Tumor necrosis factor receptor‐1‐induced neuronal death by TRADD contributes to the pathogenesis of Japanese encephalitis

Abstract

While a number of studies have documented the neurotropism of Japanese encephalitis virus (JEV), little is known regarding the molecular mechanism of neuronal death following viral infection. The tumor necrosis factor receptor (TNFR)-associated death domain (TRADD) has been suggested to be the crucial signal adaptor that mediates all intracellular responses from TNFR-1. Using mouse (Neuro2a) and human (SK-N-SH) neuroblastoma cell lines, we have shown that the altered expression of TNFR-1 and TRADD following JEV infection regulates the downstream apoptotic cascades. Activation of TRADD led to mitochondria-mediated neuronal apoptosis. As TRADD-knockout animals or deficient cell lines are unavailable, it has been difficult to definitively address the physiological role of TRADD in diseases pathology following JEV infection. We circumvented this problem by silencing TRADD expression with small-interfering RNA (siRNA) and have found that TRADD is required for TNFR-1-initiated neuronal apoptosis following in vitro infection with JEV. Interestingly, siRNA against TRADD also decreased the viral load in Neuro2a cells. Furthermore, siRNA against TRADD increased the survival of JEV-infected mice by altering the expression of pro apoptotic versus antiapoptotic molecules. These studies show that the engagement of TNFR-1 and TRADD following JEV infection plays a crucial role in neuronal apoptosis.

The contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system

“…In agreement with this hypothesis, inhibition of TNF-receptor-associated death domain (TRADD) expression -a critical factor in the TNF-α-dependent signaling cascaderesulted in decreased activation of neuronal apoptosis and microglial cell activation in vitro [171]. In mice, depletion of this protein was correlated with reduced expression of caspase 3, pro-inflammatory cytokines and pro-apoptotic factors as well as increased survival in mice, implying a role for immunopathology in the severity of JE [170,171].…”

“…However, the precise contribution of each of these mechanisms to disease is unclear. While apoptosis of neurons has been observed in neuronal progenitor cells in vitro [78] and in mice [170] following JEV infection, it remains to be established whether viral infection of neurons or immunopathological responses to neuronal infection are responsible for programmed cell death in vivo. In contrast to the protective role played by monocytic cells during WNV infection, several in vitro studies have implicated microglial cell activation and the subsequent induction of inflammatory cytokines in neuronal destruction resulting from JE [27,118].…”

Glial activation involvement in neuronal death by Japanese encephalitis virus infection

“…TNF-a and IL-1b are potentially neurotoxic molecules in JEVassociated neuronal death, as both neutralizing antibodies attenuated JEV-induced neuronal death (Fig. 8) and both TNF-a and IL-1b have been shown to directly and indirectly injure neurons (Raung et al, 2005(Raung et al, , 2007Ghoshal et al, 2007;Swarup et al, 2007Swarup et al, , 2008Das et al, 2008).…”

Regulated IRE1-dependent decay pathway is activated during Japanese encephalitis virus-induced unfolded protein response and benefits viral replication

“…In particular, an increased expression of IL-10 and reduced synthesis of IFN-c, STAT1 and STAT2 correlate with better survival in mice (Biswas et al, 2010). However, damage to neuronal tissue is an outcome of host cell death by direct virus infection and that induced by the proinflammatory factors (Ghoshal et al, 2007;Swarup et al, 2007). JEV-infected cultured mammalian cells undergo apoptotic cell death, indicating this to be one of the potential mechanisms of neuronal tissue damage (Su et al, 2002).…”