Immune remodeling in HPV-associated cervical disease

Persistent high-risk HPV infection is the principal cause of cervical dysplasia, but variation in disease phenotype may also be associated with differences in the local immune and microbial environment.

We characterized the cervicovaginal immune microenvironment in relation to HPV status, vaginal community state type (CST), and cytological grade.

HPV-positive samples showed reduced IL-4 and IL-17E/IL-25, while IFN-α2 and IL-3 varied across community state types in a non-monotonic, CST-specific manner: IFN-α2 was relatively elevated in the Lactobacillus gasseri-dominant CST II, and IL-3 was specifically reduced in the Lactobacillus jensenii-dominant CST V. Cytological category was associated with non-monotonic, marker-specific immune variation, with LSIL showing lower IL-4, IFN-γ, IL-17F, PDGF-AB/BB, IL-17E/IL-25, and PDGF-AA levels relative to NILM, while ASC-H showed a distinct rather than uniformly progressive immune profile. CLR-based multi-kingdom analyses identified a restricted set of taxon-cytokine associations after correction of the relative-abundance scale, prespecified prevalence and abundance filtering, and multiple-testing correction. Significant bacterial associations were confined to the genus level, whereas viral associations were observed at the family, genus, and species levels and fungal associations at the family level. Phocaeicola-IL-10 and Rountreeviridae-MIP-1β were the only associations that additionally remained significant after global BH-FDR correction across all taxon-immune-marker tests. Viral and fungal findings were interpreted as exploratory because of substantially lower non-bacterial sequencing depth.

These microbial associations provide additional context for the observed immune-marker differences. These findings support further investigation of multi-kingdom host-microbiome immune relationships in HPV-associated cervical abnormalities.