Chlamydia pneumoniae Infection and Disease

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2 Chlamydia pneumoniae Infection and Disease

3 INFECTIOUS AGENTS AND PATHOGENESIS Series Editors: Mauro Bendinelli, University of Pisa Herman Friedman, University of South Florida College of Medicine Recent volumes in this series: CHLAMYDIA PNEUMONIAE 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 OPPORTUNISTIC INTRACELLULAR BACTERIA AND IMMUNITY Edited by Lois J. Paradise, Herman Friedman, and Mauro Bendinelli PULMONARY INFECTIONS AND IMMUNITY Edited by Herman Chmel, Mauro Bendinelli, and Herman Friedman RAPID DETECTION OF INFECTIOUS AGENTS Edited by Steven Specter, Mauro Bendinelli, and Herman Friedman RICKETTSIAL INFECTION AND IMMUNITY Edited by Burt Anderson, Herman Friedman, and Mauro Bendinelli STAPHYLOCOCCUS AUREUS INFECTION AND DISEASE Edited by Allen L. Honeyman, 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 Chlamydia pneumoniae Infection and Disease Edited by Herman Friedman University of South Florida College of Medicine Tampa, Florida Yoshimasa Yamamoto Osaka University Osaka, Japan and Mauro Bendinelli University of Pisa Pisa, Italy KLUWER ACADEMIC PUBLISHERS NEW YORK, BOSTON, DORDRECHT, LONDON, MOSCOW

5 ebook ISBN: Print ISBN: Springer Science + Business Media, Inc. Print 2004 Kluwer Academic/Plenum Publishers New York All rights reserved No part of this ebook may be reproduced or transmitted in any form or by any means, electronic, mechanical, recording, or otherwise, without written consent from the Publisher Created in the United States of America Visit Springer's ebookstore at: and the Springer Global Website Online at:

6 Contributors LUIGI ALLEGRA Istituto di Tisiologia e Malattie dell Apparato Respiratorio, Universita degli Studi di Milano, Pad. Litta, IRCCS Ospedale Maggiore di Milano, I-20122, Milan, Italy DENAH M. APPELT Department of Biomedical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania BRIAN J. BALIN Departments of Pathology, Microbiology, and Immunology, and Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania ROBERT J. BELLAND Rocky Mountain Labs NIAID/NIH, Hamilton, Montana SVEND BIRKELUND Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark FRANCESCO BLASI Istituto di Tisiologia e Malattie dell Apparato Respiratorio, Universita degli Studi di Milano, Pad. Litta, IRCCS Ospedale Maggiore di Milano, I-20122, Milan, Italy GERALD I. BYRNE Department of Molecular Sciences, University of Tennessee, Health Science Center, Memphis, Tennessee GUNNA CHRISTIANSEN Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark ROBERTO COSENTINI Department of Emergency Medicine, IRCCS Ospedale, Maggiore di Milano, Universita degli Studi di Milano, Milan, Italy IGNATIUS W. FONG St. Michael s Hospital, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario M5B 1W8, Canada JENS GIEFFERS Medical University of Luebeck, Luebeck, Germany HÅKAN G. GNARPE Institute of Medical Sciences, University of Uppsala, Uppsala, Sweden JUDY A. GNARPE Institute of Medical Microbiology and Immunology, University of Alberta, Alberta, Edmonton, Canada SANDEEP GUPTA Department of Cardiology, Whipps Cross University Hospital, Leytonstone, London E11 1NR, United Kingdom v

