Chlamydia: Genomics and Pathogenesis Chapter Abstracts
Foreword
Gerry Byrne
Chapter 1
Lessons And Challenges Arising From the "First Wave" of ChlamydiChlamydiaceaeal Genomics
Deborah Dean, Garry S. Myers, and Timothy D. Read
Abstract
Whole genome sequencing of Chlamydiales has revolutionized the way we think about these pathogens and how they interact with their host. The six genomes of C. pneumoniae and C. trachomatis that have been sequenced to date reveal features such as integration of bacteriophages into the genome, large gram negative-like toxins, an extensive family of putative polymorphic membrane protein genes (pmp), a complete type III secretion (T3S) system, incomplete gycolysis and tricarboxylic pathways, and electron transfer systems. Comparative genomics of these genomes identified frameshift mutations, whole and partial gene deletions or reductive loss, and site specific intra- and inter-recombination events in addition to what could be considered direct target repeats (DTR) of remnants of insertion sequence (IS)-like elements. We believe that the discovery has just begun and will be greatly enhanced by comparative genomics of the most evolutionarily distant members of the order, Waddlia chondrophila and Simkania negevensis, and of sequences of recent chlamydial isolates from different human and animal anatomic disease states that represent geographic regions from all over the world. With this comprehensive approach, we will be able to better understand tissue tropism, persistence, pathogenesis, and the evolution of the Chlamydiaceae.
Chapter 2
Environmental Chlamydia Genomics
Matthias Horn, Astrid Collingro, Stephan Schmitz-Esser, and Michael Wagner
Abstract
The discovery of chlamydia-related bacteria in the environment dramatically changed our perception of chlamydial diversity and their environmental occurrence. These so-called environmental chlamydiae display the unique chlamydial developmental cycle and mainly live as symbionts of free-living amoebae. Although there are some indications that environmental chlamydiae might also be able to infect humans, their pathogenic potential is still unclear. The first complete genome analysis of an environmental Chlamydia strain, Protochlamydia amoebophila UWE25, provided novel insights into its biology, which, because of its larger genome compared to the Chlamydiaceae, opened a window on the genetic make-up of the chlamydial ancestor and the evolution of chlamydial virulence. The last common ancestor of the environmental chlamydiae and Chlamydiaceae was already adapted to intracellular survival in early eukaryotes, but was less dependent on its host cell. Several virulence factors required by Chlamydiaceae for interaction with their hosts evolved from genes of the last common ancestor of the environmental chlamydiae and the Chlamydiaceae.
Chapter 3
Chlamydia Proteomics
Svend Birkelund, Brian Vandahl and Gunna Christiansen
Abstract
Chlamydia is a microbial genus from which a high number of genomes have been sequenced. Therefore a global proteomics approach using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) and protein identification by mass spectrometry is possible. Systematic proteomic maps have been constructed for Chlamydia pneumoniae and Chlamydia trachomatis. This has given an understanding of the protein composition of the elementary body. Using proteomics, the responses of C. pneumoniae and C. trachomatis to g-interferon treatment of host cells were characterized and have revealed marked differences between C. trachomatis serovars. Proteomics studies of Chlamydia sub-fractions, such as the Chlamydia outer membrane complex, have led to renewed understanding of the chlamydial cell surface. Finally, proteins secreted by and/or translocated from the chlamydiae to the host cell were identified by use of comparative proteomics. This review describes the proteomics techniques used in Chlamydia research, which are special due to the intracellular growth of Chlamydia. Furthermore, results obtained with proteomics in Chlamydia research will be described and discussed.
Chapter 4
The Chlamydial Host-Pathogen Interaction: DNA Microarray Analysis
Robert J. Belland
Abstract
The pathogenesis of chlamydial disease derives from the complex interaction between the pathogen and its host during replication and transmission of the bacteria. A genome-wide analysis of this interaction at the cellular level has been accomplished using host and pathogen-specific microarrays. Chlamydia-specific microarrays have been used to define the coordinated nature of expression waves that give rise to the developmental cycle. In addition, in vitro modeling of non-productive or persistent growth and nutritional shifts have been analyzed. Host-specific microarrays have been used to analyze the response to infection in a variety of cell types using viable and inactivated organisms. The obligate nature of the interactions during chamydial growth lead to problems and advantages for microarray studies that are particular to the system, including the biphasic nature of the developmental cycle and the balance between acute and persistent growth. The contribution of microarray analyses to the understanding of chlamydial disease is significant and expanding rapidly. Future areas of importance include "parallel" microarray studies of the host and pathogen and microarray analysis of in vivo models of infection and disease.
