West Nile Virus Induced Cell Death in the Central Nervous System

Abstract

West Nile virus (WNV), a mosquito-borne, single-stranded flavivirus, has caused annual outbreaks of viral encephalitis in the United States since 1999. The virus induces acute infection with a clinical spectrum ranging from a mild flu-like febrile symptom to more severe neuroinvasive conditions, including meningitis, encephalitis, acute flaccid paralysis, and death. Some WNV convalescent patients also developed long-term neurological sequelae. Neither the treatment of WNV infection nor an approved vaccine is currently available for humans. Neuronal death in the central nervous system (CNS) is a hallmark of WNV-induced meningitis and encephalitis. However, the underlying mechanisms of WNV-induced neuronal damage are not well understood. In this review, we discuss current findings from studies of WNV infection in vitro in the CNS resident cells and the in vivo animal models, and provide insights into WNV-induced neuropathogenesis.

The Dual Regulation of Apoptosis by Flavivirus

“…Neuro-2a cells (neuronal cells) and K562 (immune cells) infected by WNV show typical apoptotic characteristics, and the up-regulated Bax gene is involved ( Parquet et al, 2001 ). Furthermore, WNV infection can induce T98G cells (brain-derived) death through extrinsic and intrinsic apoptotic pathways, and caspase-3 dependent apoptosis contributes to the pathogenesis of fetal WNV encephalitis ( Bimmi et al, 2003 ; Kleinschmidt et al, 2007 ; Samuel et al, 2007 ; Peng and Wang, 2019 ), which helps to clarify the pathogenesis of WNV-induced neuronal cell death and propose novel therapeutic targets that may restrict CNS damage. In Vero cells (epithelial cells), WNV can trigger the mitochondrial-mediated apoptosis pathway at low infectious doses (MOI < 10), which is initiated by the release of Cyt-c and the formation of apoptosome.…”

Pathogenicity and virulence of West Nile virus revisited eight decades after its first isolation

“…Different reports have evidenced the induction of apoptosis in neurons [ 9 , 32 , 199 , 200 ]. Expression of alpha-synuclein, a neuronal protein directly related to the pathogenesis of Parkinson’s disease and damage to the human brain, has been reported to inhibit viral infection and disease in the CNS [ 201 ].…”

Antiviral Cytokine Response in Neuroinvasive and Non-Neuroinvasive West Nile Virus Infection

“…The majority of the experimental data on the molecular mechanisms of WNV-induced neuropathogenesis are based on in vitro data and in vivo animal models showing that neurons, microglia and astrocytes represent the main cellular targets for infection in the CNS [ 9 ]. The hallmark of WNV neuroinvasive disease (WNND) pathogenesis is massive neuronal death attributed to caspase-3 and 9- mediated apoptosis involving both intrinsic and extrinsic pathways that is a result of both direct viral infection of neurons and indirect mechanisms mediated by cytotoxic factors such as proinflammatory cytokines [ 10 , 11 ]. The synthesis of neurotoxic factors and proinflammatory cytokines is mainly attributed to the WNV infection of microglia and recognition of a double stranded viral RNA intermediate in a TLR3-dependent manner [ 11 ].…”