# Trichomonas vaginalis adhesion protein 65 facilitates human papillomavirus entry via SPCS1-mediated upregulation of CD151 and HSPG2 in keratinocyte lineage

## TL;DR

This study reveals how a protein from a common parasite helps human papillomavirus infect cells, increasing cervical cancer risk.

## Contribution

The study identifies a novel TvAP65-SPCS1-CD151/HSPG2 pathway that explains how Trichomonas vaginalis enhances HPV infection.

## Key findings

- T. vaginalis increases HPV entry by upregulating CD151 and HSPG2 in epithelial cells.
- TvAP65 knockdown reduces HPV infection and receptor expression, while overexpression amplifies it.
- SPCS1 is a key mediator, and its knockdown synergistically suppresses HPV entry with TvAP65.

## Abstract

Cervical cancer driven by human papillomavirus (HPV) infection remains a critical global health challenge. Co-infection with Trichomonas vaginalis, a prevalent sexually transmitted protozoan, is strongly associated with increased susceptibility to HPV, yet the molecular basis for this synergy is unclear. Here, we investigated the role of T. vaginalis adhesion protein 65 (TvAP65) in HPV entry, focusing on its interaction with host factors in epithelium.

Using in vitro (human adult low calcium high temperature keratinocytes, HaCaT cells) and in vivo (BALB/c athymic nude mice, BALB/cA-nu mice) models, we assessed HPV infection rates and the expression of HPV entry receptors (cluster of differentiation 151, CD151 and heparan sulfate proteoglycan 2, HSPG2) under T. vaginalis exposure. TvAP65 was either knocked down or overexpressed to evaluate its functional impact. A siRNA screen targeting 12 host molecules that interact with TvAP65 identified signal peptidase complex subunit 1 (SPCS1) as a key mediator. Dual knockdown of TvAP65 and SPCS1 or HPV receptors (CD151/HSPG2) was performed to dissect mechanistic hierarchies. Statistical analyses were performed using Student’s t-test for two-group comparisons and analysis of variance (ANOVA) for comparisons involving three or more groups (P < 0.05).

T. vaginalis markedly enhanced HPV entry in epithelial cells by upregulating CD151 and HSPG2 (P < 0.001). TvAP65 knockdown reversed this effect, reducing HPV infection by 21.76 ± 0.12% (P < 0.001) and protein-level expression of the receptors (P < 0.001), while overexpression amplified both. Strikingly, SPCS1 knockdown alone attenuated HPV infection by 33.61 ± 0.40% and abolished T. vaginalis-driven CD151/HSPG2 upregulation. Dual knockdown of TvAP65 and SPCS1 synergistically suppressed HPV entry (54.64 ± 0.39% reduction, P < 0.001), confirming the central role of SPCS1 in TvAP65-mediated receptor activation.

Our study unveils a previously uncharacterized mechanism by which T. vaginalis exacerbates HPV infection: TvAP65 hijacks SPCS1 to transcriptionally upregulate CD151 and HSPG2, thereby facilitating HPV entry into host cells. This TvAP65-SPCS1-CD151/HSPG2 axis highlights potential therapeutic targets to disrupt the synergy between HPV and T. vaginalis, offering new strategies for cervical cancer prevention.

The online version contains supplementary material available at 10.1186/s40249-025-01381-x.