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Correspondence: Robert C. Brunham, University of British Columbia and British Columbia Centre for Disease Control, 655 West 12th Avenue, Vancouver, BC, Canada V5Z 4R4. Tel.: +1 604 660 1437; fax: +1 604 660 6066; e-mail: email@example.com
Chlamydia disease expression is the result of complex molecular and cellular interactions between the host and a pathogen which appears to have been sculpted by evolutionary forces. Recent genomic, immunologic, and epidemiologic findings are reviewed. A synthesis is offered which suggests that Chlamydia disease expression results from persistent infection and host immune responses.
One of the most striking features of human infection with Chlamydia is the extraordinary range of clinical manifestations and disease states that infection elicits. On the one hand, each Chlamydia species and biovar is associated with well-described and clinically discernible disease states. On the other, Chlamydia infection in any given host ranges from a subclinical to a clinically recognizable disease. This review offers a perspective on determinants for the remarkable plasticity in Chlamydia disease expression. Much of the perspective focuses on our understanding of disease pathogenesis.
For a full evolutionary understanding of Chlamydia pathobiology, the relationship between Chlamydia disease expression and transmission efficiency will ultimately be essential (Brunham, 2006). Most adapted human pathogens demonstrate linkage between disease mechanisms and transmission efficiency, and this is likely to be the case for Chlamydia (Wolfe et al., 2007). While at this stage a full evolutionary understanding is lacking, certain molecular, cellular and epidemiological findings are now beginning to shape an underlying model for pathobiology.
Host reaction to acute Chlamydia infection ranges from a subclinical response to erythema, edema and mucopurulent discharge, and is histopathologically characterized by neutrophilic and lymphocytic infiltrates (Kuo, 1988). The cellular features of chronic disease include fibrosis and mononuclear cell infiltration, with the intensity of inflammation during acute infection predicting the fibrotic sequelae of chronic infection. Like many other obligate intracellular pathogens, Chlamydia persists in the host after the development of immune responses, thereby producing chronic infection. Furthermore, protective immunity to reinfection is relatively weak, strain specific and long to acquire; thus, reinfection is also a common clinical feature of Chlamydia infection. Accordingly, both persistence and reinfection characterize Chlamydia–host pathobiology.
Two competing hypotheses lie at the heart of the current understanding regarding Chlamydia disease pathogenesis. These hypotheses have been encapsulated as the cellular and immunological paradigms (Brunham & Peeling, 1994; Stephens, 2003). In their most extreme versions, they argue that disease is solely due to innate host responses (the cellular paradigm) or that disease requires antigen-specific adaptive cellular immune responses, which induce immunopathological tissue damage (the immunological paradigm). Persuasive data support both hypotheses and likely both play roles in pathogenesis. To directly prove the immunological hypothesis over the cellular hypothesis would require non-human primate models in which animals with and without an adaptive immune system [such as recombination-activating gene (RAG) knockout] are challenged with Chlamydia. Currently, RAG knockout primates are unavailable. Although T-cell knockout mice are available, the relationship between dissemination and chronicity of Chlamydia muridarum infection observed in murine models and Chlamydia trachomatis disease pathogenesis in humans remains obscure (Morrison & Caldwell, 2002).
Short of primate experiments, it is fair to ask what have less direct lines of research (such as genomics, immunology and epidemiology) contributed to improving our understanding of Chlamydia disease pathogenesis? The findings summarized below are at best fragmentary – each offering a small piece in a larger jigsaw puzzle, whose picture is yet to come into focus. But nonetheless, progress is being made.
