Modelling Chlamydia and HPV co-infection in patient-derived ectocervix organoids reveals distinct cellular reprogramming

Stefanie Koster, Rajendra Kumar Gurumurthy, Naveen Kumar, Pon Ganish Prakash, Jayabhuvaneshwari Dhanraj, Sofia Bayer, Hilmar Berger, Shilpa Mary Kurian, Marina Drabkina, Hans-Joachim Mollenkopf, Christian Goosmann, Volker Brinkmann, Zachary Nagel, Mandy Mangler, Thomas F. Meyer and Cindrilla Chumduri ()
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Stefanie Koster: Max Planck Institute for Infection Biology
Rajendra Kumar Gurumurthy: Max Planck Institute for Infection Biology
Naveen Kumar: University of Würzburg
Pon Ganish Prakash: University of Würzburg
Jayabhuvaneshwari Dhanraj: University of Würzburg
Sofia Bayer: Max Planck Institute for Infection Biology
Hilmar Berger: Max Planck Institute for Infection Biology
Shilpa Mary Kurian: University of Würzburg
Marina Drabkina: Max Planck Institute for Infection Biology
Hans-Joachim Mollenkopf: Max Planck Institute for Infection Biology
Christian Goosmann: Max Planck Institute for Infection Biology
Volker Brinkmann: Max Planck Institute for Infection Biology
Zachary Nagel: Harvard T.H. Chan School of Public Health
Mandy Mangler: Vivantes Auguste-Viktoria-Klinikum
Thomas F. Meyer: Max Planck Institute for Infection Biology
Cindrilla Chumduri: Max Planck Institute for Infection Biology

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Coinfections with pathogenic microbes continually confront cervical mucosa, yet their implications in pathogenesis remain unclear. Lack of in-vitro models recapitulating cervical epithelium has been a bottleneck to study coinfections. Using patient-derived ectocervical organoids, we systematically modeled individual and coinfection dynamics of Human papillomavirus (HPV)16 E6E7 and Chlamydia, associated with carcinogenesis. The ectocervical stem cells were genetically manipulated to introduce E6E7 oncogenes to mimic HPV16 integration. Organoids from these stem cells develop the characteristics of precancerous lesions while retaining the self-renewal capacity and organize into mature stratified epithelium similar to healthy organoids. HPV16 E6E7 interferes with Chlamydia development and induces persistence. Unique transcriptional and post-translational responses induced by Chlamydia and HPV lead to distinct reprogramming of host cell processes. Strikingly, Chlamydia impedes HPV-induced mechanisms that maintain cellular and genome integrity, including mismatch repair in the stem cells. Together, our study employing organoids demonstrates the hazard of multiple infections and the unique cellular microenvironment they create, potentially contributing to neoplastic progression.

Date: 2022
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DOI: 10.1038/s41467-022-28569-1

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