Abstract
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 Junín 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.
Highlights
Virus entry is a major determinant of cellular tropism, host-range, and pathogenesis
We show that Signal-regulatory protein alpha (SIRPA), which is a major inhibitor of phagocytosis, inhibits infection by a variety of viruses that enter via acidic compartments, including many human pathogens such as Zika, Ebola and SARS-CoV-2
We previously showed that the E3 ubiquitin ligase Tripartite Motif 2 (TRIM2) in complex with Signal Regulatory Protein Alpha/Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA/SHPS1), a negative regulator of phagocytosis, limited New World arenavirus (NWA) entry but did not alter infection by other viruses, such as the Old World arenaviruses (OWA) Lassa fever virus and lymphocytic choriomeningitis virus (LCMV), or the rhabdovirus vesicular stomatitis virus (VSV) [4]
Summary
Virus entry is a major determinant of cellular tropism, host-range, and pathogenesis. Several host cell restriction factors limit virus entry when expressed on the cell membrane, like. We previously showed that the E3 ubiquitin ligase Tripartite Motif 2 (TRIM2) in complex with Signal Regulatory Protein Alpha/Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA/SHPS1), a negative regulator of phagocytosis, limited New World arenavirus (NWA) entry but did not alter infection by other viruses, such as the Old World arenaviruses (OWA) Lassa fever virus and lymphocytic choriomeningitis virus (LCMV), or the rhabdovirus vesicular stomatitis virus (VSV) [4]. It has been shown that SIRPA inhibits integrin activation at the phagocytic synapse, thereby limiting the ability of macrophages to spread across the surface of the engulfment target [8]. CD47 is a “Don’t Eat Me” signal that protects healthy cells from macrophage engulfment but is highly expressed on tumor cells, thereby preventing their phagocytosis; it is a current target of anti-tumor therapies [9]
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