A gut microbiota-bile acid axis inhibits the infection of an emerging coronavirus by targeting its cellular receptor aminopeptidase N

Abstract

Porcine deltacoronavirus (PDCoV) is a significant pathogen of swine with a global distribution, leading to severe gastrointestinal disease and substantial economic losses. Furthermore, PDCoV poses a potential threat to human health, as evidenced by the recent identification of three cases of infection in Haitian children. This study aimed to investigate the effects of PDCoV infection on host intestinal microbiota and bile acid metabolism, as well as the antiviral effects of lithocholic acid (LCA) in vitro and in vivo. Our results revealed that PDCoV infection caused microbiota dysbiosis in piglets, significantly reducing the intestinal abundance of Bacteroides fragilis (B. fragilis), a reduction that correlated with disruptions in bile acid metabolism. Colonization with bile salt hydrolase (BSH)-producing B. fragilis increased the levels of unconjugated bile acids and inhibited PDCoV infection, highlighting the role of microbiota-associated bile acid metabolism in viral pathogenesis. LCA, a prominent unconjugated bile acid, was shown to effectively inhibit PDCoV infection in porcine small intestinal epithelial cells and porcine intestinal enteroids. Notably, LCA inhibited PDCoV replication independently of bile acid receptor signaling and innate immune modulation. Mechanistic studies indicated that LCA prevents PDCoV infection by disrupting the viral entry process, specifically inhibiting the binding between the PDCoV spike protein and its cellular receptor, aminopeptidase N. In vivo experiments further confirmed that LCA significantly inhibited PDCoV infection in piglets. These results collectively highlight the potential of LCA as a therapeutic agent against PDCoV by targeting and disrupting the viral entry process, providing a novel strategy to control zoonotic PDCoV infections.

Keywords

aminopeptidase N / Bacteroides fragilis / lithocholic acid / metabolomic / microbiota dysbiosis / porcine deltacoronavirus

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