7 vi CONTRIBUTORS DAVID L. HAHN Arcand Park Clinic Division of Dean Medical Center, Madison, Wisconsin MARGARET R. HAMMERSCHLAG Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, New York CHRISTINE J. HAMMOND Departments of Pathology, Microbiology, and Immunology, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania ALAN P. HUDSON Wayne State University School of Medicine, Detroit, Michigan C. SCOTT LITTLE Departments of Pathology, Microbiology and Immunology, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania ANGELA MACINTYRE Department of Biomedical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania AKIRA MATSUMOTO Department of Urology, Okayama University, Okayama, Japan TOSHIHARU MATSUSHIMA Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School, Kurashiki City, Okayama , Japan NAOYUKI MIYASHITA Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School, Kurashiki City, Okayama , Japan JOSEPH B. MUHLESTEIN Division of Cardiology, LDS Hospital, Salt Lake City, Utah JOSEPH NGEH Department of Clinical Gerantology, Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom KAZENOBU OUCHI Department of Pediatrics, Kawasaki Medical School, Kurashiki, Okayama, Japan SCOT P. OUELLETTE Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee ANTONIO ROTHFUCHS Microbiology and Tumorbiology Center, Karolinska Institute, Stockholm, Sweden MARTIN E. ROTTENBERG Microbiology and Tumorbiology Center, Karolinska Institute, Stockholm, Sweden H. RALPH SCHUMACHER University of Pennsylvania School of Medicine and D.V.A. Medical Center, Philadelphia, Pennsylvania SUBRAMANIAM SRIRAM Department of Neurology, Multiple Sclerosis Research Laboratory, Vanderbilt School of Medicine, 1222H Vanderbilt Stallworth Rehabilitation Hospital, Nashville, Tennessee CHARLES W. STRATTON Departments of Pathology, Multiple Sclerosis Research Laboratory, Vanderbilt School of Medicine,1222H Vanderbilt Stallworth Rehabilitation Hospital, Nashville, Tennessee HELJÄ-MARJA SURCEL National Public Health Institute, Department of Microbiology, Oulu, Finland PAOLO TARSIA Department of Emergency Medicine, IRCCS Ospedale Maggiore di Milano, Universita degli Studi di Milano, Milan, Italy

8 CONTRIBUTORS vii BRIAN VANDAHL Loke Diagnostics ApS, Science Park, Aarhus, Denmark JUDITH A. WHITTUM-HUDSON Wayne State University School of Medicine, Detroit, Michigan HANS WIGZELL Microbiology and Tumorbiology Center, Karolinska Institute, Stockholm, Sweden YOSHIMASA YAMAMOTO Division of Molecular Microbiology, Department of Basic Laboratory Sciences, School of Allied Health Sciences, Osaka University, Osaka, Japan

9 Preface to the Series The mechanisms of disease production by infectious agents are presently the focus of an unprecedented flowering of studies. The field has undoubtedly received impetus from the considerable advances recently made in the understanding of the structure, biochemistry, and biology of viruses, bacteria, fungi, and other parasites. Another contributing factor is our improved knowledge of immune responses and other adaptive or constitutive mechanisms by which hosts react to infection. Furthermore, recombinant DNA technology, monoclonal antibodies, and other newer methodologies have provided the technical tools for examining questions previously considered too complex to be successfully tackled. The most important incentive of all is probably the regenerated idea that infection might be the initiating event in many clinical entities presently classified as idiopathic or of uncertain origin. Infectious pathogenesis research holds great promise. As more information is uncovered, it is becoming increasingly apparent that our present knowledge of the pathogenic potential of infectious agents is often limited to the most noticeable effects, which sometimes represent only the tip of the iceberg. For example, it is now well appreciated that pathologic processes caused by infectious agents may emerge clinically after an incubation of decades and may result from genetic, immunologic, and other indirect routes more than from the infecting agent in itself. Thus, there is a general expectation that continued investigation will lead to the isolation of new agents of infection, the identification of hitherto unsuspected etiologic correlations, and, eventually, more effective approaches to prevention and therapy. Studies on the mechanisms of disease caused by infectious agents demand a breadth of understanding across may specialized areas, as well as much cooperation between clinicians and experimentalists. The series Infectious Agents and Pathogenesis is intended not only to document the state of the art in this fascinating and challenging field but also to help lay bridges among diverse areas and people. ix Mauro Bendinelli Herman Friedman

