pneumophila and Coxiella burnetii Genome Redundancy Gene Family Expansion in Legionella Comparative Genomics of Legionella pneumophila and the Genus Legionella a Perspective References vii

8 viii Contents 2. Iron Assimilation and Type II Protein Secretion NICHOLAS P. CIANCIOTTO 1. Iron Assimilation The Importance of Iron for Legionella pneumophila Legionella Siderophores Ferrous Iron Transport The L. pneumophila Iron Acquisition/Assimilation Locus Cytochrome C Maturation and Iron Assimilation Legionella Ferric Reductases Concluding Remarks Type II Protein Secretion Type II Protein Secretion in Gram-Negative Bacteria Discovery of Type II Secretion in Legionella pneumophila Factors Secreted by the Type II System of L. pneumophila Role of Type II Secretion in Pathogenesis Role of Type II Secretion in Environmental Survival Concluding Comments References The Dot/Icm Type IVB Secretion System JASON J. LEBLANC and JOSEPH P. VOGEL 1. Introduction Dot/Icm Type IV Secretion System Structural Components Adaptor/Chaperone Complexes Regulation of Effector Export Genetic Regulation of the Dot/Icm System Possible Effector Proteins and Associated Functions RalF The Sid Family LidA and SidM LepA and LepB Ylf and the Vips Temporal Modulation of the LCV Surface Conclusion References Life Cycle, Growth Cycles and Developmental Cycle of Legionella pneumophila RAFAEL A. GARDUÑO 1. Introduction The Life Cycle of L. pneumophila as Currently Understood Attachment and Invasion

9 Contents ix 2.2. Post-Internalization Events and Intracellular Growth End of Replication and Exit What Role Do Ciliates Play in the Life Cycle of L. pneumophila? The Growth Cycles of L. pneumophila The Developmental Cycle of L. pneumophila Legionella pneumophila Development Along the Extracellular Growth Cycle MIF: The Result of L. pneumophila Intracellular Differentiation The Central Role of MIFs in the Study of L. pneumophila Virulence Concluding Remarks References Legionella in the Environment BARRY S. FIELDS 1. Introduction The Distribution of Legionella as a Function of Various Detection Methods Natural Environments Man-Made Environments Interaction with Other Organisms Association with Biofilms References Regulation of the Legionella pneumophila Life Cycle RACHEL L. EDWARDS and MICHELE S. SWANSON 1 Introduction Life Cycle of L. pneumophila Broth Model Amino Acid Availability Governs Differentiation Pht Family of Transporters Stringent Response Evidence that Other Factors Trigger Differentiation Acetyl-phosphate Transcriptional Control of Differentiation via Sigma Factors RpoS RpoN and FleQ FliA Post-Transcriptional Control of Differentiation LetA/LetS Two-Component System Carbon Storage Regulatory (Csr) System Hfq and Small RNAs (srnas)

10 x Contents 8. Regulation of the Dot/Icm Type IV Secretion System Genomic Methods of Studying Differentiation References Microbial Physiology PAUL S. HOFFMAN 1. Introduction Intracellular Growth Morphology, Ultrastructure, and Surface Proteins Envelope Structure and Lipopolysaccharide (LPS) Outer Membrane Proteins Secreted Proteins Motility and Chemotaxis Respiratory Metabolism Central Intermediary Metabolism Biosynthetic Capacity and Amino Acid Auxotrophies Protection from Oxidative Stress Heat Shock Response Stationary Phase Genes and Cell Wall Assembly Conclusions References Legionnaires Disease Clinical Picture THOMAS J. MARRIE 1. Introduction Epidemiology Clinical Features of Legionnaires Disease Diagnosis of Legionella Infection Routine Laboratory Data Specific Tests Treatment Pontiac Fever Nosocomial Legionnaire s Disease Summary References Legionella pneumophila: Innate and Adaptive Immunity HERMAN FRIEDMAN, CATHERINE NEWTON and THOMAS KLEIN 1. Introduction Legionella Immunogens Innate Immunity to L. pneumophila Adaptive Immunity to L. pneumophila Infection

