Tuft-cell-intrinsic and -extrinsic mediators of norovirus tropism regulate viral immunity

Murine norovirus (MNoV) is a model for human norovirus and for interrogating mechanisms of viral tropism and persistence. We previously demonstrated that the persistent strain MNoV^CR6 infects tuft cells, which are dispensable for the non-persistent strain MNoV^CW3. We now show that diverse MNoV strains require tuft cells for chronic enteric infection. We also demonstrate that interferon-λ (IFN-λ) acts directly on tuft cells to cure chronic MNoV^CR6 infection and that type I and III IFNs signal together via STAT1 in tuft cells to restrict MNoV^CW3 tropism. We then develop an enteroid model and find that MNoV^CR6 and MNoV^CW3 similarly infect tuft cells with equal IFN susceptibility, suggesting that IFN derived from non-epithelial cells signals on tuft cells in trans to restrict MNoV^CW3 tropism. Thus, tuft cell tropism enables MNoV persistence and is determined by tuft cell-intrinsic factors (viral receptor expression) and -extrinsic factors (immunomodulatory signaling by non-epithelial cells).