10 This volume on the topic Chlamydia pneumoniae infection and disease is appropriate, we believe, for our continuing series on infectious agents and pathogenesis. This book concerns both basic and clinical concepts and implications of infection by the ubiquitous, opportunistic intracellular bacterium Chlamydia pneumoniae (Cpn), which was recognized only in the last few decades as a cause of significant morbidity and disease in humans. Infections by Chlamydia are now believed to cause chronic diseases, including serious sequelae. C. pneumoniae infection was first recognized as a cause of acute upper respiratory tract infection, especially pneumonia and bronchitis in young individuals. However, nearly all adults have evidence of being exposed to this organism, since relatively high serum antibody levels are present in the blood of most individuals, even those with no evidence of previous clinical disease. Thus, there is now much interest in the likelihood that chronic sequelae developing after either acute or, most likely, asymptomatic infections may result in chronic inflammatory diseases, including coronary heart disease, such as atherosclerosis, and possibly some neurologic autoimmune disease like multiple sclerosis and, even, Alzheimer s disease. This volume presents up-to-date reviews of Chlamydia infection and disease by acknowledged experts on the basis of basic science and clinical studies. The first chapter of this volume is a general overview of the expanding knowledge that this ubiquitous intracellular bacterium may be associated with many diseases besides pulmonary infections. Drs. Oulette and Byrne from the University of Tennessee review the basic biology of this organism, including information concerning different forms of Chlamydia, such as the EB and RB bodies. Dr. Miyashita and colleagues from Japan describe the morphology of these bacteria. The cellular and molecular biology of this obligate intracellular bacterium are discussed by Dr. Christiansen and colleagues from Sweden. An overview of the immune response to Chlamydia, including involvement of innate and adoptive immune defenses, is discussed by Dr. Surcel and colleagues from Finland. Dr. M. Rottenberg and associates from Sweden describe current information concerning development of vaccines against this bacterium. Dr. Margaret Hammerschlag from New York presents a review of the efficacy of antibiotic treatment for C. pneumoniae infection, while Dr. Yamamoto from xi

11 xii INTRODUCTION Japan describes newer laboratory techniques, especially PCR methods, for rapid detection of Chlamydia in blood. A review by Drs. Nge and Gupta from England details the possible role of this microorganism in cardiovascular disease pathogenesis. Dr. Byrne from Tennessee gives an introduction into current concepts that C. pneumoniae is associated with important chronic diseases, especially atherosclerosis. Animal models of Cpn infection, especially as related to atherosclerosis, are discussed by Dr. Fong from Canada. Dr. Oulette and colleagues from Tennessee then describe some of the known factors associated with this bacterium in the pathogenesis of cardiovascular disease. Dr. Muhlestein from Utah describes some of the clinical evidence aimed at determining whether antimicrobial treatment of Chlamydia infection has a significant effect on coronary artery disease. Drs. Harken and Judy Gnarpe from Canada present information concerning myocarditis associated with Cpn infection. Involvement of this bacterium with other chronic diseases, including reactive arthritis, as well as the possibility that infection with Cpn is associated with diseases of the nervous system, including late onset of Alzheimer s disease and multiple sclerosis, is discussed. Drs. Stratton and Sriram from Vanderbilt University present a summary of their study, indicating that Cpn infection is associated with multiple sclerosis, an association which has been controversial but has also been confirmed by a number of other investigators. Dr. Balin and colleagues from Philadelphia describe histologic evidence suggesting that C. pneumoniae may be associated with the pathogenesis of Alzheimer s disease, at least late disease. Dr. Whittin-Hudson and colleagues from Detroit discuss the possible involvement of this bacterium in arthritis. Dr. David Hahn from Madison, WI, discusses the role of C. pneumoniae in asthma. Dr. Ouchi from Japan discusses the classic situation of respiratory infections caused by C. pneumoniae from the viewpoint of pediatric patients. Dr. Blasi and colleagues from Italy also discuss information concerning pneumonia caused by this organism. It is widely acknowledged that research and clinical studies concerning infection by this pathogen will have numerous beneficial results for both the medical and the scientific communities. The editors of this volume, as well as authors of individual chapters, are encouraged by recent developments concerning advances in knowledge about this organism and its association not only with acute infections such as respiratory diseases but also chronic inflammatorydiseases like atherosclerosis and autoimmunity, especially CNS diseases. We believe the emerging interest in this important opportunistic intracellular bacterium is of value not only for clinicians but also for laboratory investigators and biomedical scientists, as well as students and health professionals in general. The editors wish to express their thanks and gratitude to Ms. Ilona Friedman, who again served as an outstanding editorial assistant for this volume, as for all the books in this series. Yoshimasa Yamamoto Herman Friedman Mauro Bendinelli

12 Contents Chlamydia pneumoniae: Prospects and Predictions for an Emerging Pathogen SCOT P. OUELLETTE and GERALD I. BYRNE Overview Insights: Basic Biology Insights: Respiratory Infections Insights: Cardiovascular Disease Comments on Various Chronic Diseases Concluding Remarks Morphology of Chlamydia pneumoniae NAOYUKI MIYASHITA and AKIRA MATSUMOTO Chlamydial Developmental Cycle Morphology of EB Structure of the Outer Membrane Surface Projections and Related Structures Persistent Infection and Aberrant Forms Summary Cell and Molecular Biology of Chlamydia pneumoniae GUNNA CHRISTIANSEN, BRIAN VANDAHL, and SVEND BIRKELUND Ultrastructure of Chlamydia EB and RB Components Responsible for the Structural Appearance xiii