The principal finding emerging from Chlamydia genomics research has been the extraordinary conservation of gene order in the genomes from the many different Chlamydia species and biovars (Read et al., 2000, 2003). Clearly, evolution has conserved the genome architecture for Chlamydia over vast expanses of time. Remarkably, all C. trachomatis biovars are highly related, with >99.6% nucleotide identity (Stephens et al., 1998; Carlson et al., 2005; Thomson et al., 2008). The striking biological difference among C. trachomatis strains therefore necessarily suggests that small genome differences must determine the disease phenotype that distinguishes different C. trachomatis strains. Recent research is beginning to shed light on gene correlates with disease expression. In particular, genome-wide comparisons of nine trachoma-causing strains of C. trachomatis found that subtle changes in 22 genes correlated with profound differences in in vitro growth rate, burst size, plaque morphology, interferon-γ sensitivity and virulence in primate ocular models of infection (Kari et al., 2008). Best understood, however, are genome differences located at the replication termination region, or the plasticity zone, of the Chlamydia genome. Differences in the genes at this locus that encode tryptophan synthase strictly correlate with ocular and genital tract tropism for C. trachomatis serovars causing trachoma vs. sexually transmitted diseases (Caldwell et al., 2003). Furthermore, differences in the plasticity zone genes encoding the Chlamydia toxins correlated with epitheliotrophic vs. lymphotrophic properties for C. trachomatis serovars causing trachoma and genital tract infection vs. lymphogranuloma venereum (Belland et al., 2001). Most of these genetic differences are speculated to encode molecules that evade innate or adaptive immune defenses. How these molecules mediate the mechanisms for disease pathogenesis remains an area of active research (Kari et al., 2008).
Importantly, disease pathogenesis mechanisms are also determined by properties of the host genome as well, because multiple allelic variations have been correlated with differences in Chlamydia immunobiology. As much as 40% of the variance in Chlamydia disease expression is speculated to result from host genetic variation. Most identified polymorphisms map to immune defense loci; thus, genomic variations in human leukocyte antigens (Conway et al., 1996; White et al, 1997), interferon-γ, interleukin-10, tumor necrosisfactor-α and matrix metalloproteinase 9 (Natividad et al., 2005, 2006, 2007) have all individually been correlated with differences in resistance and susceptibility. Because T cells are speculated to mediate both protective and pathologic host responses, it is of great interest that the chemokine receptor deletion mutation, CCR5-Δ32, involved in T-cell migration to tissue sites, has been correlated with resistance to C. trachomatis tubal infertility (Barr et al., 2005). While no clear picture has emerged yet, host genomic findings that track both susceptibility and resistance to infection and disease suggest that immunity to and pathogenesis of Chlamydia disease are likely to be deeply entangled at the genetic level and possibly involve tolerance loci in addition to immune defense loci (Ragerg et al., 2007).
Given this entanglement between genetic loci that confer resistance or tolerance to infection and disease, what is known about the molecular interaction between the Chlamydia proteome and the host immune system? Immunological research continues to demonstrate the remarkable finding that specific immune responses to individual Chlamydia proteins bear strong relationship with the observed immunobiology of infection. Such differences in antigen-specific immune responses and their correlation with immunity or disease pathogenesis are likely a reflection of the complex developmental cycle of Chlamydia (Belland et al., 2003). In particular, serovar-specific immunity to infection has been correlated with genotypic variation in omp1 and speculated to be mediated by a conformationally dependent neutralizing antibody to the major outer membrane protein (Brunham et al., 1996; Fan & Stephens, 1997). Interestingly, increasing genotypic variations in omp1 has also been correlated with a higher prevalence of infection at the population level, suggesting the development of herd immunity and a mechanism of immune evasion (Zhang et al., 2004). Interferon-γ responses to the highly conserved Chlamydia heat shock protein 60 (Hsp60) have been correlated with serovar-independent immunity among Kenyan sex workers, while high antibody responses to Hsp60 have been correlated with increased susceptibility to Chlamydia pelvic inflammatory disease among the same group of women (Peeling et al., 1997; Cohen et al., 2005). Overall, however, heterogeneity in effector T- and B-cell responses to specific Chlamydia antigens is unlikely to be simply linked to T helper type 1 (Th1) vs. Th2 CD4 T-cell polarization. A newly defined CD4 T-cell lineage, Th17, with a specific transcriptional regulation of a unique cytokine secretion pattern, has been implicated in mucosal defense against extracellular microbial pathogens and in a number of autoimmune and immunopathological disorders (Medzhitov, 2007). The Th17 cytokine repertoire is proinflammatory but does not include interferon γ, suggesting that such antigen-specific lineages could cause inflammation without mediating clearance for intracellular pathogens such as Chlamydia. The study of Th17 cells in Chlamydia pathogenesis is an urgent research priority. Because dendritic cells orchestrate the developmental pathway for T-cell responses, identification of Chlamydia-specific T-cell peptides and the effector T-cell lineages they elicit should provide the molecular markers to track in vivo the cellular basis for disease pathogenesis and immunity including the role of antigen-specific CD4 T-cell subsets such as Th17 (Karunakaran et al., 2008).
