Tropism for tuft cells determines immune promotion of norovirus pathogenesis

Abstract

Complex interactions between host immunity and the microbiome regulate norovirus infection. However, the mechanism of host immune promotion of enteric virus infection remains obscure. The cellular tropism of noroviruses is also unknown. Recently, we identified CD300lf as a murine norovirus (MNoV) receptor. Here we show that tuft cells, a rare type of intestinal epithelial cell, express CD300lf and are the target cell for MNoV in the mouse intestine. We found that type 2 cytokines, which induce tuft cell proliferation, promote MNoV infection in vivo. These cytokines can replace the effect of commensal microbiota in promoting virus infection. This is the first report of viral infection of tuft cells and provides insight into how the immune system and microbes can coordinately promote enteric viral infection.

CD300 receptor family in viral infections

“…In this context, it was also demonstrated that mouse CD300f receptor determines MNV host tropism, as human cells and cells from other species were only infected by MNV when they ectopically expressed the murine, but not the human CD300f . A rare chemosensory epithelial cell type known as tuft or brush cells has been shown to express CD300f and to represent the physiological target cell for MNV in the mouse intestine . Since tuft cells have been described as orchestrators of anti‐parasite type 2 responses in the gut , Wilen et al.…”

The Dual Tropism of Noroviruses

“…Deletion of CD300lf from mice renders them resistant to MNV-1 and MNV-CR6 infection (21,31). Studies using bone marrow transplants between wild-type (wt) and CD300lf-deficient mice aimed at identifying the infected cell type revealed that during the persistent phase of the infection (i.e., 21 days postinfection), MNV-CR6 required wt radiation-resistant cells (e.g., epithelial cells) (31).…”

“…Studies using bone marrow transplants between wild-type (wt) and CD300lf-deficient mice aimed at identifying the infected cell type revealed that during the persistent phase of the infection (i.e., 21 days postinfection), MNV-CR6 required wt radiation-resistant cells (e.g., epithelial cells) (31). In contrast, detection of the MNV-1 genome at 7 days postinfection is dependent on both radiation-resistant and -nonresistant (e.g., immune cells) cells.…”

“…In contrast, detection of the MNV-1 genome at 7 days postinfection is dependent on both radiation-resistant and -nonresistant (e.g., immune cells) cells. Subsequent studies of MNV-CR6 persistence identified a specialized intestinal epithelial cell type, called tuft cell, as the source of infectious virus (31). Tuft cells are a rare type of epithelial cell that express certain immune cell genes, including CD300lf (31).…”

“…Infection in B cells was improved in the presence of H-type HBGA glycans, either free or associated with bacteria (8). The dual tropism of HuNoV for intestinal epithelial and immune cells in vitro is shared with MNV (28,31). Whether this dual cellular tropism also extends to infections in vivo has not been addressed fully.…”