The impact of HPV and Chlamydia (co-)infections on the cellular crosstalk and squamous metaplasia development in the Cervical Transition Zone.

• Applicant: Cindrilla Chumduri, Ph.D.
• Subject Area: Gynaecology and Obstetrics
• Term: from 2021 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466164375

The uterine cervix is the first line of defence against the invading pathogens into the upper female genital tract. It consists of an endocervix lined with single-layered columnar epithelium and ectocervix lined with stratified squamous epithelium, which merges to form a transitional zone (TZ). The TZ is predisposed to squamous metaplasia, in which the squamous epithelium replaces the columnar epithelium in the endocervical region. Chlamydia and human papillomavirus (HPV) are among the most common pathogens that infect the cervix. Active metaplastic changes in TZ are associated with an increased risk of HPV infection and neoplasia development. In addition, co-infection with Chlamydia and HPV are more frequently observed in cervical cancer patients. Despite these clear associations, to date, there has been no systematic analysis of the increased susceptibility of TZ to infections, the induction of squamous cell metaplasia in TZ, or the effect of infections on the TZ niche. Our recent studies with newly developed human cervical organoids, mouse models, lineage-tracing, single-cell sequencing, single-molecule RNA in situ hybridizations showed that vitamin A deficiency alters the cellular composition in the microenvironment of cervical tissue and contributes to the development of squamous cell metaplasia. In parallel, modelling the HPVE6E7, Chlamydia and co-infection using cervical organoids revealed the unique and synergistic reshaping of cellular signalling in the cervical epithelial tissue. In this proposal, the two interdisciplinary research areas of tissue homeostasis and epithelial innate response to infection will be investigated together to (1) elucidate the signalling crosstalk between the epithelial and stromal compartments during vitamin A diet-induced squamous cell metaplasia and (2) understand the modulation of the immune compartment and its role in the development of squamous cell metaplasia. Furthermore, we will analyze (3) how HPV persistence affects chlamydial infections and predisposes to the development of squamous cell metaplasia and (4) which cellular and molecular changes are shared or distinct between vitamin A-induced squamous metaplasia and infections. This study will provide insights into basic principles about how vitamin A deficiency and (co-)infection provide a specific stromal and immunological microenvironment for the establishment of cervical infections and diseases.

• DFG Programme: Research Grants