Arguably, it has been epidemiological research that has provided the most important new data regarding Chlamydia disease pathogenesis. These insights have been inferred from detailed analysis of Chlamydia control programs (Brunham et al., 2005). Many jurisdictions are now entering the third decade of large-scale public health programs to control sexually transmitted Chlamydia. The goal of such programs has been to improve the reproductive health of women, and the strategy has been to reduce the duration of Chlamydia infection through laboratory-based case finding, tracing of the source and spread of sexual contacts and single-dose or short-duration antimicrobial treatment.
In jurisdictions where population-wide control programs have been rolled out, the incidence of infection substantially declined for the first decade or so after program launch. However, since the mid-1990s, all Chlamydia control programs have witnessed a rising incidence. This has been associated with increasing rates of reinfection and declining rates of population-level Chlamydia immune experience. Remarkably, similar data have been reported for trachoma control programs based on the SAFE strategy (Atik et al., 2006). These findings suggest that control programs have perturbed the equilibrium of Chlamydia infection in the population, perhaps through reducing herd immunity, and this has been termed the arrested immunity hypothesis (Brunham & Rekart, 2008).
An underlying mechanism for arrested immunity is still speculative. We have suggested that the findings can be understood by considering two attributes of Chlamydia immunobiology. The first is that the development of an immune response that clears infection takes many months to acquire (Molano et al., 2005). The second is that the ‘seek and treat’Chlamydia control strategy by shortening the average duration of infection interferes with the acquisition of this long-to-acquire protective immune response (Brunham, 2006). The direct demonstration that Chlamydia control programs shorten the average duration of infection and interfere with the acquisition of protective immunity, however, remains to be confirmed at the individual and population level.
Given that the goal of Chlamydia control is to improve the reproductive health of women, it is fair to ask what has been the trend in population measures for pelvic inflammatory disease, ectopic pregnancy and tubal infertility during the Chlamydia control era? The figures below show data for British Columbia, Canada, and, surprisingly, indicate that reproductive health has in fact improved throughout the two decades of Chlamydia control even in the face of increasing incidence and reinfection rates (Brunham et al., 2006) (Figs 1 and 2).
At face value, the observations seem paradoxical. How can disease sequelae rates decline if infection rates are increasing? However, these findings can be reconciled if the two previously mentioned attributes of Chlamydia immunobiology are recalled. Chlamydia control has likely shortened the duration of infection, thus eliminating persistent infection from the population. This implies that persistent infection is likely more important than reinfection in the pathogenesis of Chlamydia reproductive diseases. Secondly, Chlamydia control has also uncoupled population infection rates from population prevalence rates of immune responses (Lyytikainen et al., 2008). This implies that immune responses drive disease pathogenesis. Arresting immunity thus also appears to be arresting immunopathology.
Thus, the ‘experiment of nature’ that the Chlamydia control represents can be understood on the basis of the arrested immunity hypothesis, which simultaneously explains both declining population-wide immunity and improving reproductive health if we accept that immunity and disease pathogenesis have underlying immunological mechanisms.
While we are left with more questions than answers, we can conclude that Chlamydia control is achieving its public health goal of improving reproductive health. However, the paradoxical consequences of Chlamydia control have now made Chlamydia immunoepidemiology the most pressing area for new research. Molecular and cellular characterization of Chlamydia immunoepidemiology has the possibility of unmasking Chlamydia disease pathogenesis and providing a means of Chlamydia vaccine development (Brunham, 2006).
Adapted with permission from the Proceedings of the 6th Meeting of the European Society for Chlamydia Research, July 1–4, 2008, Aarhus, Denmark.