Chlamydia Trachomatis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

CHLAMYDIA TRACHOMATIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Chlamydia Trachomatis: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00230-2 1. Chlamydia Trachomatis-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on Chlamydia trachomatis. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CHLAMYDIA TRACHOMATIS .................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Chlamydia Trachomatis ................................................................ 6 E-Journals: PubMed Central ....................................................................................................... 59 The National Library of Medicine: PubMed ................................................................................ 89 CHAPTER 2. NUTRITION AND CHLAMYDIA TRACHOMATIS ........................................................ 137 Overview.................................................................................................................................... 137 Finding Nutrition Studies on Chlamydia Trachomatis............................................................. 137 Federal Resources on Nutrition ................................................................................................. 140 Additional Web Resources ......................................................................................................... 141 CHAPTER 3. ALTERNATIVE MEDICINE AND CHLAMYDIA TRACHOMATIS .................................. 143 Overview.................................................................................................................................... 143 National Center for Complementary and Alternative Medicine................................................ 143 Additional Web Resources ......................................................................................................... 150 General References ..................................................................................................................... 150 CHAPTER 4. DISSERTATIONS ON CHLAMYDIA TRACHOMATIS .................................................... 151 Overview.................................................................................................................................... 151 Dissertations on Chlamydia Trachomatis.................................................................................. 151 Keeping Current ........................................................................................................................ 155 CHAPTER 5. PATENTS ON CHLAMYDIA TRACHOMATIS ............................................................... 157 Overview.................................................................................................................................... 157 Patents on Chlamydia Trachomatis ........................................................................................... 157 Patent Applications on Chlamydia Trachomatis ....................................................................... 168 Keeping Current ........................................................................................................................ 172 CHAPTER 6. BOOKS ON CHLAMYDIA TRACHOMATIS .................................................................. 173 Overview.................................................................................................................................... 173 Book Summaries: Federal Agencies............................................................................................ 173 Book Summaries: Online Booksellers......................................................................................... 174 Chapters on Chlamydia Trachomatis ......................................................................................... 174 CHAPTER 7. PERIODICALS AND NEWS ON CHLAMYDIA TRACHOMATIS ..................................... 177 Overview.................................................................................................................................... 177 News Services and Press Releases.............................................................................................. 177 Academic Periodicals covering Chlamydia Trachomatis ........................................................... 179 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 183 Overview.................................................................................................................................... 183 NIH Guidelines.......................................................................................................................... 183 NIH Databases........................................................................................................................... 185 Other Commercial Databases..................................................................................................... 187 APPENDIX B. PATIENT RESOURCES ............................................................................................... 189 Overview.................................................................................................................................... 189 Patient Guideline Sources.......................................................................................................... 189 Finding Associations.................................................................................................................. 193 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 195 Overview.................................................................................................................................... 195 Preparation................................................................................................................................. 195 Finding a Local Medical Library................................................................................................ 195 Medical Libraries in the U.S. and Canada ................................................................................. 195 ONLINE GLOSSARIES................................................................................................................ 201

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Online Dictionary Directories ................................................................................................... 201 CHLAMYDIA TRACHOMATIS DICTIONARY .................................................................... 203 INDEX .............................................................................................................................................. 265

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with Chlamydia trachomatis is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about Chlamydia trachomatis, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to Chlamydia trachomatis, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on Chlamydia trachomatis. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to Chlamydia trachomatis, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on Chlamydia trachomatis. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON CHLAMYDIA TRACHOMATIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on Chlamydia trachomatis.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and Chlamydia trachomatis, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “Chlamydia trachomatis” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Gastrointestinal Manifestations Source: Medical Clinics of North America. 76(1): 45-62. January 1992. Contact: Available from W.B. Saunders Company, Periodicals Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 654-2452. Summary: Gastrointestinal (GI) involvement is common during the course of the acquired immunodeficiency syndrome (AIDS). In this article, the authors review the GI symptoms that attend AIDS and their causes. Topics include esophageal symptoms; abdominal pain; biliary tract disease; pancreatic disorders; obstruction and perforation of the GI tract; GI bleeding; general considerations regarding diarrhea; protozoal causes of diarrhea, including coccidiosis, microsporidia, entamoeba histolytica, and giardia

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Chlamydia Trachomatis

lamblia; bacterial and fungal causes of diarrhea, including mycobacterium aviumintracellulare infections, salmonella, shigellosis, campylobacter jejuni, clostridium difficile, and Chlamydia trachomatis; and viral causes of diarrhea, including HIV itself, cytomegalovirus, and herpes. The authors conclude with a brief discussion of AIDS enteropathy and its treatment. 1 table. 95 references. •

Evaluation of Dysuria in Men Source: American Family Physician. 60(3): 865-872. September 1, 1999. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Summary: Men with pain or a burning sensation on urination (dysuria) should be evaluated with a thorough history, a focused physical examination, and urinalysis (both urine dipstick and microscopic examination of the urine specimen). This article reviews the evaluation of dysuria in man. The authors note that although dysuria may be caused by anything that leads to inflammation of the urethral mucosa, it is most often the result of urinary tract infection (UTI). In younger patients, the infectious agent is usually a sexually transmitted organism such as Chlamydia trachomatis. In patients over 35 years of age, coliform bacteria predominate. Infection in older men most often occurs as a result of urinary stasis secondary to benign prostatic hyperplasia. Other conditions that may cause dysuria include renal calculus, genitourinary malignancy, spondyloarthropathy, and medications. The authors conclude that successful treatment of dysuria depends on correct identification of its cause. 1 figure. 2 tables. 35 references.

