A collaboration of sorts between viruses and bacteria may lead to cervical cancer, report scientists based at the Max Planck Institute for Infection Biology and the University of Würzburg. To arrive at this finding, the scientists used patient-derived ectocervical organoids to model individual and coinfection dynamics of a human papillomavirus (HPV16 E6E7) and Chlamydia trachomatis.
“Our cervical 3D organoids provide the much-needed near-physiological in vitro models to investigate various facets of cervix biology, including the influence of female reproductive tract infections and coinfections and their molecular mechanisms,” the scientists indicated in a Nature Communications paper. The paper’s senior author, Cindrilla Chumduri, PhD, chair of microbiology at the University of Würzburg, added that multiple infections “create a unique cellular microenvironment that potentially contributes to the reprogramming of tissues and thus to the development of cancer.”
The new findings confirm an old suspicion. For some time, it has been noticed that patients who develop cervical cancer are often infected not only with the human papillomavirus but also simultaneously with the bacterial pathogen Chlamydia trachomatis. This observation suggested that the two pathogens work together to reprogram the cells they infect in such a way that they degenerate and multiply uncontrollably.
Details of the work accomplished by Chumduri and colleagues appeared in a paper titled, “Modeling Chlamydia and HPV co-infection in patient-derived ectocervix organoids reveals distinct cellular reprogramming.” For example, the paper described how ectocervical stem cells in the organoids were genetically manipulated to introduce E6E7 oncogenes to mimic HPV16 integration. Also, the paper presented evidence that the organoids developed the characteristics of precancerous lesions, retained self-renewal capacity, and produced mature stratified epithelium similar to healthy organoids.
“Unique transcriptional and post-translational responses induced by Chlamydia and HPV lead to distinct reprogramming of host cell processes,” the article’s authors wrote. “Strikingly, Chlamydia impedes HPV-induced mechanisms that maintain cellular and genome integrity, including mismatch repair in the stem cells.”
It has long been proven that HPV can cause cancer. Indeed, HPV DNA can be found in more than 90% of all cervical cancers. However, HPV is not the sole culprit. Even though more than 80% of women become infected with HPV during their lifetime, not even 2% develop cancer.
Coinfection with C. trachomatis, then, has been thought to be a major cofactor in driving malignant tissue formation in HPV-associated cervical cancer. “[HPV and C. trachomatis] are among the most widespread sexually transmitted pathogen infections,” observed Stefanie Koster, PhD, a researcher at Max Planck Institute for Infection Biology and one of the first authors of the study. “However, the dynamics of this coinfection and the underlying mechanisms have been largely unknown,” added Rajendra Kumar Gurumurthy, PhD, a group leader at the Max Planck Institute for Infection Biology and another first author of the study.
The problem is that “unlike tumor viruses, whose DNA can be found in tumors, bacteria associated with cancer rarely leave detectable elements in cancer cells,” explained Chumduri. Nevertheless, to link bacteria to cancer development, she said, it is necessary to identify those cellular and mutational processes that contribute to cells undergoing pathological changes. Chumduri and her team have now systematically decoded precisely these processes in the organoids they have developed.
The result: “Our analyses show that HPV and Chlamydia cause a unique cellular reprogramming of the host,” explained the scientists. Several genes are up- or downregulated by the two pathogens in different ways, which is associated with specific immune responses. Among other things, pathogens influence a significant subset of all regulated genes responsible for DNA damage repair.
Overall, the study shows “co-persistence of HPV and Chlamydia in a stem cell could adversely affect cellular and genomic stability and promote neoplastic progression.” The study also demonstrates that 3D organoids of the cervix are suitable for studying various aspects of cervical biology, including drug testing under near-physiological conditions.
Chumduri’s research focuses on two tissue types. The first is the so-called ectocervix—the part of the cervical mucosa that extends into the vagina. The second is the endocervix—the part of the mucosa that lines the cervix further inside, connecting the uterus. The essential task of these tissues is to prevent pathogens from entering the uterus and thus help keep the upper female reproductive tract sterile.
“The areas where the ecto- and endocervix merge forms a transition zone, Chumduri pointed out. “[These areas] are particularly prone to infections and neoplasms.” Most cervical cancers originate there, she added.
“The long-term culturability of [our] organoids and the ability to genetically manipulate them opens avenues of approach to investigate the initiation, progression, and outcome of chronic infections in an authentic preclinical setting,” the authors of the Nature Communications article concluded. “By utilizing this powerful development, we show here the complex tripartite interactions of epithelial tissue, viral and bacterial coinfection, and the impact on host cell response and fate.”