HPV infection alters vaginal microbiome through down-regulating host mucosal innate peptides used by Lactobacilli as amino acid sources

Abstract

Despite the high prevalence of both cervico-vaginal human papillomavirus (HPV) infection and bacterial vaginosis (BV) worldwide, their causal relationship remains unclear. While BV has been presumed to be a risk factor for HPV acquisition and related carcinogenesis for a long time, here, supported by both a large retrospective follow-up study (n = 6,085) and extensive in vivo data using the K14-HPV16 transgenic mouse model, we report a novel blueprint in which the opposite association also exists. Mechanistically, by interacting with several core members (NEMO, CK1 and β-TrCP) of both NF-κB and Wnt/β-catenin signaling pathways, we show that HPV E7 oncoprotein greatly inhibits host defense peptide expression. Physiologically secreted by the squamous mucosa lining the lower female genital tract, we demonstrate that some of these latter are fundamental factors governing host-microbial interactions. More specifically, several innate molecules down-regulated in case of HPV infection are hydrolyzed, internalized and used by the predominant Lactobacillus species as amino acid source sustaining their growth/survival. Collectively, this study reveals a new viral immune evasion strategy which, by its persistent/negative impact on lactic acid bacteria, ultimately causes the dysbiosis of vaginal microbiota.

Prevotella as the hub of the cervicovaginal microbiota affects the occurrence of persistent human papillomavirus infection and cervical lesions in women of childbearing age via host NF‐κB/C‐myc

“…Previous studies have shown that the incidence of BV 25,26 in women aged 20-45 years ranged from 29.2% to 38.5%, and the HR-HPV infection rate 27 in China was as high as 18.9%. Women with BV may also have a higher risk of HR-HPV infection.…”

“…Women with BV may also have a higher risk of HR-HPV infection. 10,12,25 However, the relationship between persistent infection of different genotypes of HR-HPV and BV remains unclear. To address this major issue, a 2-year prospective cohort study was performed including 920 women aged 20-45 years with different BV statuses (BV positive and BV negative).…”

Disturbances of Vaginal Microbiome Composition in Human Papillomavirus Infection and Cervical Carcinogenesis: A Qualitative Systematic Review

“…Mechanistically, HPV inhibits basal and proinflammatory-induced host defense peptide expression by subverting the NF-κB and Wnt/β-catenin signaling cascades, thus leading to a significant reduction in the Lactobacillus species that rely on amino acid sources, which further promotes an imbalance in vaginal flora. In turn, oxidative stress resulting from BV infiltration promotes the progression of preneoplastic lesions ( 49 ).…”

Influence of Lacidophilin Vaginal Capsules plus rh-IFN-α2b on Efficacy, Vaginal Microecology, and Safety of Patients with HPV Infection

“…Another drug, lacidophilin vaginal capsule is a living bacterium preparation based on lactic acid bacteria (LAB), which can not only improve vaginal microecological flora and abnormalities of acid-base balance but also has a reactivation effect on vaginal immune defense [ 10 ]. It is worth mentioning that HPV infection will lead to the imbalance of vaginal microecology, disrupting the checks, and balances between LAB and other microorganisms [ 11 ]. Given the current lack of research on the application of lacidophilin vaginal capsules plus rh-IFN- α 2b in treating HPV-infected patients, we conduct relevant research in the hope of providing novel insights into the treatment of patients with HPV infection.…”