Tropism for tuft cells determines immune promotion of norovirus pathogenesis

• Published in: Science (American Association for the Advancement of Science) Vol. 360; no. 6385; pp. 204 - 208
• Main Authors: Wilen, Craig B., Lee, Sanghyun, Hsieh, Leon L., Orchard, Robert C., Desai, Chandni, Hykes, Barry L., McAllaster, Michael R., Balce, Dale R., Feehley, Taylor, Brestoff, Jonathan R., Hickey, Christina A., Yokoyama, Christine C., Wang, Ya-Ting, MacDuff, Donna A., Kreamalmayer, Darren, Howitt, Michael R., Neil, Jessica A., Cadwell, Ken, Allen, Paul M., Handley, Scott A., van Lookeren Campagne, Menno, Baldridge, Megan T., Virgin, Herbert W.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 13.04.2018
• Subjects: Animals; Caliciviridae Infections - immunology; Cell Proliferation; Cytokines; Cytokines - metabolism; Enterocytes - immunology; Enterocytes - virology; Epithelial cells; Immune clearance; Immune system; Immunity; Infections; Interleukin 4; Intestine; Mice; Microbiomes; Microbiota; Microbiota - immunology; Norovirus; Norovirus - physiology; Pathogenesis; Promotion; Receptors, Immunologic - metabolism; Tropism; Viral infections; Viral Tropism - immunology; Viruses
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aar3799

Norovirus is highly infectious and usually causes transient, acute disease. In some individuals, norovirus persists and is associated with inflammatory bowel disorders. While investigating the cell tropism for murine norovirus, Wilen et al. discovered that a rare cell type, tuft cells, carrying the CD300lf receptor were the virus's specific target. Tuft cells proliferate in response to the type 2 cytokines interleukin-4 and interleukin-25, which thereby amplify norovirus infection. Moreover, infected tuft cells are resistant to immune clearance. This effect may explain the associated persistent disease symptoms that humans can suffer. Science , this issue p. 204 Specialized, immune-privileged intestinal cells are specific targets for norovirus and thus promote infection. 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. In this study, we have shown 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. Our work thus provides insight into how the immune system and microbes can coordinately promote enteric viral infection.