TWiV 214: This is your brain on polyomavirus

On episode #214 of the science show This Week in Virology, Vincent, Alan, and Kathy discuss how coagulation factor X binding to adenovirus activates the innate immune system, and a novel polyomavirus associated with brain tumors in raccoons.

You can find TWiV #214 at www.microbe.tv/twiv.

The inflammatory response

neutrophil-migrationDuring the earliest stages of a virus infection, cytokines are produced when innate immune defenses are activated. The rapid release of cytokines at the site of infection initiates new responses with far-reaching consequences that include inflammation.

One of the earliest cytokines produced is tumor necrosis factor alpha (TNF-α), which is synthesized by activated monocytes and macrophages. This cytokine changes nearby capillaries so that circulating white blood cells can be easily brought to the site of infection. TNF-α can also bind to receptors on infected cells and induce an antiviral response. Within seconds, a series of signals is initiated that leads to cell death, an attempt to prevent the spread of infection.

Inflammation is a very prominent response to TNF-α. There are four typical signs of inflammation: erythema (redness), heat, swelling, and pain. These are a consequence of increased blood flow and capillary permeability, the influx of phagocytic cells, and tissue damage. Increased blood flow is caused by constriction of the capillaries that carry blood away from the infected area, and leads to engorgement of the capillary network. Erythema and an increase in tissue temperature accompany capillary constriction. In addition, the permeability of capillaries increases, allowing cells and fluid to leave and enter the surrounding tissue. These fluids have a higher protein content than the fluids normally found in tissues, causing swelling.

Another feature of inflammation is the presence of immune cells, largely mononuclear phagocytes, which are attracted to the infected area by cytokines. Neutrophils are one of the earliest types of phagocytic cells that enter a site of infection, and are classic markers of the inflammatory response (illustrated). These cells are abundant in the blood, and usually absent from tissues. Together with infected cells, dendritic cells, and macrophages, they produce cytokines that can further shape the response to infection, and also modulate the adaptive response that may follow.

The precise nature of the inflammatory response depends upon the virus and the tissue that is infected. Viruses that do not kill cells – noncytopathic viruses – do not induce a strong inflammatory response. Because the cells and proteins of the inflammatory response come from the bloodstream, tissues with reduced access to the blood do not undergo the destruction associated with inflammation. However, the outcome of infection in such ‘privileged’ sites – the brain, for example – may be very different compared with other tissues.

As expected, the inflammatory response is highly regulated. One of the critical components is the ‘inflammasome’ – very large cytoplasmic structure with properties of pattern receptors and initiators of signaling (e.g. MDA-5 and RIG-I). Recent experimental findings demonstrate that the inflammasome is critical in innate immune response to influenza virus infection, and in moderating lung pathology in influenza pneumonia.

Thomas, P., Dash, P., Aldridge Jr., J., Ellebedy, A., Reynolds, C., Funk, A., Martin, W., Lamkanfi, M., Webby, R., & Boyd, K. (2009). The Intracellular Sensor NLRP3 Mediates Key Innate and Healing Responses to Influenza A Virus via the Regulation of Caspase-1 Immunity, 30 (4), 566-575 DOI: 10.1016/j.immuni.2009.02.006

Allen, I., Scull, M., Moore, C., Holl, E., McElvania-TeKippe, E., Taxman, D., Guthrie, E., Pickles, R., & Ting, J. (2009). The NLRP3 Inflammasome Mediates In Vivo Innate Immunity to Influenza A Virus through Recognition of Viral RNA Immunity, 30 (4), 556-565 DOI: 10.1016/j.immuni.2009.02.005