Understanding the Antiviral Mechanism of Signal-Regulatory Protein Alpha

New world arenaviruses (NWAs) that cause viral hemorrhagic fever, such as Junín virus (JUNV), have few therapeutic options. Entry of these viruses into cells is mediated by binding to cell surface receptors, followed by endocytosis and trafficking to a low pH compartment. We showed previously that Signal Regulatory Protein Alpha (SIRPA), a critical cell surface receptor that inhibits macrophage phagocytic activity, also decreases internalization by NWAs and other RNA viruses that traffic to low pH compartments. Because SIRPA’s anti-phagocytic activity is thought to be the result of its ability to block integrin signaling needed for phagocytosis, we tested whether this was also the case for blockage of virus endocytosis. We show here that multiple proteins involved in the SIRPA/integrin signaling axis, including Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), src family kinases (SFK), particularly FYN, focal adhesion kinase (FAK), and alpha-integrin, play a role in viral endocytosis and in SIRPA’s ability to inhibit this process. This study thus reveals additional therapeutic targets for the inhibition of infection by viruses that traffic to acidic compartments.