Modelling Chlamydia and HPV Co-infection in Patient-derived Ectocervix Organoids Reveals Distinct Cellular Reprogramming

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Feb 25

PMID 35210413

Authors

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

Cindrilla Chumduri

Affiliations

Soon will be listed here.

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.

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References

Koskela P, Anttila T, Bjorge T, Brunsvig A, Dillner J, Hakama M . Chlamydia trachomatis infection as a risk factor for invasive cervical cancer. Int J Cancer. 1999; 85(1):35-9. DOI: 10.1002/(sici)1097-0215(20000101)85:1<35::aid-ijc6>3.0.co;2-a. View

Griffiths E, Pedersen A, Fenton A, Petchey O . The nature and consequences of coinfection in humans. J Infect. 2011; 63(3):200-6. PMC: 3430964. DOI: 10.1016/j.jinf.2011.06.005. View

Nagel Z, Margulies C, Chaim I, McRee S, Mazzucato P, Ahmad A . Multiplexed DNA repair assays for multiple lesions and multiple doses via transcription inhibition and transcriptional mutagenesis. Proc Natl Acad Sci U S A. 2014; 111(18):E1823-32. PMC: 4020053. DOI: 10.1073/pnas.1401182111. View

Moody C, Laimins L . Human papillomaviruses activate the ATM DNA damage pathway for viral genome amplification upon differentiation. PLoS Pathog. 2009; 5(10):e1000605. PMC: 2745661. DOI: 10.1371/journal.ppat.1000605. View

Spriggs C, Laimins L . Human Papillomavirus and the DNA Damage Response: Exploiting Host Repair Pathways for Viral Replication. Viruses. 2017; 9(8). PMC: 5580489. DOI: 10.3390/v9080232. View

Ssedyabane F, Amnia D, Mayanja R, Omonigho A, Ssuuna C, Nambi Najjuma J . HPV-Chlamydial Coinfection, Prevalence, and Association with Cervical Intraepithelial Lesions: A Pilot Study at Mbarara Regional Referral Hospital. J Cancer Epidemiol. 2019; 2019:9092565. PMC: 6348791. DOI: 10.1155/2019/9092565. View

Kaul D, Rathnasinghe R, Ferres M, Tan G, Barrera A, Pickett B . Author Correction: Microbiome disturbance and resilience dynamics of the upper respiratory tract during influenza A virus infection. Nat Commun. 2020; 11(1):3132. PMC: 7298031. DOI: 10.1038/s41467-020-17020-y. View

Polager S, Kalma Y, Berkovich E, Ginsberg D . E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis. Oncogene. 2002; 21(3):437-46. DOI: 10.1038/sj.onc.1205102. View

Gurumurthy R, Kumar N, Chumduri C . Spatial analysis of organ-wide RNA, protein expression, and lineage tracing in the female mouse reproductive tract. STAR Protoc. 2021; 2(4):100969. PMC: 8605433. DOI: 10.1016/j.xpro.2021.100969. View

10.

Antill Y, Dowty J, Win A, Thompson T, Walsh M, Cummings M . Lynch syndrome and cervical cancer. Int J Cancer. 2015; 137(11):2757-61. PMC: 4573262. DOI: 10.1002/ijc.29641. View

11.

Stanley M, Browne H, Appleby M, Minson A . Properties of a non-tumorigenic human cervical keratinocyte cell line. Int J Cancer. 1989; 43(4):672-6. DOI: 10.1002/ijc.2910430422. View

12.

McLaughlin-Drubin M, Christensen N, Meyers C . Propagation, infection, and neutralization of authentic HPV16 virus. Virology. 2004; 322(2):213-9. DOI: 10.1016/j.virol.2004.02.011. View

13.

Chumduri C, Turco M . Organoids of the female reproductive tract. J Mol Med (Berl). 2021; 99(4):531-553. PMC: 8026429. DOI: 10.1007/s00109-020-02028-0. View

14.

Klaus B, Reisenauer S . An end to end workflow for differential gene expression using Affymetrix microarrays. F1000Res. 2018; 5:1384. PMC: 6063319. DOI: 10.12688/f1000research.8967.2. View

15.

Brake T, Lambert P . Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model. Proc Natl Acad Sci U S A. 2005; 102(7):2490-5. PMC: 548999. DOI: 10.1073/pnas.0409883102. View

16.

Zhong G, Fan P, Ji H, Dong F, Huang Y . Identification of a chlamydial protease-like activity factor responsible for the degradation of host transcription factors. J Exp Med. 2001; 193(8):935-42. PMC: 2193410. DOI: 10.1084/jem.193.8.935. View

17.

Jeon S, Lambert P . Integration of human papillomavirus type 16 into the human genome correlates with a selective growth advantage of cells. J Virol. 1995; 69(5):2989-97. PMC: 188998. DOI: 10.1128/JVI.69.5.2989-2997.1995. View

18.

Aguilar-Lemarroy A, Gariglio P, Whitaker N, Eichhorst S, Zur Hausen H, Krammer P . Restoration of p53 expression sensitizes human papillomavirus type 16 immortalized human keratinocytes to CD95-mediated apoptosis. Oncogene. 2002; 21(2):165-75. DOI: 10.1038/sj.onc.1204979. View

19.

Bracken A, Ciro M, Cocito A, Helin K . E2F target genes: unraveling the biology. Trends Biochem Sci. 2004; 29(8):409-17. DOI: 10.1016/j.tibs.2004.06.006. View

20.

Yim E, Park J . The role of HPV E6 and E7 oncoproteins in HPV-associated cervical carcinogenesis. Cancer Res Treat. 2009; 37(6):319-24. PMC: 2785934. DOI: 10.4143/crt.2005.37.6.319. View