Characterisation of surfactant protein a as a novel prophylactic means against oncogenic HPV infections

Infection with Human Papillomavirus (HPV) presents a continuous global health challenge due to its incurable nature, particularly impacting low- and middle-income countries (LMIC). Although highly effective prophylactic vaccines targeting the most prevalent HPV types exist, they do not cover all oncogenic HPV types found in malignant lesions and the extent of cross protection against other oncogenic HPV types is limited. Moreover, these vaccines are ineffective for women already infected with high-risk HPV types. These limitations are more prominent in LMIC, where limited healthcare access, awareness, and proper transport and storage hinder vaccine accessibility. Cervical cancer's persistent status as the fourth most common cancer in women globally underscores the urgent need for alternative interventions that broadly target HPV infections. In an effort to identify alternative broad-spectrum protective means against HPV infection, our previous research identified surfactant protein A (SP-A), an innate immune opsonin, as a novel molecule capable of recognising HPV16 pseudovirions (HPV16-PsVs) with functional consequences for reduced infection in a murine cervicovaginal HPV challenge model. Building on these findings, our aim was to assess SP-A's suitability as a novel broad-spectrum HPV targeting molecule to prevent initial viral infection of the human keratinocyte cell line, HaCaT. Additionally, we aimed to study SP-A's ability to agglutinate HPV-PsVs and to assess potential consequences of this SP-A coating on immune cell recognition and elicited immune responses in human-derived immune cells. Our study demonstrated SP-A's ability to agglutinate and opsonise multiple oncogenic HPV PsVs types, which was accompanied by their enhanced uptake and clearance by RAW264.7 murine macrophages, THP-1 monocytes, and THP-1-derived immature dendritic cells (DC0). Importantly, SP-A-opsonised HPV-PsVs resulted in decreased viral uptake and infection of HaCaT keratinocytes. These results were supported by increased lysosomal accumulation of SP-A-opsonised HPV16-PsVs as observed for both RAW264.7 and HaCaT cells. Co-culturing selected immune cells with HaCaT keratinocytes further reduced HPV-PsV infection in the presence of SP-A which might be explained by SP-A's behaviour in driving a proinflammatory immune response in THP-1 and DC0, in the presence of HPV16-PsVs, as identified by cytokine profiling. These results unveiled SP-A's versatility and substantial influence on various HPV interactions with immune cells and keratinocytes and laid the foundation for future research into the development of alternative prophylactic interventions. Increasing innate immune recognition by exogenous supplementation with SP-A (or SP-A derivatives) holds promise for broader protection against diverse HPV types and potentially other sexually transmitted infections.

Grantor dc:publisher.institution

Division of Medical Biochemistry

Year dc:date.issued

2024

Author dc:creator

• Carse, Sinead

Advisor dc:contributor.advisor

• Schäfer, Georgia

• medical biochemistry

Handle dc:identifier.uri

http://hdl.handle.net/11427/40821

OAI identifier oai:identifier

oai:open.uct.ac.za:11427/40821