The circadian clock and viral pathogenesis (360G-Wellcome-208790_Z_17_Z)

Diverse biological processes exhibit circadian rhythms that are driven by cell-autonomous biological clocks, including most facets of the immune response. Using herpesviruses and influenza A virus, I recently demonstrated that circadian rhythms affect virus progression in vivo and replication in cells. Furthermore, I discovered that disruption of circadian rhythms enhances infection. I now want to understand, mechanistically, how the circadian clock influences viral pathogenesis. I will investigate whether cell-intrinsic antiviral pathways are under circadian clock control, using comparative transcriptomics to monitor responses to herpesvirus and influenza A infection at different circadian times and in different ‘clock mutants’. Circadian rhythms in candidate pathways will then be ablated or inverted to assess their impact on time-of-day differences in viral replication in single cells, and as the virus spreads. I will delineate the relative contribution that these endogenous cellular rhythms make to viral pathogenesis, compared with circadian rhythms in systemic host immune responses by examining infection in mice with desynchronised peripheral circadian rhythms compared with tissue-specific ‘clock knockouts’ (arrhythmic epithelial, myeloid-lineage or lymphocyte-lineage mice). Collectively, my research will address the constraints that host circadian rhythms place on viral infection and whether viruses exploit the predictability that biological timekeeping confers upon host physiology.