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Prostatitis Source: Clinical Microbiology Reviews. 11(4): 604-613. October 1998. Contact: Available from American Society for Microbiology. Institutional or Nonmember Subscription Office, P.O. Box 11127, Birmingham, AL 35201-1127. (800) 633-4931 or (205) 995-1567. Fax (205) 995-1588. E-mail: [email protected]. Summary: Prostatitis (infection of the prostate) is a common urologic condition that many clinicians find difficult to treat effectively. Culture diagnosis of acute bacterial prostatitis is straightforward and easily accomplished in the laboratory. On the other hand, the microbiologic diagnosis of chronic prostatitis and chronic idiopathic (nonbacterial) prostatitis (more commonly referred to as prostatodynia) is more of a challenge. This article reviews prostatitis, focusing on its etiology and diagnosis. Topics include acute versus chronic bacterial prostatitis, specimen collection and bacteriologic culture, common bacterial etiologic agents, chronic idiopathic prostatitis (including prokaryotic DNA sequences in patients, bacterial cultures for commensal and fastidious bacteria, difficult to culture Coryneforms in expressed prostatic secretions, Chlamydia trachomatis, and Ureaplasma urealyticum), mycobacterial infection, gonococcal prostatitis, parasitic prostatitis, fungal prostatitis, abscesses of the prostate gland, viral prostatitis, prostatitis in benign prostatic hyperplasia (BPH), urovirulence determinants of bacteria causing prostatitis, antibiotic pharmacokinetics in prostatitis, chemical inflammatory reactions as the cause of nonbacterial prostatitis, and the autoimmune disease hypothesis. The author concludes that reports published within the past 2 years strongly suggest an association between bacteria and chronic idiopathic prostatitis. It is important to undertake research to determine whether there is persistence of bacterial antigens in prostatic tissue and fluids, since these antigens could trigger immunologic

Studies

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and biochemical events that may result in initiation and maintenance of chronic inflammation in this troublesome condition. 1 figure. 73 references. •

Reactive Arthritis: Preliminary Microbiologic Analysis of the Human Temporomandibular Joint Source: Journal of Oral and Maxillofacial Surgery. 58(10): 1137-1142. October 2000. Contact: Available from W.B. Saunders Company. Periodicals Department, P.O. Box 629239, Orlando, FL 32862-8239. (800) 654-2452. Summary: The presence of Chlamydia trachomatis has been previously shown in the temporomandibular joint (TMJ). This article reports on a study that investigated whether the presence of other bacteria associated with reactive arthritis (ReA) can be identified in the TMJ. Posterior bilaminar (2 layer) tissue removed during TMJ surgery from 26 patients (24 female, 2 male) was evaluated for the presence of bacteria, including C. trachomatis, Mycoplasma fermentans, Mycoplasma genitalium, Campylobacter jejuni, Yersinia enterocolitica, Salmonella spp, and Shigella spp by highly specific PCR (polymerase chain reaction) assays. Bacterial DNA was identified in the TMJ as follows: C trachomatis, 11 of 26 patients (42 percent); M. fermentans orale, 6 of 26 patients (23 percent); M. genitalium, 9 of 26 patients (35 percent). Nine of 26 TMJs (35 percent) had the presence of a single bacterial species. Eight of 26 TMJs (31 percent) had more than 1 species. A total of 17 of 26 patients (65 percent) had the presence of bacteria identified in the TMJ. The authors note that the presence of M. genitalium in the human TMJ has not been previously reported. The presence of bacteria in the TMJ, either singly or concurrently with other bacteria, may serve as the pathogenetic mechanism of TMJ inflammation. The presence of 2 bacteria from the urogenital tract in the TMJ suggests that internal derangement of the TMJ may occur as a result of a sexually acquired infection. 2 figures. 43 references.

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Do Minocycline and Other Tetracyclines Have a Place in Rheumatology? Source: Revue du Rhumatisme (English ed.). 64(7-9): 474-480. July-September 1997. Summary: This journal article provides health professionals with information on the potential usefulness of antimicrobials such as tetracycline for the treatment of rheumatoid arthritis. Tetracyclines are a family of antimicrobials with activity against a broad range of organisms, including those that develop intracellularly. Links have been reported between some infections and some inflammatory joint diseases, with the most notable example involving mycoplasmas and rheumatoid arthritis. Reactive arthritides are known to be triggered by organisms found in the gastrointestinal or genitourinary tract, and antigenic material from these organisms has recently been demonstrated in synovial tissue from patients with reactive arthritis. These factors led to the hypothesis that tetracyclines may be useful in rheumatoid arthritis and reactive arthritis. Two controlled studies found that minocycline benefited patients with rheumatoid arthritis when it was given either as an adjunct to another second line treatment or as the only slow acting drug. Lymecycline has been found to expedite recovery from reactive arthritis due to Chlamydia trachomatis, and tetracycline to decrease the incidence of reactive arthritis due to sexually transmitted diseases. The safety profiles of these treatments were acceptable in all available studies but require further investigation for long term administration. The benefits may be related to the immunomodulating effects of tetracyclines or their ability to inhibit metalloproteases such as collagenases. Whether tetracycline therapy influences the course of radiologic lesions in rheumatoid arthritis remains unknown. However, minocycline therapy has given sufficient proof of its

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Chlamydia Trachomatis

efficacy to make it an attractive alternative in rheumatoid arthritis. No data are available on the usefulness of tetracycline therapy in human osteoarthritis. 2 tables and 42 references. (AA-M). •

Management of the Patient with Urethritis Source: IHS Provider. 19(2): 29-40. February 1994. Contact: Available from IHS Clinical Support Center. 1616 East Indian School Road, Suite 375, Phoenix, AZ 85016. (602) 640-2140. Fax (602) 640-2138. Summary: Urethritis, or inflammation of the urethra, is caused by an infection characterized by the discharge of mucoid or purulent material and by burning during urination. This article outlines the management of the patient with urethritis. The two bacterial agents primarily responsible for urethritis among men are Neisseria gonorrhoeae and Chlamydia trachomatis. Testing to determine the specific diagnosis is recommended because both of these infections are reportable to State health departments. In addition, with a specific diagnosis, treatment compliance may be better and the likelihood of partner notification may be improved. If diagnostic tools are unavailable, health care providers should treat patients for both infections. The authors discuss patient care management, followup considerations, the management of sex partners, and special considerations for nongonococcal urethritis (NGU), mucopurulent cervicitis, chlamydial infections, gonococcal infections, human papillomavirus infection, trichomoniasis, and pelvic inflammatory disease (PID). (AA-M).

