Signal-regulatory protein alpha is an anti-viral entry factor targeting viruses using endocytic pathways

Signal-regulatory protein alpha (SIRPA) is a well-known inhibitor of phagocytosis when it complexes with CD47 expressed on target cells. Here we show that SIRPA decreased in vitro infection by a number of pathogenic viruses, including New World and Old world arenaviruses, Zika virus, vesicular stomatitis virus and pseudoviruses bearing the Machupo virus, Ebola virus and SARS-CoV-2 glycoproteins, but not HSV-1, MLV or mNoV. Moreover, mice with targeted mutation of the Sirpa gene that renders it non-functional were more susceptible to infection with the New World arenaviruses Junin virus vaccine strain Candid 1 and Tacaribe virus, but not MLV or mNoV. All SIRPA-inhibited viruses have in common the requirement for trafficking to a low pH endosomal compartment. This was clearly demonstrated with SARS-CoV-2 pseudovirus, which was only inhibited by SIRPA in cells in which it required trafficking to the endosome. Similar to its role in phagocytosis inhibition, SIRPA decreased virus internalization but not binding to cell surface receptors. We also found that increasing SIRPA levels via treatment with IL-4 led to even greater anti-viral activity. These data suggest that enhancing SIRPA's activity could be a target for anti-viral therapies. Author summary Viruses enter cells via different routes. Many RNA viruses require trafficking to a low pH compartment to accomplish entry. Similarly, phagocytosis of dead cells by macrophages results in their degradation in an acidic compartment. Here we show that SIRPA, which is a major inhibitor of phagocytosis, also inhibits infection by a variety of viruses that enter via acidic compartments, including many human pathogens such as Zika, Ebola and SARS-CoV-2. These findings suggest that phagocytosis and virus endocytosis share a common mechanistic pathway, and could lead to new approaches to the development of anti-viral therapeutics.

Automated summary

SIRPA serves as a potent inhibitor of viral infection, particularly viruses that require trafficking to low pH compartments. Increasing SIRPA levels through treatment with IL-4 enhances its antiviral activity, suggesting it could be a potential target for antiviral therapies. The findings also imply a common mechanistic pathway between phagocytosis and virus endocytosis, which could lead to the development of new approaches for antiviral therapeutics.