IPS-1 Is Essential for the Control of West Nile Virus Infection and Immunity

Suthar, Mehul S.; Ma, Daphne Y.; Thomas, Sunil; Lund, Jennifer M.; Zhang, Nu; Daffis, Stephane; Rudensky, Alexander Y.; Bevan, Michael J.; Clark, Edward A.; Kaja, Murali-Krishna; Diamond, Michael S.; Gale, Michael

West Nile virus (WNV) is a neurotropic flavivirus and is an emerging public health threat. Infection with WNV now constitutes the leading cause of mosquito-borne and epidemic encephalitis in humans in the United States [1] . WNV is enveloped and contains a single strand positive sense RNA genome of approximately 11 kb in length that encodes three structural (C, prM/M, and E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). It cycles enzootically between birds and Culex mosquitoes, with humans infected as dead-end hosts. WNV infection has been modeled in inbred mice wherein infection and pathogenesis recapitulate many of the features of human infection (reviewed in [2] ). Following subcutaneous inoculation, WNV replicates in dendritic cells (DCs) at the portal of entry and in the draining lymph node. A primary viremia develops and virus spreads to visceral organs including the spleen, where further amplification occurs, leading to central nervous system (CNS) dissemination and encephalitis. In humans, WNV causes an acute febrile illness that can progress to severe and sometimes lethal neuroinvasive disease, especially in the elderly and immunocompromised [3] . However, healthy young adults are also afflicted with severe neurological disease [4, 5, 6] , indicating that virulence can occur independently of immune deficiencies or aging.