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Potent mechanism helps viruses shut down body's defense system against infection

John Young, Erin Lew, Greg Lemke, Anna Zagorska, John Naughton

From left: John Young, Erin Lew, Greg Lemke, Anna Zagorska, John Naughton

In the immune system, TAM receptors are used by cells such as macrophages and dendritic cells to clean up dead cells. They are also central inhibitors of the body's innate immune response to bacteria, viruses and other pathogens.

As reported in Cell Host and Microbe, researchers in the labs of John A.T. Young and Greg Lemke have discovered that a substance called phosphatidylserine (PtdSer), found on the surface of enveloped viruses (viruses with an outer wrapping of a lipid membrane), binds to extracellular proteins and activates TAM receptors on immune cells. In dendritic cells, a type of immune cell that interacts with T and B cells to initiate the adaptive immune response, TAM receptor activation turns off a set of genes called interferons that play a key role in antiviral defense. The findings suggest a unique way in which TAM receptors contribute to the establishment of viral infection by disabling the interferon response. As a consequence, the interferon-stimulated defense genes are not turned on, rendering the target cell more vulnerable.

This is a previously unknown mechanism for enveloped viruses, which are very common, to inhibit the body's normal antiviral response. Since PtdSer exposure seems to be a general feature of enveloped viruses, the researchers say many different viruses may use the mechanism to counteract the antiviral response in cells with TAM receptors.

Understanding this mechanism will allow researchers to work on developing broad-spectrum antiviral drugs that prevent viruses from shutting down the interferon response in cells by blocking TAM receptor activation. Young and Lemke tested a small-molecule drug initially developed for anti-cancer therapy that does just that, and with other scientists around the country, they are now testing other small-molecule drugs that work, in large part, by blocking the virus's ability to activate TAM receptors, leaving the interferon-mediated antiviral response intact in such viruses as West Nile, dengue, influenza, Ebola, Marburg and hepatitis B. This is a completely novel approach, says Young, and if it works, it may prove effective at clearing enveloped viruses during the acute phase of infection and perhaps in chronic viral infections as well.