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

Author

Listed:
  • 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
    Charité University Medicine)

  • Thomas F. Meyer

    (Max Planck Institute for Infection Biology
    Christian Albrechts University of Kiel)

  • Cindrilla Chumduri

    (Max Planck Institute for Infection Biology
    University of Würzburg)

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.

Suggested Citation

  • Stefanie Koster & Rajendra Kumar Gurumurthy & Naveen Kumar & Pon Ganish Prakash & Jayabhuvaneshwari Dhanraj & Sofia Bayer & Hilmar Berger & Shilpa Mary Kurian & Marina Drabkina & Hans-Joachim Mollenko, 2022. "Modelling Chlamydia and HPV co-infection in patient-derived ectocervix organoids reveals distinct cellular reprogramming," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28569-1
    DOI: 10.1038/s41467-022-28569-1
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    References listed on IDEAS

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    1. Drishti Kaul & Raveen Rathnasinghe & Marcela Ferres & Gene S. Tan & Aldo Barrera & Brett E. Pickett & Barbara A. Methe & Suman R. Das & Isolda Budnik & Rebecca A. Halpin & David Wentworth & Mirco Schm, 2020. "Author Correction: Microbiome disturbance and resilience dynamics of the upper respiratory tract during influenza A virus infection," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
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