Oral human papillomavirus infection aligns with a coordinated bacterial microbiome inferred virulence ecology

<h4>Background</h4>The biological relationship between oral human papillomavirus (HPV) infection and the community-level virulence ecology of the oral bacterial microbiome remains unresolved due to taxon-centric analyses. We profiled non-cancer oral HPV infection status and the ecological virulence architecture of the oral bacterial microbiome by integrating with bacterial genomics.<h4>Methods</h4>We used publicly available 16S rRNA gene sequencing data of the oral bacterial microbiome from 127 participants. Raw sequencing reads were quality filtered, denoised and taxonomically assigned at the genus level using standard amplicon-processing pipelines. Oral HPV status was derived from the original study metadata. Microbiome structure was characterised using diversity metrics, unsupervised ecotype and multivariate analyses. To interrogate functional organisation, bacterial genera were mapped to curated virulence-associated domains from published bacterial genomics databases. Variance partitioning was performed using PERMANOVA analysis to assess the independent contributions of HPV status and virulence ecology.<h4>Results</h4>We observed a gross overlap across oral HPV groups (64 HPV-negative and 63 HPV-positive) with no dominant bacterial microbiome taxa after multiple-testing correction (all FDR > 0.10). Alpha diversity was modestly higher in HPV-positive samples, but differences were not statistically significant (Median difference = 0.18; 95% CI 0.05-0.41, p = 0.12). Unsupervised ecotype analysis identified three independent bacterial microbiome states, none defined by HPV status (All p > 0.20). In the multivariate PERMANOVA analysis, microbial diversity (R² = 8.9%, p < 0.001) and virulence ecology (R² = 3.9%, p < 0.001) explained significantly more community bacterial microbiome variance than HPV status (R² = 0.9%, p = 0.24). The structured network-level reprogramming of taxa and genera virulence ecology by HPV status showed almost similar genus-virulence coordination, particularly within adhesion, invasion and immune-interface modules and no significant differences in the mean virulence module abundance (all Cliff's δ < 0.15). HPV-positivity aligned more with high virulence-pressure, low terrain of the oral bacterial microbiome ecological landscapes. Relative to the protected terrain (Q1), HPV positivity was more frequent in the higher-pressure ecological states, with odds ratios of 3.62 for Q2 (95% CI 1.19-11.06; p=0.024), 3.13 for Q3 (95% CI 1.02-9.58; p=0.045), and 3.68 for Q4 (95% CI 1.06-12.77; p=0.040). The strongest point estimate was observed in the low-diversity, high-pressure danger zone (Q4).<h4>Conclusions</h4>In this hypothesis generation study, oral HPV infection aligns with coordinated inferred virulence ecology of the oral bacterial microbiome rather than discrete taxonomic or abundance-based changes.