Chapter 5
[Obligate Intracellular Parasitism]2. The Chlamydiaphages
Zhi Liu, Hui-zhong Shou, Ru-ching Hsia and Patrik M. Bavoil
Abstract
Chlamydiaphages are obligate intracellular parasites of bacteria of the family Chlamydiaceae, themselves obligate intracellular parasites of eukaryotic cells. These phages, which are genetically and structurally related to the prototypic coliphage fX174, gain access to replicating chlamydiae by first attaching to the extracellular, metabolically inert elementary body (EB), "riding in" during EB internalization and replicating within aberrantly enlarged reticulate bodies (RBs) that resemble stress-induced persistent forms. Phage-induced lysis of the host chlamydiae and their eukaryotic host cells releases abundant phage progeny that displays high avidity for chlamydial membranes. Five chlamydiaphages have been isolated to date, although oddly none from the human pathogen Chlamydia trachomatis. Although the chlamydiaphages are lytic, phage genomic DNA is stably inserted into the genomes of C. pneumoniae and C. caviae. Possible implications of phage "super"-infection on chlamydial infection and disease are considered. Most importantly, the potential exploitation of chlamydiaphages as vectors for the development of a genetic system for their host chlamydiae is discussed.
Chapter 6
Regulation of Gene Expression
Ming Tan
Abstract
Chlamydia is able to regulate its gene expression so that gene products are available when they are needed. There is accumulating evidence of patterns of coordinated gene expression, which has led to interest in the underlying mechanisms of regulation, especially at the level of transcription. Assays have been developed to study the major form of chlamydial RNA polymerase and to define the promoter that is recognized to initiate transcription. Information from the genome sequence, and functional studies, have demonstrated that transcription is regulated by two general mechanisms that are conserved in other bacteria. In the first mechanism, RNA polymerase activity can be positively or negatively regulated by cis-acting DNA elements and transcription factors. A second mechanism involves the use of alternative forms of RNA polymerase to transcribe subsets of genes through recognition of a different promoter structure. Examples of both mechanisms have been functionally reconstituted, allowing us to define some of the components that are necessary for regulation in Chlamydia. This review will cover these recent advances in our understanding of chlamydial gene regulation and will discuss future directions.
Chapter 7
In Silico Identification of Chlamydial Promoters and Their Role in Regulation of Development
Sarah Mathews and Peter Timms
Abstract
Even though Chlamydia has a relatively small genome, remarkably little is known about gene regulation in this important human and animal pathogen. The three sigma (σ) factors, σ66, σ28 and the alternate σ factor, σ54 are differentially expressed during the chlamydial developmental cycle, suggesting an involvement in stage-specific regulation. The chlamydial σ66 is unusual in that it has unique C- and N-terminal amino acid extensions which might explain why many chlamydial genes are not readily transcribed by the E. coli σ70. Recent work has made use of the rapid advances in bioinformatics screening tools to analyze the increasing number of whole chlamydial genome sequences. Simple pattern matching algorithms have been successful in identifying σ54 promoters due to the high conservation of this type of promoter. However, the identification of σ70-like (σ66) and σ28 promoters in Chlamydia requires a more sophisticated pattern matching approach due to the degeneracy allowed in the consensus sequences. A promoter weighted matrix search with subsequent phylogenetic foot-printing is proving to be a useful approach for predicting promoters with up to 70% of in silico predicted promoters being identified biologically as true promoters. Interestingly, a significant number of transcript-mapped promoters in one species (C. trachomatis) do not readily foot-print across to other species (C. pneumoniae), which may indicate significantly different mechanisms for regulating key genes between the species.
