Immunomodulatory cytokines determine the outcome of Japanese encephalitis virus infection in mice

Abstract

Japanese encephalitis virus (JEV) induces an acute infection of the central nervous system, the pathogenic mechanism of which is not fully understood. To investigate host response to JEV infection, 14-day-old mice were infected via the extraneural route, which resulted in encephalitis and death. Mice that received JEV immune splenocyte transfer were protected from extraneural JEV infection. Pathology and gene expression profiles were then compared in brains of mice that either succumbed to JEV infection or were protected from infection by JEV immune cell transfer. Mice undergoing progressive JEV infection had increased expression of proinflammatory cytokines, chemokines, and signal transducers associated with the interferon (IFN) pathway. In contrast, mice receiving immune cell transfer had increased production of the Th2 cytokine IL-4, and of IL-10, with subdued expression of IFN-gamma. We observed IL-10 to be an important factor in determining clinical outcome in JEV infection. Data obtained by microarray analysis were further confirmed by quantitative RT-PCR. Together, these data suggest that JEV infection causes an unregulated inflammatory response that can be countered by the expression of immunomodulatory cytokines in mice that survive lethal infection.

Acute Encephalitis Syndrome in Adults and Its Correlation with Cytokine Levels in the Serum and Cerebrospinal Fluid

“…CSF IL-6 and IL-10 levels were significantly higher in non-JE cases compared with JE cases. Significantly higher levels of IL-10 in non-JE patients compared to JE patients have also been observed by Kalita et al and Pandey et al (19,27). High IL-10 levels in the non-JE group could be related with the protective response seen early in the course of infection, which may contribute to the decreased severity of disease and enhanced survival observed in non-JE patients.…”

“…The anti-inflammatory nature of IL-10 is well known. Biswas et al investigated the host response to JE infection in mouse models and showed that mice with increased production of IL-10 had a reduced expression of the pro-inflammatory cytokine interferon gamma (IFN-γ) and hence better survival (19). The protective effect of IL-10 in tick-borne encephalitis was shown in a recent study by Tun et al where IL-10 knockout mice were seen to have a higher mortality after infection with the Oshima strain of tick-borne encephalitis (20).…”

Glutamate released by Japanese encephalitis virus‐infected microglia involves TNF‐α signaling and contributes to neuronal death

“…The neuroinvasive form of JEV infection is characterized both by neuronal death and the activation of resident glial cells as well as the infiltration of mononuclear effector cells, whose activities promote both viral clearance and neuronal injury (German et al, 2006;Ghoshal et al, 2007;Ravi et al, 1997). Accumulating evidence shows that an antiinflammatory strategy is beneficial against JEV-associated neuronal death and encephalitis (Biswas et al, 2010;Mishra and Basu, 2008). Thus, neurons may be destroyed by a variety of direct and indirect mechanisms including JEV-or cytokine-mediated cytotoxicity.…”

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

“…JEV neuropathogenesis is thought to be largely an outcome of the unregulated inflammatory response of the host neuronal immune system. 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).…”