TAM receptor tyrosine kinases as potential mediators of the non-lytic spread of non-enveloped viruses

Tyro3, Axl, and Mer are receptor tyrosine kinases that comprise the TAM receptor family. These receptors, originally identified as orphan receptors, do not bind growth factors but rather ligands that can facilitate processes such as phagocytosis and dampening the innate inflammatory immune response. Enveloped viruses can hijack TAM receptors for viral entry through the fairly well-established mechanism of apoptotic mimicry. This mechanism involves 'tricking' the targeted host cell into endocytosing the virus through binding to exposed phosphatidylserine in the viral lipid bilayer envelope. While enveloped viruses utilize apoptotic mimicry for entry, it remains unclear how non-enveloped viruses enter the host cell through phosphatidylserine receptors such as TAM receptors. There is evidence that non-enveloped viruses can usurp host cell signaling pathways to cloak their particles in membranes, creating 'quasi-enveloped' viruses that enter the host through a sort of 'faux apoptotic mimicry.' These quasi-enveloped viruses can spread through non-lytic mechanisms to evade the host immune response and deliver virus particles to the targeted host cell. With the present review, we evaluate increasing evidence that TAM receptors may play a role in this process through their ability to indiscriminately bind phosphatidylserine in membranes, leading to the internalization of non-enveloped viruses packaged within phosphatidylserine-enriched extracellular vesicles.