Chapter 8
Tryptophan Metabolism in Chlamydiae
Heidi Wood, Harlan Caldwell and Grant McClarty
Abstract
The trpRBA operon is unique to human C. trachomatis isolates, an observation that intuitively suggested that it might be important in host-pathogen interactions. In support of this hypothesis, C. trachomatis genital and ocular isolates can be unambiguously distinguished from one another by specific mutations in their trpRBA operon; specifically, genital isolates were shown to have an intact operon and encoded a functional tryptophan synthase, whereas ocular strains exhibited mutations in the trpA or trpB genes that resulted in a non-functional synthase. The ability to synthesize a functional synthase was a potential virulence factor for genital, but not ocular strains. For example, the synthesis of a functional synthase was clearly associated with the ability of genital strains to be rescued by exogenous indole from the inhibitory effects of IFN-g, which depletes intracellular tryptophan pools through the induction of the tryptophan-catabolizing enzyme, indoleamine-2,3-dioxygenase. The ability to synthesize tryptophan from indole could be a major pathogenic mechanism that allows genital strains to avoid host cellular immune responses, particularly in environments where mixed microbial infections predominate and indole producers are found.
Chapter 9
Iron and Micronutrients
Jane E. Raulston
Abstract
The ability of a microorganism to attach, colonize, invade and spread within mammalian hosts depends on the sequestration of iron and other micronutrients at each step of the infectious process; only the most successful will emerge as pathogens. During infection, the withholding of iron is an early defense mechanism used by the host which, in turn, stimulates increased expression of toxins, virulence factors, surface adhesins and iron transporters, multidrug resistance pumps and DNA recombination and repair proteins by the pathogen. The host immune system responds to many of these pathogenic factors in both protective and destructive manners. This complex relationship is best understood for pathogens that do not require the intracellular environment of a eukaryotic cell for growth. However, most investigators and members of the medical community agree that the role of iron and micronutrients in infection is a crucial process for obligate intracellular pathogens. Several Chlamydia investigators have shown interest in the effect of iron withholding on chlamydial pathogenesis, but we are only at the beginning stages of dissecting this complex interaction. Current and future studies, using imaginative approaches, will undoubtedly constitute an exciting journey to provide insight into how and why these organisms are pathogens.
Chapter 10
The Polymorphic Membrane Protein Gene Family of the Chlamydiaceae
Chun Tan, John K. Spitznagel, Hui-zhong Shou, Ru-ching Hsia, and Patrik M. Bavoil
Abstract
Comparative genomics in the Chlamydiaceae have revealed the scale and diversity of a unique family of polymorphic membrane proteins (Pmps). Nine to 21 pmp genes encode large proteins that are all phylogenetically related to one of six basic subtypes (pmpA, B, D, E, G and H). Pmp proteins are secreted via autotransport whereby an immunogenic amino terminal passenger domain remains associated with the outer surface of the outer membrane. Differential expansion of subtypes pmpE and pmpG is notable in C. pneumoniae, caviae and abortus. Frameshift mutations in tracks of Cs in some pmp genes are consistent with a high frequency phase variation mechanism through mispairing during replication. These genetic features and the Pmps' strong immunogenicity suggest that the pmp gene family may form the basis of a mechanism of antigenic variation designed for immune evasion and/or adaptation to varied environments. Key roles in pathogenesis are emerging with the highly conserved, single copy PmpD protein proposed to function as an adhesin for C. pneumoniae, and several Pmps observed to stimulate production and release of pro-inflammatory cytokines in animal model systems.
Chapter 11
The Chlamydia Type III Secretion System: Structure and Implications for Pathogenesis
Kenneth A. Fields and Ted Hackstadt
Abstract
Chlamydia genomes contain a complement of genes capable of encoding type III secretion machinery and sufficient data are now available to indicate that these genes are expressed and the products constitute a functional secretion apparatus. Given the association of the type III secretion mechanism with virulence in other Gram negative pathogens, the finding that chlamydiae employ this mechanism has generated considerable interest in elucidating the contributions of this system to chlamydial pathogenesis and development. We summarize herein current progress in the characterization of the chlamydial type III mechanism and discuss the mechanism as inferred from characterized type III secretion systems with emphasis on possibilities for novel interactions of the chlamydial apparatus with the host cell. Finally, we consider possible contributions of secreted effector proteins to the unique pathogenesis of Chlamydia spp.
