An inhibitor of leukotriene-A(4) hydrolase from bat salivary glands facilitates virus infection

Bats are increasingly accepted as potential reservoirs of many viruses that cause zoonotic disease outbreaks through spillover to other animals and humans. However, our understanding of the factors that contribute to virus spillover from bats is very limited. Here, we identified and characterized an immunosuppressant protein (MTX) that is highly concentrated in the submandibular salivary gland of the bat, Myotis pilosus. By selectively inhibiting the epoxide hydrolase function of leukotriene-A(4) hydrolase (LTA(4)H) to inhibit LTA(4) hydrolysis and the generation of leukotriene B(4) (LTB(4)), a potent lipid chemoattractant for host defense against infection, MTX inhibited the antiviral responses of the host and facilitated viral infection. MTX had no effect on the aminopeptidase function of LTA(4)H and therefore did not impair the antiinflammatory function of LTA(4)H. MTX potently inhibited proinflammatory proteases (i.e., plasmin, trypsin, and elastase) to induce immune tolerance and maintain high stability. In mouse models, influenza A virus (IAV) H1N1 infection and pathogenicity were exacerbated by MTX but were reversed by interfering with the effects of MTX on LTA(4)H or exogenous LTB(4) administration. This study provides deeper insight into immunologically privileged sites for microbial community residence in bats and supports the therapeutic potential of targeting MTX-LTA(4)H.