Federally Funded Research on Chlamydia Trachomatis The U.S. Government supports a variety of research studies relating to Chlamydia trachomatis. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to Chlamydia trachomatis. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore Chlamydia trachomatis. The following is typical of the type of information found when searching the CRISP database for Chlamydia trachomatis: •

Project Title: A HIGH TRACHOMATIS TEST

ACCURACY

POINT-OF-CARE

CHLAMYDIA

Principal Investigator & Institution: Helms, Michael K.; Quidel Corporation 10165 Mc Kellar Ct San Diego, Ca 921214201 2

Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-DEC-2004 Summary: (provided by applicant): Urogenital disease caused by Chlamydia trachomatis (Ct) is a major public health problem affecting 3-4 million people in the U.S. and over 100 million worldwide annually. Sequelae include urethritis, cervicitis, salpingitis (which can lead to infertility in women), pelvic inflammatory disease, adverse pregnancy outcomes (e.g. abortion, still birth or premature birth), and epididymitis (which can lead to infertility in men), as well as being a risk factor for HIV infection. Chlamydial infections are asymptomatic in up to 70% of women and 50% of men, thus delaying treatment and facilitating transmission. This asymptomatic feature coupled with the ease and efficacy of treatment (e.g. a single dose of azithromycin) places the burden for disease management on diagnosis. Furthermore, a persistent and unmet need exists for rapid, accurate, cost effective and simple (RACES format) diagnostic tests for Ct due to patient noncompliance with treatment and delays in providing treatment to infected patients. Currently marketed point-of-care (POC) Ct tests are rapid, but less sensitive than the more complex, slow and expensive laboratory methods such as cell culture and nucleic acid amplification tests (NAAT). To improve sensitivity without sacrificing specificity, the key challenge, we propose novel and proprietary methods that will provide enhanced sensitivity and reduced background signal, therefore maintaining specificity. The sensitivity enhancement will be assessed by comparison to gold standard tests including cell culture and a NAAT. We hypothesize that the proposed test system will increase testing accuracy while adding the speed and simplicity necessary for widespread POC clinical utilization. The resulting enhanced accuracy Ct POC test is directly relevant to the goal of improving diagnosis of infectious diseases stated by organizations such as the National Institute of Allergy and Infectious Diseases, the Bill and Melinda Gates Foundation and the World Health Organization. Furthermore the novel aspects of the test system are expected to result in significant intellectual property rights for the company. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A DEVELOPMENT

NOVEL

CHLAMYDIAL

VECTOR

FOR

HIV

VACCINE

Principal Investigator & Institution: Watkins, David I.; Professor; Pathology and Lab Medicine; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2006 Summary: (provided by applicant): The ultimate application of the proposed research is the development of vaccines for HIV. The express goal of the research is to use a novel approach to first develop a vaccine that will provide immunity against SIV in a simian AIDS model. A basic premise of the Research Plan is the desirability of initiating immunity at mucosae that are natural sites of infection with HIV. SPECIFIC AIM 1. Chlamydia trachomatis (Ct) will be used as a vaccine "vector" for SIV genes because it naturally infects mucosae. The gag, nef, tat and rev SIV genes will be introduced into Ct by the use of homologous recombination vectors (HRV): plasmids in which SIV genes are flanked by segments of Ct chromosomal DNA. Ct transformants (Ct(SIV)) resulting from such recombinations, will be isolated by selection for a selection gene that is also present in the HRV. SPECIFIC AIM 2. The expression of SIV genes in Ct(SIV) strains will be studied both in vitro and in vivo. Expression will be examined in HeLa cells and immunogenicity studies will be carded out in Cynomolgus macaques. SPECIFIC AIM 3. The ability of Ct(SIV) strains to induce immunity that might reduce rate of infection or ameliorate disease course after SIV challenge will be investigated by repeatedly challenging (intravaginally, i.vag.) cynomolgous macaques with a low dose of

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Chlamydia Trachomatis

SIVmac239. Immune responses to the SIV proteins encoded in the Ct(SIV) strains will be monitored, as will the outcome after challenge with SIV. This is a first attempt to use Chlamydia as a vaccine vector to induce immune responses at mucosae. Subsequent experiments might include the use of attenuated strains of Chlamydia vectors to deliver additional SIV genes (Env and Pol). However, the immediate goal of this limited R21 application is to explore the innovative idea of using Chlamydia as a vaccine vector. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AN INTERNET INTERVENTION TO INCREASE CHLAMYDIA SCREENING Principal Investigator & Institution: Allison, Jeroan J.; Associate Professor of Medicine; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 29-SEP-2004 Summary: Background. Chlamydia trachomatis is the most common sexually transmitted bacterial infection in the United States, with 3 to 4 million cases occurring annually. Most cases occur in those less than 25 years old. Increased prevalence has been found in patients who live in inner cities, have a lower socioeconomic status, or are black. Up to 80 percent of women infected with Chlamydia are asymptomatic and do not seek medical care. In addition to Pelvic Inflammatory Disease (PID) and its sequelae, chlamydial infections also may facilitate acquisition of HIV. Treatment is simple, effective, and cost effective. Despite recommendations by the Centers for Disease Control and Prevention, most high-risk women are not being screened. The UAB Center for Outcomes and Effectiveness Research and Education, in collaboration with U.S. Quality Algorithms, the performance measurement subsidiary of Aetna U.S. Healthcare, proposes a controlled, group-randomized trial to increase adherence to guidelines for chlamydial screening in at-risk women. Specific Aims. (1) to increase rates of chlamydial screening for at-risk female patients; (2) to increase rates of treatment for Chlamydia; and (3) to decrease the incidence of PID. Methods. We will randomize 220 primary care physician offices and their at- risk female patients to either an intervention or control arm. Patient risk status will be defined by the specifications of HEDIS 2000. Our intervention consists of a year-long series of physician Internet learning modules that integrate case-based education with audit, feedback, and benchmarking of practice profiles. Analysis. The major comparison will be the differential improvement in screening rates of the two study arms as ascertained from administrative data. Patientlevel multivariable analyses will adjust for the extra-binomial variation resulting from patients being nested within physicians from the group randomized design. Significance. With a research team that has a proven record of collaboration, this project will produce an evidence-based and replicable intervention than can be sustained in the "real world," readily adapted by other health care organizations, and easily modified for other diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANTICHLAMYDIAL PROTECTION BY MOLECULAR MIMCRY Principal Investigator & Institution: Whittum-Hudson, Judith A.; Professor; Internal Medicine; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-JUN-1998; Project End 31-MAY-2004 Summary: (Adapted from the applicant's abstract): Chlamydia trachomatis is the leading cause worldwide of sexually transmitted disease and the most prevalent ocular pathogen. In addition to being the major cause of non-gonococcal urethritis and pelvic