11 Contents xi 5. Immune Mechanisms Discussion and Conclusions Summary References Nonspecific Stimulation of Immunity Against Legionella JAMES ROGERS, AMAL HAKKI and HERMAN FRIEDMAN 1. Introduction Stimulation of Immunity by Natural Products Antibacterial and Antiviral Effects of Epigallocatechin Gallate Modulation of Cytokines by Natural Products The Effects of EGCG on Cytokine Production by Legionella-Infected Dendritic Cells The Effects of EGCG on Co-stimulatory Molecule Expression by Legionella-infected Dendritic Cells The Effects of EGCG on Chemokine Production by Legionella-infected Dendritic Cells Immunomodulatory Effects of Natural Products on TLR Expression and Signal Transduction Summary and Conclusions References Interaction of Legionella pneumophila with Amoeba MAËLLE MOLMERET, MARINA SANTIC, and YOUSEF ABU KWAIK 1. Introduction Legionellae: A Facultative Intracellular Pathogen of Free-Living Amoebae The Role of Amoebae in Persistence of Legionella in the Environment The Role of Amoebae in Pathogenesis of Legionella Entry of L. pneumophila into Protozoa Intracellular Trafficking and Multiplication of L. pneumophila Role of the dot/icm Genes in Evasion of the Endocytic Pathway Egress of L. pneumophila from Amoebae References Index

12 Preface and Introduction The summer of 2006 marked the 30th anniversary of the outbreak of Legionnaires disease, an acute pneumonia that occurred among veterans who had gathered in Philadelphia, Pennsylvania, in 1976 to celebrate the bicentennial of the founding of the United States. Ironically, the nation and world were braced for an epidemic of swine influenza, which never materialized and no one expected the emergence of a new bacterial pathogen, since most in the medical field sincerely believed that all the pathogens of humans were now known. This new bacterial agent of Legionnaires disease, Legionella pneumophila (named in memory of the deceased veterans) was a harbinger of diseases to come (emerging pathogens) that has included HIV/AIDS, SARS, Lyme disease, hamburger disease, and many others. The further discovery that L. pneumophila was ubiquitous to aquatic environments worldwide and resided as an intracellular parasite of amoeba and protozoa provided a link between natural environments and human disease. Thus, environmental monitoring, especially of potable water, cooling towers, and related sources, has become a major focus in efforts to control the spread of this disease. Fortunately, as noted in the 1976 epidemic and holds true today, the disease is not spread from human to human. The remarkable ability of L. pneumophila to multiply in alveolar macrophages, as if they were amoebae, has further contributed to our understanding of the disease and stimulated much research in the area of cellular microbiology of pathogenesis. Today, Legionnaires disease is both sporadic (community acquired) and epidemic (explosive point sources such as cooling towers) and is on the rise worldwide attributed to a greater dependence on technology and air conditioning together with an increasingly susceptible population due to medical technology. Despite all the advances in medicine, Legionnaires disease continues to have a high mortality rate, not uncommon when pneumonia is involved. Advances in understanding pathogenesis and immunity have benefited greatly from the availability of three genome sequences for L. pneumophila and one for close relative Coxiella burnetii. Both Legionella and Coxiella produce survival forms and display a developmental cycle which contribute to pathogenesis, persistence, and resistance to biocides in natural environments. There have been many major developments in the Legionella field ranging from strategies to treat infections to how xiii

13 xiv Preface and Introduction this organism interacts with innate immune mechanisms to promote infections. This book represents the first collection of chapters written by experts in each of the specialty areas in this field. Unlike past books, which have been proceedings from international meetings, we have provided an opportunity for each of the authors to present state of the art detailed descriptions of specific areas that permit interesting reading for the non-expert and a solid reference for those researchers active in this field. The authors of each of the chapters in this book are internationally recognized experts concerning Legionella infections. The first chapter by Drs. Christel Cazalet and Carmen Buchreiser from the Institute Pasteur, Paris, France, concerns the molecular biology and genetics of L. pneumophila pathogenesis. The authors describe in-depth laboratory investigations of the genetic differences between the numerous strains of these opportunistic bacteria and provide important new information how these microbes interact with environmental factors and their host. The next chapter by Dr. Nicholas Cianciotto, Northwestern University Medical School, Chicago, Illinois, stresses important physiological aspects of Legionella host interactions, especially the important role of iron assimilation and the nature and mechanism of protein secretion by these bacteria. Drs. J. Le Blanc, Dalhouse University, Halifax, Nova Scotia from Canada, and Joseph P. Vogel from St. Louis, Missouri, then describe the metabolic activity of these ubiquitous microbes, especially the nature and mechanism of their secretion system. Dr. Rafael Garduño, Dalhousie University, Halifax, Nova Scotia Canada, then discusses pathogenesis and immunity to that bacterium, including some unique features of the life as well as developmental cycle of L. pneumophila in a host, both human and protozoa in their natural habitat. Dr. Barry Fields, Centers for Disease Control and Prevention, Atlanta, Georgia, then presents detailed observations how Legionella are widely dispersed in the environment, especially freshwater habitats. Drs. Rachel Edwards and Michele Swanson, University of Michigan, Ann Arbor, Michigan, describe how the life cycle of these bacteria is regulated and information necessary to control the presence of the bacteria, especially in the environment, and treatment modalities with antibiotics which abrogate bacterial replication and/or disease progression. Although no effective vaccine has yet been developed, information concerning interaction of these Legionella with the human host and how they infect host cells, as well as various antigenic structures of the bacteria important for infectivity and replication, provide a foundation necessary for developing protective vaccines which can induce adaptive immunity. Dr. Paul Hoffman, University of Virginia, provides new information about the interesting unique physiology of L. pneumophila and other species of these bacteria. He compares different aspects of their physiology in the human host vs. replication in amoeba and protozoa. Dr. Thomas J. Marrie, Walter C. Mackenzie Health Science Center, Edmonton, Alberta, Canada, then describes medical and clinical aspects of Legionnaire s disease which first attracted attention in the epidemic pneumonia outbreak in a hotel in Philadelphia during the annual convention of Pennsylvania State Legionnaires after which the disease is named. His chapter describes clinical aspects of the

