Inflammation is a component of neurodegeneration in response to Venezuelan equine encephalitis virus infection in mice

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

“…Consistent with this, it has been shown that increased expression of TNF-α after infection with WNV and JEV is correlated with neuronal death [154,195], and that neutralizing antibodies specific for IL-1β and TNF-α protected neurons from WNV-induced cell death [195]. The release of inflammatory cytokines by neurons can trigger gliosis (i.e., microglial and astrocyte activation), which is one of the major hallmarks of arboviral neuropathogenesis [154,186,198].…”

“…Nonetheless, an earlier study demonstrated a neuroprotective role for SARM-1 against lethal WNV infection [193]. Finally, neuronal apoptosis can be induced by increased expression of apoptotic-related genes, that is, TNFα, FasL, and TRAIL, which have been shown following infection with some encephalitic arboviruses such as TBEV and VEEV [186,194]. In VEEV-infected mice, neuronal apoptosis was observed in areas of the brain that contained astrogliosis and inflammation in the absence of viral antigens [185,186].…”

“…Neuronal damage and loss can occur by either direct arboviral infection or indirectly by uncontrolled immune responses to the replicating virus [181,182]. In vitro and in vivo studies have shown that neurons undergo morphologic changes that are characteristic of apoptosis, that is, nuclear and membrane condensation, after infection with several encephalitic flaviviruses, including WNV [183], JEV [154], TBEV [184], and alphaviruses [145,185,186]. Neuronal degeneration, necrosis, and apoptosis were also demonstrated in various CNS regions in mice infected with LACV [146].…”

“…Finally, neuronal apoptosis can be induced by increased expression of apoptotic-related genes, that is, TNFα, FasL, and TRAIL, which have been shown following infection with some encephalitic arboviruses such as TBEV and VEEV [186,194]. In VEEV-infected mice, neuronal apoptosis was observed in areas of the brain that contained astrogliosis and inflammation in the absence of viral antigens [185,186]. Similarly, apoptosis of uninfected neurons was identified in a primate model of JEV infection [154], indicating an alternate, indirect mechanism of neuronal death.…”

“…Activated astrocytes and microglia play an important role in inflammatory responses during natural infection with encephalitic flaviviruses, namely JEV [200], WNV [201], and TBEV [198], as well as encephalitic alphaviruses [186]. Upon activation, astrocytes and microglia release several chemokines and cytokines such as TNF-α, IL-6, C-X-C motif chemokine ligand (CXCL)10, chemokine (C-C motif) ligand 2, monocyte chemoattractant protein-1, RANTES, IFN-γ-induced protein 10, and matrix metalloproteinases [154,195,[202][203][204].…”