Mechanisms of Chlamydia and human papillomavirus co-infection in metaplastic tissue of the uterine cervix
Dr. Cindrilla Chumduri
Squamous metaplasia is an adaptive precancerous state that develops in the uterine cervix due to chronic stressors like a vitamin deficient diet. Metaplastic sites show enhanced susceptibility to infections, including human papillomavirus (HPV) and Chlamydia. Importantly, Chlamydia infections have been proposed as a decisive cofactor of HPV-induced carcinogenesis in the cervix. Despite a strong association between enhanced virulence and persistence of pathogens in the squamous metaplastic tissue microenvironment, there has been no systematic analysis of the underlying molecular mechanisms. Our preliminary investigation revealed that the squamous metaplastic epithelium has distinct innate immune features such as altered pattern recognition receptor expression compared to healthy ectocervical and endocervical epithelium. Further, we found that the immune stromal compartment is remodelled to an immunosuppressive state in the metaplastic microenvironment. Therefore, I hypothesise that changes in the innate immunity of metaplastic epithelial and local immune cell microenvironment of the metaplastic epithelial niche promotes enhanced colonisation and persistence of pathogens driving carcinogenesis. Here, we aim to investigate Chlamydia and HPV co-infection processes in metaplastic cervical tissue. We will investigate how infection alters the host tissue microenvironment and which molecular decision points contribute to virulence, persistence, and enhanced carcinogenesis. Towards this aim, we will induce squamous metaplasia in the cervix of wild-type and KRT14-HPV transgenic mice, which express the early genes of HPV, and these mice will then be infected with Chlamydia. We will investigate the extent of alterations in the epithelial-stromal-immune crosstalk upon Chlamydia infection and their influence with and without HPV E6E7 expression on Chlamydia virulence and persistence. This study will identify novel host mechanisms that can be used for therapeutic interventions against pathogens and the prevention of cancer development.