West Nile virus (WNV) is a neurotropic flavivirus that has emerged globally as a significant cause of
viral encephalitis in humans. The WNV-induced innate immune response, including production of
antiviral cytokines, is critical for controlling
virus infection. The adaptor
protein ASC mediates a critical step in innate immune signaling by bridging the interaction between the pathogen recognition receptors and
caspase 1 in
inflammasome complexes, but its role in WNV immunopathogenesis is not defined. Here, we demonstrate that ASC is essential for interleukin-1β (IL-1β) production and development of effective host immunity against WNV. ASC-deficient mice exhibited increased susceptibility to
WNV infection, and reduced survival was associated with enhanced virus replication in the peripheral tissues and central nervous system (CNS).
Infection of cultured bone marrow-derived dendritic cells showed that ASC was essential for the activation of
caspase 1, a key component of
inflammasome assembly. ASC(-/-) mice exhibited attenuated levels of proinflammatory
cytokines in the serum. Intriguingly, infected ASC(-/-) mice also displayed reduced levels of
alpha interferon (IFN-α) and
IgM in the serum, indicating the overall protective role of ASC in restricting
WNV infection. However, brains from ASC(-/-) mice displayed unrestrained
inflammation, including elevated levels of proinflammatory
cytokines and
chemokines, such as IFN-γ, CCL2, and CCL5, which correlated with more pronounced activation of the astrocytes, enhanced infiltration of peripheral immune cells in the CNS, and increased neuronal cell death. Collectively, our data provide new insights into the role of ASC as an essential modulator of
inflammasome-dependent and -independent immune responses to effectively control
WNV infection.