TAM receptor signaling and viral infection

Viruses must evade or inhibit innate immune responses in order to infect and propagate within their hosts. We have identified a novel mechanism of immune evasion involving viral activation of the TAMs. In a process termed ‘apoptotic mimicry’, many different enveloped viruses display PtdSer on their surface membranes, which allows them to bind to and present Gas6 and Protein S5-8. We find that engagement of TAM-ligand-coated virus particles with TAM receptors expressed on the surface of target cells immediately activates the receptors. Activated TAM receptors in turn induce the cytokine signaling inhibitors SOCS1 and SOCS3. These cytoplasmic inhibitors markedly dampen signaling by type I interferons (IFNs), which are among the most potent of anti-viral cytokines. When challenged with virus, DCs deficient in TAM receptors display dramatically elevated type I IFN responses and correspondingly reduced infectivity relative to TAM-expressing cells. These results illuminate a powerful and very general mechanism of viral immune evasion, and suggest that TAM receptor inhibition may represent an attractive approach to new broad-spectrum anti-viral therapeutics. We are currently assessing the utility of TAM receptor inhibitors in this context in vivo.

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