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inflammatory disease, chlamydia are also the leading cause of preventable infectious blindness (trachoma) and are also associated with arthritis in a significant number of patients with Reiter's syndrome/Reactive arthritis. The public health costs of chlamydial infections and their sequelae are enormous. Identification of a protective antichlamydial vaccine would have important public health significance. We propose studies in a BALB/c ocular infection model induced by a human chlamydial biovar to further characterize the demonstrated long-lasting protective immunity against ocular infection induced by oral or systemic immunization with a monoclonal anti-idiotypic antibody (mAb2). The mAb2 is a functional and molecular mimic of the genus-specific chlamydial glycolipid exo-antigen, GLXA. We hypothesize that the basis for anti-id induced protection is that detrimental Th1- driven responses are shifted to Th2mediated protection and that the targeted specificity for GLXA rather than for surface proteins such as MOMP accounts for the protective responses. Since the anti-id is an immunogenic protein, it induces more effective immune responses than would be induced by the glycolipid GLXA Ag itself. Studies will be performed to test this hypothesis using primarily the mouse ocular model as a mucosal infection paradigm; immunization with the mAb, vaccine candidate will be used to (1) characterize the relative role of T and B cells in protective responses, (2) distinguish between requirements for mucosal versus systemic immunization with encapsulated vaccine, (3) determine requirements for maximal protection including adjuvants or additional chlamydial antigens in a cocktail vaccine, and (4) test for anti-id- induced protection in other chlamydial infection models including C. trachomatis and C. psittaci genital infection and arthritides. Humoral responses in sera and secretions and cytokine responses will be used to define the Th1 and Th2 components of protective immunity; immunohistochemistry, in situ hybridization, RT-PCR methods and functional assays will be used in normal and immunodeficient mice to distinguish local and systemic immune responses which correlated with reduced microbiologic and clinical disease. These studies will potentially reveal strategies to assess protection against chlamydial disease induced by other vaccine candidates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTI-HIV MICROBICIDE: CELLULOSE ACETATE PHTHALATE (CAP) Principal Investigator & Institution: Neurath, Alexander R.; Member; New York Blood Center 310 E 67Th St New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 26-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): Cellulose acetate phthalate (CAP) has been used as an enteric film coating material or as a matrix binder for tablets and capsules. It is widely used in oral pharmaceutical products and is generally regarded as a nontoxic material free of adverse effects. It is included in the FDA Inactive Ingredients Guide and is listed in pharmacopoeias internationally. CAP is available in large quantities and is inexpensive. It was demonstrated that CAP: 1) has antiviral activity against HIV-1 and several herpesviruses (HSV); and 2) when formulated in a micronized form a) inactivated in vitro HIV-1, HSV-1. HSV-2, cytomegalovirus, Neisseria gonorrhoeae, Trichomonas vaginalis, Haemophilus ducreyi and Chlamydia trachomatis; b) inactivated bacteria associated with bacterial vaginosis; c) protected mice against vaginal infection by HSV-2; and d) protected 4/6 rhesus monkeys from vaginal infection with simian immunodeficiency virus (SIVmac251). These results have established the promise of CAP as a microbicide for prevention of sexual transmission of HIV-1. Additional preclinical studies are needed to further support this promise. This includes:

