Abstract
Human papillomavirus (HPV) is the underlying cause of most cervical cancers. This virus infects nearly all sexually active women at least once in their lifetime. Although most HPV infections are transient and resolve without long-term consequences, a subset persists, creating the foundation for malignant transformation. Yet, the mechanisms that determine whether an infection persists or clears remain poorly defined. This poses a significant challenge in the diagnosis of HPV infections, which often carries a considerable psychological burden for women due to anxiety about cancer risk and uncertainty around prognosis. While host immune responses are essential for viral clearance, growing evidence indicates that the vaginal microbiome plays a pivotal role in shaping these outcomes. Lactobacillus-dominated communities are associated with a lower risk of persistence, whereas diverse or dysbiotic microbiomes, enriched in taxa such as Gardnerella or Fannyhessea, correlate with chronic infection and progression to high-grade lesions. However, the causal pathways through which the microbiome influences HPV dynamics remain largely unexplored. This project aims to uncover the mechanistic basis of microbiome-driven HPV clearance, thereby positioning the microbiome as both a diagnostic and therapeutic target.
First, we seek to go beyond descriptive associations and identify protective taxa that contribute to viral elimination. The vaginal microbiome of women with clearance versus persistent HPV infections will be characterised. Shotgun metagenomics will provide high-resolution profiles of microbial diversity and dominance patterns. This will give us an insight into microbial biomarkers for clearance and persistence of the infection, guiding the development of a predictive model to determine whether an infection is likely to resolve or persist.
Next, host-virus-microbial functional interactions will be investigated by using metatranscriptomics. This will allow us to map the transcriptional activity of both host epithelial cells and the present bacteria during clearance versus persistence. Particular attention will be given to immune pathways such as type I and III interferon signalling, cytokine expression (e.g. IFN-γ, IL-17, IL-10), and epithelial barrier integrity, as well as bacterial metabolic pathways linked to lactic acid production and metabolite production. Correlating microbial activity with host gene expression will provide mechanistic insight into how beneficial strains promote an antiviral mucosal environment.
The vaginal strains that are identified as protective will be isolated, sequenced, and functionally characterized. These isolates will then be tested in advanced HPV infection models, including HeLa cells infected with pseudoviruses, E6/E7-expressing cell systems, and 3D cervicovaginal tissue or organ-on-chip platforms to uncover the mechanisms linked to immune modulation, antiviral metabolite production, or epithelial adhesion. These models will enable mechanistic interrogation of how specific bacterial strains alter viral replication, immune signalling, and epithelial homeostasis in both acute and persistent infection contexts.
By integrating clinical expertise, host transcriptomics, and mechanistic validation, this project moves beyond correlation to establish causal mechanisms in microbiome–HPV research. The expected outcomes include the identification of clinically relevant microbial and host biomarkers predictive of HPV clearance, characterisation of host-virus–microbiome pathways that regulate mucosal antiviral immunity, and mechanistic insights into viral clearance derived from testing bacterial strains in advanced 3D HPV infection models. Ultimately, this work will establish an actionable framework for how the vaginal microbiome modulates HPV infection, with implications for developing microbiome-based diagnostics and therapeutics that enhance natural clearance and prevent progression to cervical cancer.
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