Oshinowo, T. O.; Maples, R. W.; Woods Acevedo, M. A.; McCune, B. T.; Dalton, H.; Johnson, I.; Simpkins, D. A.; Basu, U.; Dende, C.; Tarakanova, V. L.; Pfeiffer, J. K.; Brooks, J. F.

Susceptibility to viral infection varies widely but is not fully explained by genetics, immune status, or exposure level. We show that time of day strongly influences infection outcome, with up to 100-fold differences in enteric viral burden depending on infection timing. This temporal gating is abolished in mice lacking a functional circadian clock. We identify the antiviral transcription factor IRF1 as a direct target of the circadian transcription factor BMAL1, resulting in rhythmic expression of a basal antiviral gene program prior to infection. Loss of IRF1 eliminates this program and abrogates time-of-day dependent differences in viral replication. This circuit operates within intestinal myeloid cells, establishing a preexisting antiviral state. These findings indicate that the circadian clock programs host susceptibility in the intestine, before infection occurs.