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Chlamydia Trachomatis

(Project I): Prevention of infection by primary HIV-1 isolates and distinct HIV-1 clades in cell cultures in vitro and in human cervical and rectal tissue models; (Project II): a) Assess the safety of CAP in a monkey model by colposcopic examinations and measurement of pro-inflammatory chemokines and cytokines; b) Assessment of CAP distribution after vaginal application in monkeys using chemically tagged CAP and colposcopy, and magnetic resonance imaging (MRI); and c) Evaluate the efficacy of CAP against infection with pathogenic X4- and R5-specific simian/human chimeric HIV viruses (SHIV), respectively; (Project III): Measurement of pro-inflammatory chemokines and cytokines after exposure of cervical and vaginal epithelial cells in culture to CAP; (Project IV): Studies on CAP-human sperm interactions to assess the spermicidal/contraceptive potential of CAP and its formulations. Information gained from the proposed studies, coordinated and supplied by uniform and quality controlled formulations by Cores A, B, respectively, is expected to facilitate the design of Phase I, II and III human clinical trials. CAP meets criteria proposed for an ideal microbicide: activity in presence of semen and blood; activity against sexually transmitted infections other than HIV-1; condom compatibility, negligible systemic absorption (due to its large, molecular mass and micronized state); lack of color and unpleasant taste; and low cost. The proposed research is expected to help transform this ideal into a reality. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AZITHROMYCIN IN CONTROL OF TRACHOMA II Principal Investigator & Institution: Schachter, Julius; Professor of Epidemiology; Laboratory Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-MAY-2006 Summary: Trachoma is the world's leading cause of preventable blindness. This disease, caused by Chlamydia trachomatis, is endemic in many parts of the developing world. Several years ago in a project called Azithromycin in Control of Trachoma (ACT I) we evaluated the use of community-wide treatment with oral Azithromycin. This approach resulted in clinical improvement and dramatic reduction in prevalence of chlamydial infection through a 1- year follow-up. We now propose to return to these villages and do clinical surveys to assess trachoma activity, and to test conjunctival swabs for the presence of C. trachomatis by ligase chain reaction (LCR). The villages will include the previous treatment sites (oral) azithromycin versus topical tetracycline) as well 2 new villages that have not had any prior treatments. Thus we will determine the longterm (5 year) effects of the azithromycin, and follow them for 3 years. We will compare singledose treatment with the 3 doses used in ACT I to determine the efficacy of this simpler, less expensive regime. All LCR positive specimens from the ACT I villages will have the major outer membrane gene amplified and sequenced. The genovars will be mapped for location within villages and families and then their distribution will be followed over time, after treatment to provide a better understanding of the epidemiology of the infection. Results of the study will be used as data input for the generation of mathematical model to predict whether community-wide retreatment (or alternate strategies) will be needed, and the optimal timing for such retreatment. In sum, this study should provide a rational approach to use of community-wide azithromycin treatment to eliminate blinding trachoma as a public health problem. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOGENESIS OF THE CHLAMYDIA TRACHOMATIS VACUOLE Principal Investigator & Institution: Engel, Joanne N.; Associate Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2005 Summary: (Adapted from the Applicant's Abstract): Chlamydia trachomatis is the leading cause of sexually transmitted diseases in this country and a major cause of blindness in third world countries. The ability of this obligate intracellular parasite to enter a non-phagocytic epithelial cell and survive within the hostile intracellular environment of the eukaryotic cytoplasm is key to its pathogenesis. The intimate interactions between chlamydia and its eukaryotic host is likely to involve natural biological pathways of the eukaryotic cell that the parasite usurps for its own survival. Study of these processes will yield insights into eukaryotic cell biology as well as insights into chlamydial disease pathogenesis. From these studies may emerge new therapeutic approaches to treating or preventing chlamydial infections. Specific Aim 1: The investigators hypothesize that successful C. trachomatis biovar LGV entry and intracellular development in epithelial cells involves at least two separate pathways, one of which is clathrin-independent, and have preliminary evidence that entry and/or development is dependent upon the host actin cytoskeleton and is modulated by c-src. (A) They will test the role of clathrin mediated endocytosis by assessing the effect in epithelial cells of expression of dominant negative (DN) alleles of dynamin, ARF-6, or clathrin on C trachomatis binding, entry, and replication. (B) They will further investigate the role of the actin cytoskeleton in the C trachomatis life cycle by determining whether the actin-regulating GTPases rac, rho, and CDC42 affect LGV and serovar E binding, entry, and replication in polarized and non-polarized epithelial cells. (C) They will determine the mechanism of c-src-mediated stimulation of C. trachomatis infectivity. Specific aim 2: An unusual aspect of the C. trachomatis life cycle is the receipt of sphingomyelin from the trans Golgi Network (TGN) by the bacteriacontaining vacuole. They will test the hypothesis that the C. trachomatis vacuole interacts with one or more apical exocytic pathways including the newly proposed exocytic pathway in which lipid rafts transport sphingolipids, glycosylphosphatidylinositol (GPI)-anchored proteins, and other designated proteins to the apical surface of polarized epithelial cells. Using several approaches, they will identify specific host cell factors required for the delivery of sphingomyelin from the TGN to the C. trachomatis vacuole. This will help to further define the pathway involved. These studies may lead to the development of new anti-chlamydial drug therapies and further our understanding of lipid trafficking in eukaryotic cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EVOLUTION

C.

TRACHOMATIS

GENOMICS,

STRAIN

TYPING,

AND

Principal Investigator & Institution: Dean, Deborah A.; Adjunct Professor of Medicine; Children's Hospital & Res Ctr at Oakland Research Center at Oakland Oakland, Ca 946091809 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Chlamydia trachomatis (CT) is the leading cause of preventable blindness (trachoma) and sexually transmitted diseases (STD) worldwide. While much has been learned about human chlamydial infections in the last decades, we are still lacking a complete understanding of the pathogenesis of CT diseases, and do not have an appropriate tool for precisely typing CT strains both for molecular

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Chlamydia Trachomatis

epidemiologic and basic research studies. The major outer membrane protein (MOMP) of CT is an immunodominant protein and the primary target for serotyping, and hence strain typing along with the ompA gene, which encodes MOMP. Yet, MOMP does not fully reflect the phylogeny of the organism or distinguish strains by biologic or phenotypic properties. Other genes/proteins that may contribute to phylogeny, or these properties include the inter-genic region (IGR), polymorphic membrane proteins (Pmps), cytotoxin genes in the replication termination region (RTR) or "plasticity zone", partial tryptophan operon proteins (TrpB/A), Type III secretion system proteins, chlamydial protease- or proteasome-like activity factor (CPAF), and the porin protein, PorB. Further, the majority of research on CT has used laboratory-adapted strains that may not reflect current clinical isolates that are responsible for the myriad of CT diseases described today. Our goal is to advance the genetic discovery initiated by the CT genome sequences of serovars D and L2 and other genomes of the family Chlamydiaceae by providing genome sequences of six of the 13 remaining reference serovars along with genomes of recent clinical isolates to advance our understanding of CT tissue tropism, virulence, disease pathogenesis, and evolution. Within the context of our Specific Aims, we will develop and make publicly available the data and research tools described: 1) Sequence six genomes of the remaining 13 reference serovars of CT and four genomes of selected recent clinical isolates (see #2), and develop a multi-locus sequence typing (MLST) scheme for global epidemiologic studies; MLST screening of the seven remaining reference serovars and -500 isolates from CT STD and trachoma populations worldwide will fine-tune the MLST and identify unique clinical isolates for additional genome sequencing; 2) Develop a Chlamydia GeneChip for rapid, robust genotyping of CT based on genome data and MLST findings; and 3) Develop a strain identification database to address specific research questions related to unraveling the association between genetic determinants and tissue tropism, virulence, and disease outcome in addition to the evolution of the organism and how new strain types might evolve over time. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELLULAR TRAFFICKING TO INFLAMED FEMALE GENITAL MUCOSA Principal Investigator & Institution: Kelly, Kathleen A.; Assistant Professor; Pathology and Laboratory Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2004 Summary: Pelvic inflammatory disease, tubal infertility and ectopic pregnancy typically emerge in females after a chronic infection with Chlamydia trachomatis or Neisseria gonorrhoeae. Due to the insidious nature of chlamydial infections, efforts have been put forth to develop a vaccine that would enhance the clearance of organisms, avoid chronic infections, and in turn, eliminate reproductive disability. Based on the theory of a common mucosal immune system, lymphocyte recruitment to the genital mucosa is predicted to occur when lymphocytes are activated at distant mucosal surfaces. Studies of Chlamydia genital infection in the mouse have shown that T cells are required for protection and effector T cells are found in the genital mucosa following immunization at other mucosal sites. Currently, the degree of T cell migration to the genital mucosa following antigen delivery at other mucosal surfaces is unknown in humans. In this proposal, we will test the hypothesis that T cells activated at other mucosal surfaces can be recruited to the genital mucosa during an inflammatory process. Since T cells are not commonly recruited to the genital mucosa, we will study females infected with C.