Chapter 12
Proteins in the Chlamydial Inclusion Membrane
Daniel D. Rockey and Damir Alzhanov
Abstract
All chlamydiae develop and multiply within a unique non-acidified vacuole termed the inclusion. This vacuole is decorated with a group of proteins (Inc proteins) that are unique to the chlamydial lineage. Each chlamydial genome encodes several demonstrated or candidate Inc proteins, most of which have no known function. While these proteins were initially identified in the pregenomic era, the sequencing of chlamydial genomes has provided significant information regarding inc genes and Inc proteins. Genomics studies support a model in which many Inc proteins are produced by each chlamydial species and several of these are produced very early in development. Inc proteins may also be important antigens in cell-mediated immune responses following chlamydial infection. We anticipate that the next several years will see significant progress describing Inc protein structure and function, and this will provide a clearer window into the nature of chlamydial inclusion biogenesis and chlamydial intracellular biology.
Chapter 13
Chlamydial Exploitation of Host Signaling, Cytoskeletal, and Membrane Trafficking Pathways
Marci A. Scidmore
Abstract
Chlamydiae are obligate intracellular bacteria that replicate within the confines of a membrane bound vacuole, termed an inclusion. Similar to other pathogenic bacteria, chlamydiae exploit normal host cell processes to mediate and regulate every facet of their intracellular development and survival. Chlamydiae exploit host cytoskeletal, signaling and membrane trafficking pathways to mediate their entry into cells, to facilitate the intracellular redistribution of the vacuole, to regulate the fusogenic properties of the inclusion, to reroute host derived lipids, nutrients and biosynthetic precursors to the inclusion as well as to modulate and influence host inflammatory responses to the organism. This review will focus on the specific host pathways that are exploited by chlamydiae, their biological relevance to development or ability to cause disease, and, where known, the chlamydial proteins that may mediate these interactions.
Chapter 14
A Pathogen with Two Personalities: Death and Survival during Infection With Chlamydia
Philippe Verbeke, Lynn Stahl, Thomas Jungas, Christiane Delarbre and David M. Ojcius
Abstract
A number of Chlamydia species have been shown to block and induce apoptosis of the host cell. Resistance of the infected host-cell to apoptosis triggered by external pro-apoptotic stimuli is due to the ability of infection to inhibit cytochrome c release from mitochondria, which otherwise leads to caspase-dependent apoptosis. At later stages of infection, the host cells succumb to cell death, through pathways that rely on caspase-independent mediators. Resistance to apoptosis is observed early during the chlamydial developmental cycle and should favor survival of the host cell, but at longer periods could also play a role in the maintenance of chlamydial persistence. Host-cell death takes place towards the end of the developmental cycle and could contribute to propagation of infection in the host organism. While infected cells probably die through both necrosis and apoptosis, the nature of host-cell death has a profound effect on the host inflammatory response.
Chapter 15
Polarized Epithelial Cell Culture for Chlamydia trachomatis
Priscilla B. Wyrick
Abstract
Epithelial cells lining the urogenital tract are architecturally structured in a polarized orientation with distinct apical and basolateral plasma membrane domains. Each domain has a different protein and lipid composition as well as distinct receptors, ion transporters and channels, signal transduction proteins, and cytoskeletal proteins maintained by different intracellular trafficking pathways. This three-dimensional spatial asymmetry and the respective extrinsic spatial cues define the compartmental barrier and homeostatic functions of the mucosal epithelial cell. This polarized epithelial cell is also the epicenter of chlamydial biology. However, most in vitro studies of chlamydial biology are performed in non-polarized epithelial cells, which are quite different in organization from polarized epithelial cells. In vitro culture methodologies exist to mimic to some degree the polarized organization of epithelial cells in vivo. Comparisons of chlamydial infection and growth parameters in genital epithelial cells cultured in vitro in polarized versus non-polarized fashion reveal some intriguing differences, including: (i) EB infectivity; (ii) mechanisms of EB entry and exit; (iii) the duration and synchronization of the developmental cycle; (iv) a prolonged persistent state; and (v) reactivity to antibiotics, (vi) hormones and (vii) innate inflammatory response cells. In our earnest pursuit to better understand chlamydial biology, pathogenesis and infection, we must remember to think about the host epithelial cell and think about the patient.
