25-hydroxycholesterol inhibits human papillomavirus infection in cervical epithelial cells by perturbing cytoskeletal remodeling

Abstract

Persistent high-risk human papilloma virus (HR-HPV) infection is the main risk factor for cervical cancer, threatening women’s health. Despite growing prophylactic vaccination, annual cervical cancer cases are still increasing and show a trend of younger onset age. However, therapeutic approaches towards HPV infection are still limited. 25-hydrocholesterol (25HC) has a wide-spectrum inhibitory effect on a variety of viruses. To explore efficient interventions to restrict HPV infection at an early time, we applied different pseudoviruses (PsV) to evaluate anti-HPV efficacy of 25HC. We tested PsV inhibition by 25HC in cervical epithelial-derived HeLa and C-33A cells, using high-risk (HPV16, HPV18, HPV59), possibly carcinogenic (HPV73), and low-risk (HPV6) HPV PsVs. Then we established murine genital HPV PsV infection models and applied IVIS to evaluate anti-HPV efficacy of 25HC in vivo. Next, with the help of confocal imaging, we targeted 25HC activity at filopodia upon HPV exposure. After that, we used RNA-seq and Western blotting to investigate 1) how 25HC disturbs actin cytoskeleton remodeling during HPV infection and 2) how prenylation regulates the cytoskeletal remodeling signaling pathway. Our findings suggest that 25HC perturbs F-actin rearrangement by reducing small GTPase prenylation. In this way, the phenomenon of HPV virion surfing was restricted, leading to failed infection.

25-hydroxycholesterol dysregulates brain endothelial cell function and exacerbates cerebral haemorrhage

“…In our zebrafish model, the mechanisms of statin-induced ICH have been linked to decreased prenylation of endothelial Rho GTPases 21 . Decreased prenylation has been proposed as another antiviral mechanism for 25HC 44 , therefore it is possible that 25HC treatment could also lead to defective prenylation in our in vitro and zebrafish models. Furthermore, other mechanisms related to shear stress response could be relevant to our zebrafish model.…”

25-Hydroxycholesterol in health and diseases

“…Human papilloma viruses are involved in cervical cancers onset and development, thus threatening women's health. 25-HC treatment of cervical epithelial-derived HeLa and C-33A cells provokes cytoskeleton remodeling, thus decreasing cells infection ( 126 ). This actin remodeling is mediated by activation of the Rho/ROCK/LIMK/cofilin axis and leads to cell death in colorectal cancer cell spheroids ( 127 ).…”