LC3-associated phagocytosis is a new strategy to inhibit picornavirus infection through increasing interferon levels and lysosomal degradation

LC3-associated phagocytosis (LAP) is a novel type of noncanonical autophagy that contributes to inflammatory responses and immune regulation in various cell and tissue types infected by DNA and RNA viruses. The role of LAP during picornavirus infection remains unclear. Here, using PK-15 cells, Vero cells and mice lacking the WD domain of ATG16L1 as a LAP deficient model, we found that infection with foot-and-mouth disease virus (FMDV), senecavirus A (SVA), and enterovirus 71 (EV71) induced LAP, and LAP inhibited the replication of these viruses. Further investigation revealed that LAP inhibited FMDV replication through increasing interferon levels and promoting lysosomal degradation. In addition, GBP1, IFITM3, OASL, IIFIT1, Mx1 and other innate immune factors related to the interferon pathway were significantly inhibited in LAP-deficient cells during FMDV infection. Furthermore, LAP-deficient mice were more susceptible to FMDV, with greater lethality and more severe pathological damage and viral loads in the blood, heart, spleen, liver, lungs and kidneys. In conclusion, this study uncovers a novel mechanism of the host antiviral effect of LAP on picornaviruses and provides a theoretical basis for the development of new antiviral strategies against picornaviruses. Importance: FMDV, SVA and EV71 all belong to the Picornaviridae family, which has single-stranded positive-sense RNA, is nonenveloped and can cause diseases in both humans and animals. A noncanonical function of the autophagy machinery known as LC3-associated phagocytosis (LAP), utilizes a portion of components of the canonical autophagy machinery, is one of the important ways for cells to cope with pathogen infection. This study revealed a new strategy to inhibit picornavirus replication through increasing interferon levels and promoting lysosomal degradation, further highlighting the important role of LAP in antiviral immunity and providing a theoretical basis and experimental support for the development of new antiviral strategies.