Chapter 16
Innate Immunity
Toni Darville
Abstract
The innate immune response can be divided into three phases: a recognition phase, an activation phase, and an effector phase. The strategy of the innate immune response is not to recognize every possible antigen, but rather to focus on a few, highly conserved structures present in large groups of microorganisms. These structures are referred to as pathogen-associated molecular patterns (PAMPs), and the receptors of the innate immune system that have evolved to recognize them are called pattern-recognition receptors (PRRs). Identification of a PAMP by an innate immune cell leads to immediate activation, with subsequent release of chemokines and cytokines. These soluble protein mediators elicit leukocyte migration into the area of infection and further activation of innate effector cells. Innate immune effector cells include macrophages, polymorphonuclear neutrophils (PMNs), and natural killer (NK) cells. Numerous reports exist regarding the roles of these cells in host defense against chlamydial infection. However, data regarding their role in disease pathogenesis are less complete. Innate immune cell PRRs involved in recognition of chlamydiae have recently been reported. Likewise, specific chlamydial molecules have been identified as PAMPs capable of initiating an innate immune response. Studies defining chlamydial PAMP - cellular PRR interactions and the specific responses induced by these interactions are in their infancy. Ongoing studies indicate that multiple host cell PRRs interact with chlamydiae, and the responses induced by specific PAMP-PRR interactions differ. Thus, the possibility exists to define chlamydial PAMP-host PRR interactions that promote a more optimum innate immune response, one that results in efficient eradication of the organism, with less tissue damage.
Chapter 17
The Role of the CD4 T Cell in the Host Response to Chlamydia
Roger G. Rank
Abstract
There are a multitude of elements which comprise the host response to infection; however, the heart of the host response is the CD4 T cell, with the other components either leading to the activation of this cell or being driven by its activation. Studies on the immune response to chlamydial infections in all of the relevant animal models have demonstrated that the CD4 cell is the critical element in the protective immune response and variations in the degree of protective immunity may relate to either down-regulation or up-regulation of its effector functions. As in most bacterial infections, it is the Th1 subpopulation of CD4 cells which is responsible for resolving chlamydial genital infection, via an effector cytokine response with gamma interferon playing a key role. In addition to the cell-mediated immune response, CD4 cells figure prominently in the activation of B cells and the resultant production of antibody, which has also been found to play an important role in both resolution of chlamydial infection and resistance to reinfection.
Chapter 18
CD8+ T cell Recognition of Cells Infected with Chlamydia
Zarine R. Balsara and Michael N. Starnbach
Abstract
CD8+ T cell responses are stimulated following infection with Chlamydia. There is increasing evidence that this component of adaptive immunity may play an important role in controlling Chlamydia infection, most likely through the secretion of interferon-gamma (IFN-g). Nevertheless, while the immune system is essential for clearance of the organism, there is also an appreciation that much of the disease states associated with Chlamydia infection are likely to be immune-related pathology resulting from chronic inflammation and persistence of the organism. For this reason, Chlamydia vaccines are likely to require the mobilization of all arms of the adaptive immune system to achieve sterilizing immunity against the pathogen. To this end, several investigators have worked to identify Chlamydia-specific CD8+ T cell antigens that could potentially be incorporated into a multi-subunit vaccine. While this is still an active area of investigation, a number of CD8+ T cell antigens have already been identified, ranging from proteins that localize to the Chlamydia inclusion membrane to those derived from the outer membrane of the bacterium. Equally exciting is the potential for this work to improve our understanding of the pathogenesis of Chlamydia. CD8+ T cell antigens represent a subset of Chlamydia proteins that access the host cell cytosol and could potentially influence host cell processes during infection.
Chapter 19
T Lymphocyte Trafficking to the Female Reproductive Mucosae
Kathleen A. Kelly
Abstract
Chlamydiae influence the recruitment of lymphocytes to the site of infection by inducing the release of local host factors. These host factors serve to modify the adhesion cascade. In turn, this modifies the particular type of T lymphocyte subsets recruited to the female reproductive tract in response to infection. In addition, the local tissue can also modulate the adhesion cascade by expressing tissue-specific adhesion molecules and chemokines. While T helper type 1 lymphocytes are necessary to eliminate Chlamydia, they or other T lymphocyte subsets may contribute to fallopian tube damage. Thus, regulation of the T lymphocyte response recruited upon infection with chlamydial organisms is central to controlling the development of female infertility. Various T lymphocyte subsets have been described and are recruited to tissues by different mechanisms. This review will provide the reader with a basic understanding of the mechanisms that are responsible for this selective homing of T lymphocyte subsets, how these apply to the female reproductive tract and how infection with Chlamydia can modify this process.
