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-l (IFN-l) 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).