13 xiv Physical Localization of the Components Chlamydia Genomes The C. pneumoniae Proteome The Pmp Gene Family Pmp Structure Type III Secretion System Secreted Proteins Vesicle Trafficking Host Attack on Chlamydia Perspectives CONTENTS Antibiotic Susceptibility and Treatment of Chlamydia pneumoniae Infections MARGARET R. HAMMERSCHLAG In Vitro Susceptibility of C. pneumoniae Is There Antimicrobial Resistance in C. pneumoniae? Treatment of Persistent C. pneumoniae Infection In Vitro Treatment of C. pneumoniae Respiratory Infections Relevance for Cardiac Clinical Treatment Intervention Studies 5. Pneumonia Caused by Chlamydia pneumoniae FRANCESCO BLASI, ROBERTO COSENTINI, PAOLO TARSIA, and LUIGI ALLEGRA Epidemiology CAP in Pediatric Patients CAP in Adults Infection in Immunocompromised Subjects Conclusions Chlamydia Detection in Blood YOSHIMASA YAMAMOTO PCR Methodological Aspects Contamination DNA Extraction Target Genes PCR Protocols 5. Detection of PCR Products

14 CONTENTS Detection of Chlamydia in Blood by PCR C. pneumoniae DNA Extraction PCR Method Detection of C. pneumoniae in Blood Location of C. pneumoniae in Blood 5. Association of Blood C. pneumoniae with Cardiovascular 5. Disease Chlamydia Antigen Detection by Immunostaining Conclusions xv Chlamydia pneumoniae Infection and Diseases: Imunity to Chlamydia pneumoniae HELJÄ-MARJA SURCEL Innate Immune Mechanisms The Role of Macrophages in C. pneumoniae Immunity Acquired Immunity Effector Mechanisms of Protective Immunity Cell-Mediated Immunity in Humans Immune Escape C. pneumoniae Specific Antibodies Conclusion 8. Vaccines Against Chlamydia pneumoniae: Can They Be Made? MARTIN E. ROTTENBERG, ANTONIO GIGLIOTTI ROTHFUCHS, and HANS WIGZELL Do We Need an Anti C. pneumoniae Vaccine? C. pneumoniae Vaccine Development Adaptive Immune Responses Escape Mechanisms Antigens 5. Adjuvants 5. Activation of Innate Immunity 5. Adjuvants and Delivery Systems 6. Conclusions Chlamydia pneumoniae and Atherosclerosis an Overview of the Association JOSEPH NGEH and SANDEEP GUPTA 113

15 xvi CONTENTS Historical Perspectives on the Association between Infection and Atherosclerosis Microbiology and Epidemiology of C. pneumoniae Evidence Linking C. pneumoniae and Atherosclerosis 5. Seroepidemiological Observations Pathological Specimen Findings Animal Experimental Models Molecular and Immunological Mechanisms Antibiotic Treatment Studies C. pneumoniae Atherosclerotic Risk Factors and Koch s Postulates Concluding Comments The Biology of Chlamydia pneumoniae in Cardiovascular Disease Pathogenesis SCOT P. OUELLETTE, ROBERT J. BELLAND, JENS GIEFFERS, and GERALD I. BYRNE Chlamydial Life Cycle and Persistence C. pneumoniae in the Pathogenesis of Cardiovascular Disease C. pneumoniae and Host Cell Signaling Chlamydiae Macrophage Interactions C. pneumoniae Strain Heterogeneity in Cardiovascular Disease The tyrp Polymorphism and SNPs Host Tropism and Polymorphic Outer Membrane Proteins 5. Concluding Remarks Animal Models of Chlamydia pneumoniae Infection and Atherosclerosis IGNATIUS W. FONG Animal Models Used in Atherosclerotic Research C. pneumoniae Lung Infection Model Murine Models of C. pneumoniae Related Atherosclerosis Rabbit Models of C. pneumoniae Infection and Atherosclerosis Effect of Antibiotics on C. pneumoniae Animal-Induced Atherosclerosis 5. Summary and Future Directions 5. Future Directions