Chlamydia trachomatis serovar D induces Th17-mediated pathology 2257997

Abstract Introduction Infection with Chlamydia trachomatis can result in chronic infection with severe reproductive consequences. The immune response elicited by natural infection fails to protect against reinfection and can also contribute to tissue inflammation and damage. CD4+ T cells are key mediators of protection against C. trachomatis. However, these same cells, together with neutrophils, also contribute to tissue pathology. The identity and effector functions of the CD4+ T cells that contribute to protection, pathology, or both remain poorly defined. Notably, pathology in C. trachomatis is serovar-specific. Infection with serovar D induces severe tissue inflammation in the female upper genital tract, whereas infection with serovar L2 does not. The contrasting yet overlapping immune responses elicited by serovars D and L2 provide a unique model for dissecting the mechanisms that distinguish protective from pathology-inducing immunity. Methods Using a murine model of genital infection, we compared immune responses between infection with serovar D and serovar L2. Flow cytometry and quantitative PCR were used to assess cytokine production and CD4+ T cell polarization, respectively. Single-cell RNA sequencing on uterine CD4+ T cells to characterize transcriptional profiles. Results Infection with serovar D selectively drove the polarization of naïve CD4+ T cells into inflammatory T helper 17 (Th17) cells through the induction of Th17-polarizing cytokines, relative to serovar L2 infection. Single-cell RNA sequencing revealed a Th17-skewed response with transcriptional features of an inflammatory phenotype, including upregulation of Bhlhe40 and Il1r1. Conclusion These findings demonstrate that serovar D promotes pro-inflammatory CD4+ T cell responses that likely contribute to immunopathology in C. trachomatis infection, in contrast to the response elicited by serovar L2. They also underscore the importance of developing a vaccine that elicits protective immunity while minimizing harmful inflammatory responses. Funding Source This work is supported by grants (AI039558 and AI178272) from the National Institutes of Health Topic Categories Mucosal and Regional Immunology (MUC)