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trachomatis or N. gonorrhoeae as a model to test this hypothesis. The specific aims of this proposal are to: 1) Develop a method to identify T cells that home to the genital mucosa in vivo using individuals with a sexually transmitted disease (STD). 2) Determine if immunization by a distant mucosal route promotes T cell trafficking to the genital mucosa. We will define the homing receptor expression pattern (gut mucosal, other mucosal, non-mucosal) on endocervical T cells and IFNgamma+ peripheral blood cells from STD infected volunteers using flow cytometric techniques. We will also determine which adhesion molecules are induced within the female genital mucosa during STD infection by utilizing an in vitro fallopian tube culture of living tissue followed by immunohistological staining. The candidate homing receptor: adhesion molecule pairs will be tested in a genital mucosa adhesion assay. The frequency of genital mucosa homing T cells and mature dendritic cells will be monitored in volunteers following immunization with Salmonella typhi vaccine via different routes. These studies will contribute to the design of STD vaccines that would provide lasting immunity in the female genital mucosa. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHLAMYDIA

CHARACTERIZATION

OF

HUMAN

T

CELLS

AGAINST

Principal Investigator & Institution: Kavathas, Paula B.; Professor; Laboratory Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2004; Project Start 01-MAY-2004; Project End 30-APR-2009 Summary: (provided by applicant): Chlamydia trachomatis (Ct) is the most common cause of bacterial sexually transmitted disease worldwide. In the majority of infected individuals they are asymptomatic. This poses a heath risk for women, causing pelvic inflammation and tubal infertility, and for newborns from infected mothers. Our goal is to characterize the human T cell immune response to Ct in infected individuals with the goal of identifying immunogenic proteins and peptides that could be used for vaccine development. We will determine whether CD4 or CD8 T cell responses can be elicited against Ct proteins that enter the MHC class I or class II antigen processing pathway or are likely to enter those pathways. Specific peptide epitopes from these proteins and the HLA allotypes that present the peptides will be determined using a unique panel of B lymphoblastoid lines expressing single HLA antigens. Our hypothesis is that some regions of immunogenic proteins will contain epitope clusters for both CD4 and CD8 T cells as we found for the major outer membrane protein MOMP. The functional characteristics of the Ct-specific T cells will be determined using antibodies against cytokines, proteins involved in cytotoxicity, and cell surface molecules. Assays such as the Lysispot assay will be used to determine CTL function. Ct-specific T cells in the blood of infected individuals will be enumerated with MHC class I tetramer and class II tetramers. We will determine if the CD8 T cells recognizing Ct antigens are functional CTL cells or potentially "exhausted" T cells lacking CTL activity, which has been found in chronic viral infections. The potential for immunogenic epitopes to cross-protect other Ct species such as C. pneumonia and C. psittaci will be determined by sequence comparisons. Characterizing human T cell responses to Ct is important for understanding immunity to Ct in humans and for future vaccine development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Chlamydia Trachomatis

Project Title: CHLAMYDIA SIGNIFICANCE

PNEUMONIAE

ANTIGENS

OF

BIOLOGICAL

Principal Investigator & Institution: Campbell, Lee Ann.; Professor; Pathobiology; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2007 Summary: (provided by the applicant): Chlamydia pneumoniae is a human respiratory pathogen that causes 5 percent to 10 percent of pneumonia, bronchitis, and sinusitis. Virtually everyone is infected in his or her lifetime and reinfection is common. Infection is difficult to treat even with sensitive antibiotics. Chronic infection is common and has been associated with asthma, reactive airway disease, Reiter's syndrome, erythema nodosum, and sarcoidosis. The potential public health impact of infection with this pathogen is underscored by the association of C. pneumoniae with atherosclerosis and related clinical manifestations such as coronary heart disease, carotid artery stenosis, aortic aneurysm, claudication, and stroke. If C. pneumoniae infection plays a role in atherogenesis, there will be an urgent need to facilitate diagnosis and develop strategies for intervention and prevention. The overall goal of this proposal is two fold. First, C. pneumoniae specific antigens that are recognized during human infection will be exploited to facilitate serodiagnosis and identify putative vaccine candidates. The second goal is to define chlamydial/host cell interactions that lead to entry and survival of C. pneumoniae in host cells relevant to atherosclerosis. The specific focus will be on the interaction of the chlamydial glycan moiety with carbohydrate binding receptors on the host cell. Importantly, infection of epithelial cells can be inhibited with N-linked high mannose type oligosaccharide, the major component of the glycan. The novel hypothesis to be tested is that C. pneumoniae enters through the mannose-6 phosphate receptor by binding to the site involved in transport of phosphomannosylated residues to the lysosome and this differs from C. trachomatis, which utilizes the mannose receptor. The ultimate goals of these studies are to identify C. pneumoniae specific antigens to facilitate laboratory diagnosis and virulence factors playing a role in pathogenesis to guide vaccine development or develop anti-adhesive strategies for prevention of infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHLAMYDIA TRACHOMATIS AND CERVICAL CANCER Principal Investigator & Institution: Madeleine, Margaret M.; Staff Scientist; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 20-MAR-2002; Project End 29-FEB-2004 Summary: (provided by applicant): Human papillomavirus (HPV) causes common, but usually transient, infections of the cervix that sometimes become cervical cancer. Since few of the women infected with HPV get cervical cancer, we are interested in cofactors in addition to HPV that promote tumor formation. One such possible cofactor is Chlamydia trachomatis, a prevalent, sexually transmitted disease that can infect the cervix for long periods of time. A recent article suggested that specific serotypes of C. trachomatis were associated with the development of cervical squamous cell cancer. We have a population based sample of 500 cervical cancer cases and 300 controls blood samples that have been tested for antibodies to HPV and have been interviewed for risk factors for cervical cancer. The tumor tissue has been tested for HPV DNA by polymerase chain reaction. This resource will allow us to quickly and efficiently test for C. trachomatis in order to evaluate two hypotheses. First, whether an increased risk of cervical carcinoma is associated with C. trachomatis, with an emphasis on the relative