Chapter 20
Alternative Mechanisms of Pathogenesis
Kyle H. Ramsey
Abstract
The hallmark of an adverse outcome of ocular and genital Chlamydia trachomatis infection is fibrosis. The process leading to fibrosis is ill-defined but variations in the host immune response are to blame because not all who are infected will sustain significant fibrosis. The central hypothesis stated herein is that factors determining the initial inflammatory insult set the stage for events that eventually lead to fibrosis. These factors are related to the degree of inflammatory proteolysis of the extracellular matrix (ECM) and the repair thereof. Related topics to be discussed are the initiation of inflammation by the infected epithelial cell, transepithelial migration (TEM) of neutrophils, oxygen and nitrogen radical production, degranulation products of inflammatory cells, control points in acute and chronic inflammation and factors that may affect the repair response following resolution of inflammation. Identification of variances in the host response that lead to susceptibility to adverse chlamydial infection outcomes could lead to the development of therapies that reduce chlamydial disease; noninvasive diagnostic or prognostic indicators of progressive scarring and abnormal physiological outcome; and, further advances in the design of a safe and effective Chlamydia vaccine through avoidance of adverse outcomes of infection and immunization.
Chapter 21
Pathogenesis of Chlamydia-Associated Arthritis
Judith A. Whittum-Hudson, Hervé C. Gérard, H. Ralph Schumacher Jr., and Alan P. Hudson
Abstract
An often severe inflammatory arthritis has long been known to follow urogenital infection with Chlamydia trachomatis, and recent research results indicate that a similar clinical entity can be elicited by the respiratory pathogen C. pneumoniae. In both cases, available data show that organisms in the persistent state of infection are responsible for synovial pathogenesis, rather than organisms undergoing full passage through the developmental cycle. Importantly, studies from many groups have demonstrated that antibiotic treatment of patients with Chlamydia-induced arthritis is ineffective. In this chapter, we review the clinical aspects of inflammatory arthritis elicited by Chlamydia. We also outline our current understanding concerning the mechanisms of joint pathogenesis elicited by persistent Chlamydia, and available information regarding host-pathogen interaction at that site. Based on this information, we suggest a number of areas for future study which should prove useful in furthering our understanding of the synovial pathogenesis process elicited by Chlamydia. In turn, such increased understanding will inform the development of new, more effective therapies to treat the disease.
Chapter 22
Interactions of Chlamydia With the Host Cell That Mediate Attachment and Uptake
Lee Ann Campbell and Cho-chou Kuo
Abstract
Chlamydiae are obligate intracellular parasites that appear to use various mechanisms to attach to host cells including electrostatic interactions and chlamydial ligands, which bind to specific receptors. Chlamydiae have been shown to enter the host cell via receptor-mediated endocytosis into clathrin coated pits. Several ligands have been implicated in attachment, including a heparan sulfate-like glycosaminoglycan (GAG), the major outer membrane protein (MOMP), a high mannose oligosaccharide glycan moiety, OmcB, and heat shock protein 70. Although a role of GAG in attachment is well supported, there is controversy in the field as to whether this moiety resides on the host cell or on chlamydiae and, if GAG resides on the organism, whether chlamydiae synthesize it or directs the host cell to synthesize GAG. Moreover, both GAG -dependent and -independent mechanisms of infectivity have been described. Various receptors have been implicated in entry of chlamydiae into host cells, including the heparan sulfate receptor, mannose and mannose 6-P receptors, and the estrogen receptor. Cumulatively, chlamydiae use various mechanisms of attachment and these mechanisms may differ depending on the host cell and the Chlamydia species or serovar.
Chapter 23
The Impact of Chlamydia Basic Research on Disease Control
Robert C. Brunham
Abstract
Basic research produced the tools (nucleic acid amplification tests for case finding and single dose azithromycin for treatment) which form the basis for today's Chlamydia control strategies. However, the present approach has yielded only transient gains and new strategies are needed. The current research enterprise based on genomics, cell biology and animal models is yielding findings at an unprecedented pace. Despite this, new research knowledge has yet to be translated into practical programs. The remaining great challenges in Chlamydia research include the development of a vaccine and the elucidation of the relationship between molecular pathogenesis and transmission patterns within defined social networks. Success in these areas will transform efforts to control and prevent Chlamydia.
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