14 Preface and Introduction xv infection in individuals showing respiratory symptoms. It is also now widely recognized that many individuals have subclinical exposure to Legionella, as evident by high titers of specific humoral antibody and marked in vitro blastogenic responsiveness of their blood lymphocytes to Legionella antigen. Drs. H. Friedman, C. Newton, and Thomas W. Klein, University of South Florida, discuss in detail the exploding new knowledge concerning immunity to L. pneumophila in terms of newer information about innate and adaptive specific immune responses to these ubiquitous opportunistic intracellular bacteria which primarily cause serious infection in immunocompromised individuals but which have their natural habitat single cell protozoa. They apparently interact with human hosts because of their ubiquitous presence in warm lakes, airconditioning cooling towers, circulating warm water in plumbing, and drinking water in institutions such as hospitals. The next chapter by Drs. J. Rogers, A. Hakki, and H. Friedman, also from the University of South Florida, is concerned with information how nonspecific immune stimulators modify host susceptibility to infection by opportunistic bacteria such as Legionella. This chapter reviews nonspecific modulators of both innate and adaptive immune mechanisms which impact the host immune response to an opportunistic pathogen like Legionella. Plant-derived nonspecific immunoenhancing substances are being investigated worldwide and various small molecular weight substances used for centuries as folk medicine to ameliorate infections have been shown clinically to significantly enhance host resistance to ubiquitous microbial infections. Drs. Maelle Molmeret and Yousef Abu Kwaik, University of Louisville, Louisville, Kentucky, then describe in detail information concerning L. pneumophila interactions with amoeba in vitro. Knowledge about such interactions is important to understand the nature and mechanism whereby these bacteria interact with phagocytic cells of the human host and the many biochemical and physiological features of legionellae common to their uptake and regulation in different cell types. The editors as well as authors of individual chapters believe the many ongoing studies of host immunity to ubiquitous opportunistic pathogens like L. pneumophila will undoubtedly lead to more effective control methods to prevent or ameliorate infections by such microorganisms, which still account for many thousands of infections annually in the United States alone. Many details concerning the nature and mechanism of interactions between host and opportunistic intracellular organisms like Legionella, which preferentially infect phagocytic cells, are being clarified and provide important knowledge directly related to mechanisms of host resistance to other important intracellular opportunistic pathogens, including Mycobacteria which cause tuberculosis. We thank Ms. Ilona Friedman for continuing excellent editorial assistance correlating and assisting in preparation of manuscripts for this book in the series. Paul S. Hoffman Herman Friedman Thomas W. Klein

15 Contributors Carmen Buchrieser Unité de Génomique des Microorganismes Pathogegens, Institut Pasteur, Paris, FRANCE Christel Cazalet Unité de Génomique des Microorganismes Pathogegens, Institut Pasteur, Paris, FRANCE Nicholas P. Cianciotto Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL Rachel L. Edwards Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI Barry S. Fields Centers for Disease Control and Prevention, Atlanta, GA Herman Friedman Department of Molecular Medicine, University of South Florida, College of Medicine, Tampa, FL Rafael A. Garduño Department of Microbiology and Immunology and Department of Medicine, Dalhousie University, Halifax, Nova Scotia, CANADA Amal Hakki Department of Molecular Medicine, University of South Florida College of Medicine, Tampa, FL Paul S. Hoffman Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health Systems, Charlottesville, VA Thomas W. Klein Department of Molecular Medicine, University of South Florida College of Medicine, Tampa, FL Yousef Abu Kwaik Department of Microbiology and Immunology, University of Louisville, Louisville, KY Jason J. LeBlanc Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, CANADA Thomas J. Marrie Department of Medicine, University of Alberta, Edmonton, Alberta, CANADA xvii