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risks associated with the three genital C. trachomatis serotype classes. Second, to examine this association separately among women with the two main histologic types of cervical cancer, squamous cell carcinoma (n=300) and adenocarcinoma (n=200) of the cervix. Control subjects selected for this study have serum antibodies to HPV-16 or -18. The benefit of screening and treatment for chlamydial infections might extend to include prevention of the proportion of cervical cancer promoted by infection with specific serotypes of C. trachomatis. If we are able to confirm the relationship between C. trachomatis and cervical cancer, repeated targeted screening of young women for C. trachomatis may become a higher public health priority. Furthermore, our results would help determine whether further follow up of the C. trachomatis and cervical cancer association is warranted in a more expensive, prospective setting. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHLAMYDIA TRACHOMATIS ENVELOPE COMPONENTS AND VIRULENCE Principal Investigator & Institution: Raulston, Jane E.; Pathology; East Tennessee State University Box 70565 Johnson City, Tn 37601 Timing: Fiscal Year 2004; Project Start 01-APR-1998; Project End 28-FEB-2009 Summary: (provided by applicant): Chlamydia trachomatis is the leading bacterial agent of sexually transmitted infections in the United States and a major culprit in urethritis, cervicitis, endometritis, salpingitis, pelvic inflammatory disease, infertility and ectopic pregnancy. The highest chlamydial infection rates are observed in young people between 15 and 34 years of age. Throughout these peak reproductive years, the endometrial epithelial cell layer lining the uterine cavity is subject to constant changes in levels of micronutrients such as iron, due to hormonal cycling during menstruation. Endometrial epithelial cells are natural target host cells for infection by chlamydiae. The availability of iron is well-known to have a tremendous influence on the production of bacterial antigens, envelope components and virulence factors; these effects are particularly prominent for obligate intracellular pathogens such as chlamydiae. In other pathogens, virulence factors produced in response to low concentrations of iron elicit tissue damage in the host. Certain bacterial iron-regulated proteins are also immunotherapeutic targets for vaccine design. In these studies, the mechanism for regulation of chlamydial iron-responsive proteins and antigens will be examined in Specific Aim 1. Specific Aims 2 and 3 will (i) determine the identities of chlamydial ironregulated proteins, and (ii) quantitatively assess the transcription of the genes encoding these components under iron-deficient growth conditions, respectively. In Specific Aim 4, an envelope transport system will be examined to determine whether or not it functions as a major iron-uptake pathway for the chlamydiae. The long-term objective for these studies are to develop a better understanding of mechanisms for the destructive tissue pathology observed in chlamydial infections and to provide new insights on specific chlamydial proteins and antigens that could be tested for their immunotherapeutic potential. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHLAMYDIA TRACHOMATIS INCA MUTANTS Principal Investigator & Institution: Rockey, Daniel D.; Professor; Microbiology; Oregon State University Corvallis, or 973391086 Timing: Fiscal Year 2002; Project Start 01-MAR-2001; Project End 28-FEB-2006

16

Chlamydia Trachomatis

Summary: (Adapted from the Applicant's Abstract): C. trachomatis variants have been described that are incapable of undergoing inclusion fusion in cell culture. These variants represent 1-2 percent of clinical isolates in Seattle and have been defined as lacking detectable IncA, a chlamydial protein that localizes to the inclusion membrane. Twenty-six independent incA mutant isolates have been sequenced and organized into several distinct categories. The overall goal of the proposed research is to identify distinctions between wild type and non-fusogenic strains and to exploit differences that are defined to better understand chlamydial development and pathogenesis. Experiments are planned to examine molecular and cell biology as well as clinical manifestations of the mutant chlamydiae. Each variant will be compared with matched wild-type controls. In the first aim molecular analyses will be done to determine mechanisms responsible for loss of expression of IncA and possibly other Inc's. In the second aim, growth and development of non-fusogenic strains will be studied in cell culture models. Finally, in the third aim the clinical relevance of the non-fusogenic phenotype will be determined using a retrospective case-control analysis and a monkey model of chlamydial infection. Study of these natural mutants will lead to a better understanding of chlamydial growth, development and pathogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHLAMYDIA TRACHOMATIS INCLUSION MEMBRANE PROTEINS Principal Investigator & Institution: Scidmore, Marci A.; Microbiology and Immunology; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Chlamydiae species are obligate intracellular bacteria that are the most frequent cause of sexually transmitted disease as well as the leading cause of preventable blindness worldwide. Chlamydiae replicate in a nonacidified vacuole, termed an inclusion, which is actively modified by chlamydiae to prevent lysosomal fusion and promote intracellular survival. The molecular determinants that mediate chlamydial pathogenesis are largely undefined primarily due to the inability to manipulate the chlamydial genome. The overall goal of this research is to identify pathogenic mechanisms utilized by chlamydiae to promote and maintain their intracellular survival. Because chlamydiae remain sequestered within a vacuole, all interactions between chlamydiae and their host must be mediated through the inclusion membrane. We have identified Chlamydia trachomatis-specific proteins (IncD/E/F/G) that are localized to the inclusion membrane. Their intracellular localization makes them potential mediators of host-pathogen interactions via direct interactions with host proteins. To achieve our overall goals, we propose to identify biological functions of IncD/E/F/G through identification and characterization of cellular targets of IncD/E/F/G We have identified mammalian 14-3-3 proteins, as the first and only cellular targets of an inclusion membrane protein, IncG. 14-3-3 proteins are dimeric phosphoserine binding proteins that regulate diverse signal transduction pathways through directed subcellular localization of signaling complexes. Specific Aim 1: Experiments are designed to define biological functions of 14-3-3 IncG interactions and determine whether chlamydiae target 14-3-3 proteins to exploit host signal and vesicular-mediated pathways. First, we will disrupt 14-3-3 IncG interactions through expression of 14-3-3 dominant negative mutants and microinjection of anti-IncG antibodies to examine whether 14-3-3's recruitment to the inclusion functions in exploitation of cellular signal transduction and vesicular-mediated pathways. Second, we will use a combination of fluorescence microscopy, yeast tri-hybrid assays and coimmunoprecipitation experiments to determine whether 14-3-3 proteins recruit

