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[Chlamydiae.com aware that its coverage of chlamydial immunology needed improving, is pleased to present this review from Drs Joseph Igietseme and Carolyn Black, two distinguished scientists at the Communicable Disease Center at Atlanta in Georgia.

The web is an informal medium. In the interests of getting this review rapidly to web browsers, only the minimal editing necessary for transfer to web format has been performed. Thus the references are in the author's original format and the old taxonomy used here has not, except at initial mention, been translated to the current taxonomy. Readers used to the new taxonomy primarily used on this web site should refer to the taxonomy diagram to get their bearings. Thanks to Joseph and Carolyn for an outstandingly useful review of the issues. Registered users of the site may download a copy of the original word document after they have logged in by clicking here. MEW October 2002].

National Center for Infectious Disease, CDC, Atlanta GA 30333 USA, and Department of Microbiology & Immunology, Morehouse School of Medicine, Atlanta, GA 30310 USA. Email: jigietseme@cdc.gov

Introduction

Members of the genus Chlamydia are obligate intracellular, gram negative-like bacteria causing numerous oculo-genital and respiratory infections in humans, animals and birds. Ocular infection by distinct genovars or serovars of C. trachomatis causes trachoma (the world most common preventable blinding disease), while genital infection with other serovars leads to cervicitis and urethritis as the primary sexually transmitted diseases (STDs). Pelvic inflammatory disease and tubal factor infertility are major complications of genital chlamydial infection, constituting enormous morbidity and socioeconomic burden of chlamydia infections. Reports suggesting that genital chlamydial infection may predispose to HIV-related AIDS [Chesson & Pinkerton, 2000; Kilmarx et al., 2001; McClelland et al., 2001; Monno et al., 2001; Rotchford et al., 2000; Thior et al., 1997; Wilkinson & Rutherford, 2001] and human papilloma virus-associated cervical dysplasia have heightened these concerns [Schachter & Grayston, 1998]. Chlamydia pneumoniae (now Chlamydophila pneumoniae) was previously known to cause mild respiratory infections but has recently emerged as an important pathogen associated with atherosclerosis, adult-onset asthma and certain other chronic diseases [Kuo et al., 1995]. The zoonotic Chlamydophila psittaci constitutes an occupational hazard for workers in the poultry and farming industry, and persons exposed to infected avian species [Saikku et al., 1985]. C. pecorum, has not been associated with any human disease.

Although chlamydial infections are treatable with antibacterial agents, such as tetracycline derivatives, especially doxycycline, and the macrolides or azalides including erythromycin and azithromycin, a high proportion of the infections are often asymptomatic and subclinical [Johnson et al., 2000; Schachter, 2001; Thein et al., 2002]. Thus, in women, severe and sometimes irreversible complications usually present as the first symptoms of a genital infection. In addition, while contemporary diagnostic methods are reliable for identifying infections [Black & Morse, 2000; Johnson et al., 2000; Schachter, 2001; Serlin et al., 2002] there are economic and acceptance issues surrounding certain intervention strategies involving frequent community-wide screening for early detection and/or mass treatment [Bain et al., 2001; Dawson & Schachter, 2002; Diamant et al., 2001; Holm et al., 2001; Thein et al., 2002]  to arrest silent or persistent infections. An efficacious vaccine is therefore a sine qua non to control the high morbidity of chlamydial infections in the human population. In fact, computer modelling of the impact of a vaccine has predicted that even a partially successful vaccination program would have a remarkable global impact in reducing chlamydial infections, disease prevalence and associated expenditure [de La Maza & de La Maza, 1995].

Functional immunobiology of Chlamydia has the dual objective to establish the essential immunologic paradigms for defining and evaluating protective anti-chlamydial immune responses to foster vaccine design, and to clarify aspects of the pathogenesis of chlamydial diseases. However, the erstwhile challenges in defining the key elements of protective immunity, to establish parameters for vaccine selection and evaluation, have been compounded by the complexities in chlamydia biology, serovariation, infection manifestations and induction of paradoxical immune effectors that can be both protective and pathologic [LaVerda et al., 1999; Rockey & Stephens, 2000; Schachter, 1985; Wang & Grayston, 1991]. Despite these challenges and the lack of tools needed to genetically manipulate the pathogen, a considerable progress has been made in chlamydial immunobiology, due mainly to major advances in novel molecular, immunologic and genetic methodologies, the convergence of diverse disciplines and technologies, including cellular immunology, cytokine biology, gene knockout model systems, and progress in the cell biology of chlamydia.

The elucidation of the immunobiology of Chlamydia has been the focus of intense research efforts for over 20 years. Experimental animal models and non-human primates have provided valuable information relating to the elements of protective immunity to infection and for testing promising vaccine candidates. The revelation that chlamydial immunity is mediated primarily by a T helper type 1 (Th1) immune response, opened a new era in the immunobiology of Chlamydia, leading to the dawn of the contemporary immunologic paradigm for measuring protective anti-chlamydial immune response and basis of vaccine evaluation. Interestingly, it appears that a major role of anti-chlamydial humoral immune response is via Fc receptor (FcR)-mediated antibody enhancement of induction of Th1 effectors. With continued progress in chlamydial genomics and proteomics, select immunogenic proteins, including structural, membrane and secretory proteins, are being targeted as potential subunit vaccines. However, current vaccine candidates will require more effective and acceptable adjuvants or delivery vehicles to optimize vaccine efficacy. Promising delivery systems include DNA and virus vectors, bacterial ghosts, dendritic cells and specific antibody isotypes. Finally, considering the urgency and enormity of the challenges, a partially protective vaccine that prevents certain severe sequelae would constitute an acceptable short-term goal to control Chlamydia. More research efforts and support are needed to broaden the frontiers of our knowledge of the immunobiology of chlamydia to provide the blueprints for an efficacious chlamydial vaccine.

This review summarizes the contemporary immunobiology of Chlamydia, with special emphasis on the factors that govern the induction of protective anti-chlamydial immunity, the established operational immunologic paradigms and practical techniques driving vaccine designs and fueling the growing optimism for an efficacious vaccine. The information is discussed in the context of a status report that reflects the progress made in defining the essential elements of protective anti-chlamydial immunity, the host, microbial and environmental factors regulating the induction of optimal anti-chlamydial immunity, and prospectives for the development of a protective chlamydial vaccine based on available information. A generalized discussion of the immunobiology of Chlamydia as it pertains to all members of the genus is presented. The validity of a unified approach includes the fact that several conserved genes and immunogenic proteins are common among members of the genus Chlamydia; moreover, vaccine design strategies advocate heterotypic protection across serovars and possibly species, and more importantly, similar immune effectors control most Chlamydia species in experimental animals and humans.

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