Nia Muhammad

Title: Bacteria driven HPV outcomes in anogenital cancers

Abstract

Cervical cancer remains a major global health burden and is the fourth most common cancer among women worldwide, with over 600,000 new cases and approximately 340,000 deaths each year. Persistent infection with high-risk human papillomavirus (HPV) is the primary etiologic factor in cervical and head and neck cancers, with HPV16 and HPV18 conferring the highest oncogenic risk. Although HPV is predominantly transmitted through sexual contact, additional transmission routes, including contaminated surfaces, shared personal items, and vertical transmission, have been reported. Following infection of cervical epithelial cells, high-risk HPV disrupts cellular replication and signaling pathways, enabling persistent infection and progression from precancerous lesions to invasive disease over years to decades. Emerging evidence suggests that microbial co-infections may influence HPV persistence and disease severity. Building on prior work demonstrating synergistic interactions between oral pathogens and oncogenic viruses, we investigated whether oral and anogenital bacterial pathogens modulate HPV-driven carcinogenesis. The healthy cervicovaginal microbiome is typically dominated by Lactobacillus species that maintain a protective, low-diversity environment; disruption of this balance (dysbiosis) has been associated with increased susceptibility to infection and disease progression. Notably, oral bacterial genera such as Porphyromonas, Fusobacterium, and Prevotella are enriched in the cervicovaginal microbiome during cervical disease, suggesting potential cross-site microbial influences shaped by sexual behaviors. In HPV16-positive cervical cancer cells, treatment with Porphyromonas gingivalis (Pg) resulted in a threefold increase in E6/E7 transcript levels compared to uninoculated controls. RNA-sequencing revealed increased expression of spliced E6/E7 transcripts and activation of oncogenic signaling pathways, including MAPK and NF-κB. Pg exposure induced global histone H3 acetylation, and increased H3K9 and H3K27 acetylation with up to a 90% enrichment of H3K9 acetylation occupancy at the HPV long control region (LCR) as determined by chromatin immunoprecipitation. Pharmacologic inhibition of p38 MAPK reduced histone acetylation and occupancy at the LCR and attenuated E6/E7 expression, implicating p38-mediated epigenetic regulation in bacteria-driven enhancement of HPV oncogene expression. Consistent with these findings, Pg and Fusobacterium nucleatum increased H3K9 acetylation in both HPV16-positive and -negative cells in a pathogen-specific, dose-dependent manner. These data suggest that bacterial metabolites may promote HPV persistence and pathogenesis, highlighting polymicrobial interactions as potential therapeutic targets in HPV-associated disease.

The audience take away from presentation:

• Will highlight polymicrobial interactions as potential therapeutic targets


• Other faculty could use to expand their own HPV-related research


• Consideration of bacterial co-infections as drivers of HPV pathogenesis