title: Inflammasome adaptor protein Apoptosis-associated speck-like protein containing CARD (ASC) is critical for the immune response and survival in west Nile virus encephalitis.
abstract: 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.
authors.affiliation: Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii at Manoa, Honolulu, Hawaii, USA.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Kumar
authors.forename: Kelsey
authors.initials: K
authors.lastname: Roe
authors.forename: Beverly
authors.initials: B
authors.lastname: Orillo
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Muruve
authors.forename: Vivek R
authors.initials: VR
authors.lastname: Nerurkar
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.forename: Saguna
authors.initials: S
authors.lastname: Verma
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D007150:Immunohistochemistry; D058847:Inflammasomes / Q000276:immunology*; D016898:Interferon-alpha / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D014901:West Nile Fever / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D018925:Chemokines; D016207:Cytokines; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D058847:Inflammasomes; D016898:Interferon-alpha; D053583:Interleukin-1beta; C498534:Pycard protein, mouse; D020170:Caspase 1