Serological variants of Chlamydia trachomatis shape host immune responses

Abstract

Chlamydia trachomatis causes the most commonly reported bacterial sexually transmitted infection (STI) in the United States. C. trachomatis is classified into 15 serovars based on antigenic variation within the major outer membrane protein (MOMP). These serovars exhibit distinct tissue tropisms, infecting conjunctival, urogenital, and lymphoid tissues. Notably, serovars that initiate infection within the same tissue can induce markedly different degrees of tissue inflammation. Although these pathologies are known to result from host immune responses rather than direct bacterial cytotoxicity, both the pathogen and host immune mechanisms that drive serovar-specific inflammatory outcomes remain poorly understood. Here, we investigated serovar-specific immune responses to serovars D and L2, which both establish infection in the urogenital tract, yet produce distinct pathological outcomes. We found that infection with serovar D, a highly inflammatory urogenital serovar, induces an enhanced IL-17-promoting immune response that is partially dependent on IL-1 signaling. These findings reveal serovar-specific host-pathogen interactions within a shared tissue niche and provide insight into mechanisms underlying differential disease pathology during C. trachomatis infection. Previous studies show that infection with serovar D induces increased trafficking of neutrophils, and CD8+ and CD4+ T cells into the murine upper genital tract. Antibody blockade of these populations via anti-Ly6G and anti-CXCR3 ameliorates immunopathology without affecting bacterial burden in serovar D-infected mice. Interestingly, IFNγ-producing CD4+ T cells are the primary protective immune population against this pathogen. Therefore, distinguishing protective immune responses from those that drive pathology, particularly within the CD4+ T cell compartment, is critical for developing therapeutic strategies against C. trachomatis infection. Here, we show that infection with serovar D, compared with serovar L2, induces increased protein levels of IL-1ß, IL-6, and IL-23p19, all cytokines that support IL-17-mediated immune responses, including IL-17A+ CD4+ T cells (Th17). As a result, there is a higher proportion and total number of Th17 cells that infiltrate the upper genital tract of serovar D-infected mice. Moreover, we find that IL-1 signaling contributes to this phenotype, as IL-1R1-deficient mice are unable to mount a similar immune response. Importantly, we find that the Chlamydia plasmid contributes to serovar Dspecific host-pathogen interactions, as plasmid exchange between serovars alters both bacterial fitness and downstream immune responses in vitro. Taken together, our study suggests that within a specific tissue niche, serovars interact differently with the immune compartment, resulting in differential tissue inflammation and pathology during C. trachomatis infection.