Chlamydia infection is a predominantly asymptomatic disease in humans which causes significant morbidity. Bacterial infection ascending to the upper genital tract of women can result in ectopic pregnancy, pelvic inflammatory disease, and possibly infertility. Although antibiotic treatment can eliminate this pathogen, it does not reverse urogenital pathology and thus a vaccine is critically needed. Chlamydia-specific immunity often results in a faulty response which does not provide sterilizing immunity or leaves the individual susceptible to reinfection. Data from human studies, and corroborated by mouse models, indicates CD4+ T cells and production of IFNg are required for immune clearance of the pathogen. However, CD8+ T cells are implicated in causing immune-mediated pathology. Understanding the priming and activity of pathogen-specific CD8+ T cells remains a gap in our knowledge which must be addressed before an efficacious Chlamydia vaccine can be designed. Chlamydia infection can spread from the urogenital tract to the gastrointestinal mucosa. Whereas vaginal and intestine mucosa are generally immune tolerizing, upper genital tract immunity primes a robust immune response. The vagina and intestines are coated with a rich commensal microbiome whereas the upper genital tract has a less abundant microbial community which is drastically different diversity from the lower genital tract. These data support our central hypothesis that both commensal microbiome and location of infection (vagina vs gut) significantly biases development of pathogen-specific immunity. Our overall objective is to understand the immune response to Chlamydia which elicits protection vs pathology. Our rationale is that manipulating commensal microbiomes at the site of inoculation can augment protective immunity and minimize pathological immune sequalae. We will test our central hypothesis by completing the following specific aims.
Aim 1 - comparing the two mouse models of Chlamydia infection (GFP-C. trachomatis ? human pathogen ? mild pathology and GFP-C. muridarum ? mouse pathogen ? heavy pathology) and subsequent CD8+ T cell immunity. A novel TCR transgenic has been created which allows tracking of xenoantigen (GFP) immune responses which, for the first time, will allow comparisons of these two mouse model CD8+ immune responses.
Aim 2 ? characterization of immune development when infection is unable to spread, isolating pathogen to either urogenital or gastrointestinal tissues. We will then examine Chlamydia infectivity and pathogen-specific immune development when commensal microbiomes are manipulated via the use of prebiotics and probiotics. Expected outcomes of this work are an understanding of CD8+ T cell immunity?s role in pathology, differences in mucosal site-specific immunity (vagina vs gut), and the impacts of commensal microbiome on developing Chlamydia- specific CD8+ T cell immunity. This information is critical to our future design of a vaccine against Chlamydia.
Chlamydia infection of the genital tract can lead to significant pathology, such as infertility, making the development of a Chlamydia vaccine a critical need. Pathology is thought to be induced by CD8+ T cell immune responses but our understanding of that immune priming event is lacking. The goal of this proposal is to 1) determine the role of CD8+ T cells in Chlamydia associated pathology, and 2) mechanistically evaluate the role of inoculation site and commensal microbiome at that mucosal site on development of Chlamydia specific CD8+ T cell immunity.
