A systems biology approach to unravel molecular signatures of host susceptibility to virus infections at mucosal surfaces

Recent virus pandemics have reminded us of the urgent need to explore key interactions determining host susceptibility to mucosal infections. Systems biology allows characterization of such interactions at high resolution.

Using host susceptibility to HIV infection as a model, we here aim to unravel molecular mechanisms of how endogenous and exogenous factors affect the risk of infection.

Clinical samples include cervical tissue and secretions from participants representing either high (non-optimal microbiome; high progestin levels), or low susceptibility to HIV infection, as well as rectal tissue from participants in a clinical trial of an antiviral compound (Griffithsin).

Bioinformatic analyses will be performed on experimental data from protein profiling, transcriptomic profiling and in situ image analysis of these samples.

Additional information will be obtained by gene set enrichment analysis of molecular pathways and associated transcription factors.

Furthermore, non-coding RNAs will be characterized and novel spatial transcriptomic analysis will allow definition of the positional context of RNA-sequencing data in the tissue sections.

The identified signals will be functionally verified by exposing an ex vivo cervical tissue explant model to selected factors, followed by experimental HIV challenge.

This proposed 3-year international collaboration can possibly define novel basic concepts of host-virus interactions as well as new targets for antiviral compounds.