Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
Chair of Microbiology, University of Würzburg, Würzburg, Germany.
Nat Commun. 2022 Feb 24;13(1):1030. doi: 10.1038/s41467-022-28569-1.
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.
致病微生物的合并感染不断侵袭宫颈黏膜，但它们在发病机制中的作用仍不清楚。缺乏能够重现宫颈上皮的体外模型一直是研究合并感染的瓶颈。我们使用患者来源的宫颈外植体类器官，系统地模拟了与致癌作用相关的 HPV16 E6E7 和衣原体的单独感染和合并感染动力学。通过基因操作，将外胚层干细胞中的 E6E7 致癌基因导入，模拟 HPV16 的整合。这些干细胞来源的类器官在保留自我更新能力的同时，发展出癌前病变的特征，并组织成类似于健康类器官的成熟分层上皮。HPV16 E6E7 干扰衣原体的发育并诱导其持续存在。衣原体和 HPV 诱导的独特转录和翻译后反应导致宿主细胞过程的显著重编程。值得注意的是，衣原体阻碍了 HPV 诱导的维持细胞和基因组完整性的机制，包括干细胞中的错配修复。总之，我们的类器官研究表明了多种感染的危害及其所创造的独特细胞微环境，这可能有助于肿瘤的进展。
