Innate immune responses are essential for WNV clearance, dissemination and neurovirulence. Pattern recognition receptors and other danger signals activate assembly of inflammasome complex, which modulates antiviral defense responses. ASC is an important adaptor molecule, which mediates downstream signaling pathways of NLRP3 inflammasomes. In this study we defined the role of ASC in WNV immunity. Infection of cultured BMDCs showed that ASC was essential for the activation of caspase-1, a key component of inflammasome assembly. ASC-/- mice were highly susceptible to WNV infection marked by increased mortality, enhanced viremia and virus replication in the CNS. As compared to wild type mice, key cytokines including IL-1β and IFN-γ were significantly reduced in the sera of ASC mice. Additionally, antiviral IFN-α levels were also decreased in the sera of ASC-/- mice. Increased virus titers in the brain of ASC-/- mice correlated with increased inflammation and neuronal apoptosis. However, intracranial inoculation of WNV did not result in significant differences in the virus titers in both groups suggesting that impaired immune response coupled with failure to clear virus in the periphery leads to increased neuropathology and mortality in ASC-/- mice. Collectively, our data provides new insights into the role of ASC as an essential modulator of inflammasome-dependent and -independent immune response to effectively control WNV infection.
- Copyright © 2013 by The American Association of Immunologists, Inc.