Alterations of Vaginal Microbiota and Chlamydia trachomatis as Crucial Co-Causative Factors in Cervical Cancer Genesis Procured by HPV

Abstract

Chlamydia trachomatis and human papillomavirus (HPV) are the most common pathogens found in sexually transmitted infections (STIs), and both are known to increase the risk of cervical cancer (CC) and infertility. HPV is extremely common worldwide, and scientists use it to distinguish between low-risk and high-risk genotypes. In addition, HPV transmission can occur via simple contact in the genital area. From 50 to 80% of sexually active individuals become infected with both C. trachomatis and HPV viruses during their lifetime, and up to 50% become infected with an HPV oncogenic genotype. The natural history of this coinfection is strongly conditioned by the balance between the host microbiome and immune condition and the infecting agent. Though the infection often regresses, it tends to persist throughout adult life asymptomatically and silently. The partnership between HPV and C. trachomatis is basically due to their similarities: common transmission routes, reciprocal advantages, and the same risk factors. C. trachomatis is a Gram-negative bacteria, similar to HPV, and an intracellular bacterium, which shows a unique biphasic development that helps the latter continue its steady progression into the host throughout the entire life. Indeed, depending on the individual’s immune condition, the C. trachomatis infection tends to migrate toward the upper genital tract and spread to the uterus, and the fallopian tubes open up a pathway to HPV invasion. In addition, most HPV and C. trachomatis infections related to the female genital tract are facilitated by the decay of the first line of defense in the vaginal environment, which is constituted by a healthy vaginal microbiome that is characterized by a net equilibrium of all its components. Thus, the aim of this paper was to highlight the complexity and fragility of the vaginal microenvironment and accentuate the fundamental role of all elements and systems involved, including the Lactobacillus strains (Lactobacillus gasseri, Lactobacillus jensenii, Lactobacillus crispatus) and the immune–endocrine system, in preserving it from oncogenic mutation. Therefore, age, diet, and genetic predisposition together with an unspecific, persistent low-grade inflammatory state were found to be implicated in a high frequency and severity grade of disease, potentially resulting in pre-cancerous and cancerous cervical lesions.

HPV co‐infections with other pathogens in cancer development: A comprehensive review

“…The co-infection of CT and HPV (especially the 16, 18, 31, 33, 53, and 56 genotypes) is considered the most important risk factor for the development of cervical cancer. 228 During the initial stages of HPV infection, LCs play a critical role in initiating the immune response against the virus. 249 They present antigens to T cells, and help immune system to recognize and eliminate the virus.…”

“…Furthermore, several studies demonstrated an association between HPV/CT co‐infection and developing abnormal cervical cytology and dysplasia 213,226,227 . The HPV and CT DNAs can be detected in approximately 99% of cervical cancer cases 228,229 . There is a mutual benefit in HPV/CT co‐infection.…”

“…Indeed, CT affects the cervical microenvironment through promotion of inflammatory conditions, and allows HPV penetration into the epithelial cells. HPV also helps CT to spread and multiply by reduction of cell‐mediated immunity 228,230–232 . Dysregulation of metabolic signaling and immune responses, chronic inflammation, epithelial barrier breach, uncontrolled cellular proliferation and apoptosis, genome instability, and angiogenesis activation are different processes that appear to be crucial in HPV/CT co‐infection and CN progression 194 .…”

“…213,226,227 The HPV and CT DNAs can be detected in approximately 99% of cervical cancer cases. 228,229 There is a mutual benefit in HPV/CT co-infection.…”

“…HPV also helps CT to spread and multiply by reduction of cellmediated immunity. 228,[230][231][232] Dysregulation of metabolic signaling and immune responses, chronic inflammation, epithelial barrier breach, uncontrolled cellular proliferation and apoptosis, genome instability, and angiogenesis activation are different processes that appear to be crucial in HPV/CT co-infection and CN progression. 194 In the next sections, we will review some mechanisms of HPV/CT co-infection that may evoke cervical cancer.…”