Cervicovaginal Microbiome Factors in Clearance of Human Papillomavirus Infection

Abstract

Persistent high-risk human papillomavirus (hrHPV) infection is the highest risk to cervical cancer which is the fourth most common cancer in women worldwide. A growing body of literatures demonstrate the role of cervicovaginal microbiome (CVM) in hrHPV susceptibility and clearance, suggesting the promise of CVM-targeted interventions in protecting against or eliminating HPV infection. Nevertheless, the CVM-HPV-host interactions are largely unknown. In this review, we summarize imbalanced CVM in HPV-positive women, with or without cervical diseases, and the progress of exploring CVM resources in HPV clearance. In addition, microbe- and host-microbe interactions in HPV infection and elimination are reviewed to understand the role of CVM in remission of HPV infection. Lastly, the feasibility of CVM-modulated and -derived products in promoting HPV clearance is discussed. Information in this article will provide valuable reference for researchers interested in cervical cancer prevention and therapy.

Keywords: CVM-derived product; CVM-targeted intervention; HPV clearance; cervical cancer; high-risk HPV.

Figure 1

Imbalanced CVM in HPV-infected cervix. The left is the normal cervicovaginal microenvironment without HPV infection, and the right is HPV-positive microenvironment (HPV-infected cells are labelled purple). Created in BioRender.com.

Figure 2

Cervicovaginal microenvironment in persistent HPV infection and natural HPV clearance. (A) L. iners- or non-Lactobacillus-dominated CVM is characterized by allowing the proliferation of anaerobes which produce sialidase to disrupt epithelial barrier and then facilitate the entry of HPV. HPV particles exist in infected keratinocytes as episomes before entry into the nucleus, and viral integration induces high expression of E6/E7 proteins to promote abnormal cell proliferation as well as carcinogenesis. L. crispatus-dominated CVM is associated with natural HPV clearance and CIN regression. (B) For HPV-positive women with L. crispatus-dominated CVM, L. crispatus can inhibit growth of anaerobes through several mechanisms (microbe-microbe interaction) and activate LCs which is the only APCs in cervical epithelium to present HPV antigens and induce HPV-specific CMI (host-microbe interaction). Both microbe- and host-microbe interaction decrease the level of factors correlated with barrier impairment (sialidase and biofilm of anaerobes) and suppressive immunity (Treg, Th2, Th17 cells, IL-10, IL-17, TGF-ß), and increase the expression of biomarkers in activated LCs (antigen-binding langerin and TLR9, antigen-presenting CD1a and MHC-I, co-stimulatory molecule CD80/86 and CD40) as well as CMI-associated molecules (cytotoxic T lymphocytes-CTLs, Th1 cells, IFN-γ, TNF-α). This figure applied icons in BioRender.com.

Figure 3

CVM-modulated and -derived products in eliminating HPV infection. (A) Strategies to modulate dysbiotic CVM were characterized by anaerobe overgrowth. (B) Molecules produced by specific microbial strains in CVM can activate LCs in the cervical epithelium, then promote T cell priming and eliminate HPV-infected cells. Icons in BioRender.com were utilized to prepare this figure.