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additional signaling proteins to the inclusion. And third, we will employ coimmunoprecipitation experiments to determine whether chlamydiae alter 14-3-3dependent signaling pathways by altering host 14-3-3/ligand interactions. Specific Aim 2 utilizes yeast two-hybrid assays to identify cellular targets of IncD/E/F. Identification of cellular targets of Incs and how these interactions contribute to chlamydial pathogenesis will lead to a better understanding of the complex host-pathogen interactions that facilitate chlamydial intracellular survival. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHLAMYDIA TRACHOMATIS OMP1 GENOTYPE HUMORAL IMMUNITY & GENITAL TRACT CHLAMYDIA Principal Investigator & Institution: Batteiger, Byron E.; Professor; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHLAMYDIAL EVASION OF IFN MEDIATED IMMUNITY Principal Investigator & Institution: Carlin, Joseph M.; Microbiology; Miami University Oxford 500 E High St Oxford, Oh 45056 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 30-APR-2005 Summary: (Adapted from the Applicant's Abstract): This proposal is in response to the program announcement 'Research on molecular immunology of STDs (ROMIS).' Interferon (IFN)-y induces an effective antichlamydial mechanism in vitro by inducing indoleamine 2,3-dioxygenase (IDO) which depletes tryptophan that is essential for chlamydial growth. Although proinflammatory cytokines produced during infection enhance the amount of IDO induced by IFN, the presence of chronic disease suggests that Chlamydia is evading this response. The goals of this research project are to identify and characterize mechanisms by which Chlamydia evades the effect of IFN. Chlamydia may be affecting IDO regulation directly by interfering with transcriptional activation of the IDO gene by IFNS, or by blocking the effect of proinflammatory cytokines. Chlamydia also may be regulating IDO indirectly by stimulating production of interieukin-10 (IL-10) leading to inhibition of IDO transcription. Specific aim 1: Molecular mechanisms of IDO potentiation. IDO regulatory mechanisms will be evaluated using HeLa cells transfected with a green fluorescent protein reporter vector containing the IDO promoter. Identification of IDO promoter regions and DNA-binding proteins will be by DNase I footprinting, EMSA, and super-shift assays. Site-directed mutagenesis will be used to confirm promoter site function. Specific aim 2: Direct mechanisms of evasion. The effect of Chlamydia on IDO promoter activity and cytokine receptor expression will be assessed using two-color flow cytometric analysis of infected HeLa cells. Specific aim 3: Indirect mechanisms of evasion. The role of IL-10 in inhibition of IDO will be assessed by quantifying IL-10 production by Chlamydia-exposed cells using ELISA, assessing the effect of IL-10 on proinflammatory cytokine production by Chlamydia-exposed cells and by measuring the effect of IL-10 on IDO regulation using the fluorescent IDO promoter reporter. Thus, the aims are to dissect the process of IDO potentiation at the transcriptional level, and to assess the means by which Chlamydia interferes with this process. Accomplishment of the aims will help resolve the long- term objectives of this research project: to determine how Chlamydia evades an otherwise

18

Chlamydia Trachomatis

effective immunological response, and to understand regulation of this response in order to overcome Chlamydia's evasive mechanisms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLINICAL EPIDEMIOLOGY OF MYCOPLASMA GENITALIUM Principal Investigator & Institution: Totten, Patricia A.; Professor; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-MAR-2002; Project End 28-FEB-2007 Summary: Large proportions of the major reproductive tract inflammatory syndromes remain idiopathic, not attributable to the major sexually transmitted pathogens such as Chlamydia trachomatis or Neisseria gonorrhoeae. Where effective STD control programs exist, most urethritis in men and endocervicitis or mucopurulent cervicitis (MPC) in women is no longer attributable to gonococcal or chlamydial infection. This is equally true for most upper genital tract complications of urethritis (epididymitis) or endocervicitis (endometritis, salpingitis and perinatal and puerperal morbidity). Mycoplasma genitalium, a fastidious bacterium discovered in 1981, now detectable by PCR, has been significantly associated with nongonococcal urethritis (NGU) in men in 11 of 11 studies over the past decade using PCR, including our own recent study which demonstrated M. genitalium in 27 (22%) of 211 men with and 5 (4%) of 117 without NGU (OR 6.5; 95% CI 2.1- 19.9). Recognition of M. genitalium as a pathogen in the male raises the important question of its role as a pathogen in the female, both in nonpregnant and in pregnant women. Since initial submission of this proposal in February 2000, we have completed two retrospective cross- sectional studies involving women. In a random sample of female STD clinic patients, we demonstrated endocervical M. genitalium infection in 24 (13%) of 191 with MPC vs. 27 (6%) of 453 without MPC (OR adjusted for cervical pathogens 3.0; 95% CI 1.6-5.8). This study also detected M. genitalium in 10 (14.3%) of 70 women with history of spontaneous miscarriage at < 20 weeks gestation vs. 41 (7.2%) of 570 without this history (adj OR=2.5; 95% CI 1.1-5.6). A cross-sectional study of 115 Kenyan women with suspected PID demonstrated M. genitalium in endometrial biopsies from 7 (12%) of 58 women with endometritis vs. 0 of 57 without endometritis (p=0.01). In our studies of male urethritis, MPC, and endometritis, associations of M. genitalium with disease were similar to, or stronger than, the associations with chlamydial infection. These data support our proposed studies as the next logical step in clinical epidemiologic studies of this pathogen. Our three specific aims are to (1) define the role of M. genitalium in acute salpingitis in women undergoing laparoscopy in Nairobi Kenya; (2) define the association of M. genitalium with abnormal pregnancy outcomes including preterm delivery of a low birthweight infant, using data and clinical specimens already available from 2500 women prospectively followed to term at University of Washington hospitals (including 625 with gestation