Cytolytic effector pathways and IFN‐γ help protect against Japanese encephalitis

Abstract

Japanese encephalitis, caused by infection with the neurotropic flavivirus, Japanese encephalitis virus (JEV), is among the most important viral encephalitides in Asia. While previous studies established an essential role of Ab and type I IFN, it is still unclear if the cell-mediated immune responses, through their direct antiviral effector functions, contribute to protection against the fatal disease. We report here that mice defective in both the granule exocytosis and death receptor pathways of cytotoxicity display increased susceptibility to JEV. The two cell contact-dependent cytotoxic effector mechanisms act redundantly within the CNS to reduce disease severity. We also demonstrate that IFN-γ is critical in recovery from primary infection with JEV by a mechanism involving suppression of virus growth in the CNS, and that T cells are the main source of the cytokine that promotes viral clearance from the brain. Finally, we show by in vivo depletion of NK cells that this innate immune cell population is dispensable for control of JEV infection in the periphery and in the CNS. Accordingly, cell contact-dependent cytolytic and IFN-γ-dependent noncytolytic clearance of virus mediated by T cells trafficking into the CNS help in recovery from lethal infection in a mouse model of Japanese encephalitis. Keywords: Fas receptor r Flavivirus r Granzyme r Mouse model r Viral encephalitisAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionTo explore the immunological correlates for recovery from primary infection with the medically important neurotropic flavivirus, Japanese encephalitis virus (JEV), we have developed an adult mouse model that resembles the physiological route of virus transmission to the mammalian host by the bite of an infected mosquito [1]. We found that s.c. deposition of a small dose of JEV into the footpad of C57BL/6 (B6) mice resulted in neuroCorrespondence: Dr. Mario Lobigs e-mail: m.lobigs@uq.edu.au invasive disease that was lethal in ∼60% of animals. Mice staged T-cell-independent IgM and T-cell-dependent IgG responses that became detectable at days 4 and 8 postinfection (pi) respectively, and neutralized virus infectivity in vitro [1]. This early and sustained humoral immune response is considered absolutely essential for survival of infection with JEV and related flaviviruses, because infections of B-cell-deficient (μMT) mice were uniformly lethal [1,2]. In addition to Ab, type I IFN responses are indispensable in the control of JEV infection [3,4]. On the other hand, the role of CD8 + T cells in recovery from Japanese encephalitis (JE) remains ambiguous. While JEV infection resulted in extensive activation and migration of CD8 + T cells into the CNS, they did not provide a significant survival advantage based on mortality rates in groups of mice subjected to in vivo depletion of this Infection of the CNS with JEV triggers extensive neuronal death induced directly by viral infection as well as bystander damage resulting fr...

Memory B cells: a proposed new immunological correlate for protective efficacy of Japanese encephalitis vaccine

“…Further investigations are needed to provide a more detailed mechanism to explain this high susceptibility to JEV. A recently published study by the authors showing the importance of IFN-γ production for protection against JE [10] may provide an answer. The advantages of this model, as well as the relatively fast reduction in antibody levels, warrant its utility for evaluating the protective efficacy of JE vaccine candidates, in particular, the induction of memory B cells that have protective functions without pre-existing neutralizing antibodies.…”

Interactions of human microglia cells with Japanese encephalitis virus

“…In contrast, the signalling CXCL10/CXCR3 is implicated in the infiltration of virus-specific CD8 + T lymphocytes into the brain leading to a prolong survival of WNV-infected mice [33]. In JEV-infected mice, CD8 + T lymphocytes accumulate in the brain [27] and the activity of cytotoxic lymphocytes partly mediates protection against JEV [34]. Indeed, impaired activity and trafficking of CD8 + T-cell into the CNS contribute to increased mortality of CCR5-deficient mice exposed to JEV [27].…”

“…MHC class II is involved in the reactivation of virus-specific CD4 + T-lymphocytes. Helper T-cells accumulate in the CNS of JEV-infected mice [27] and are a critical source of IFN-γ which promotes JEV clearance [34]. In this context, it was interesting to note that human microglia exposed to live JEV showed weak modification of MHC class II on CX 3 CR1 + microglia.…”

Role of Natural Killer and Gamma-Delta T cells in West Nile Virus Infection

“…Therefore, WNV may evade NK-cell mediated killing by upregulation of MHC class I on infected cells. Lastly, although the depletion approach has been commonly used to determine the functional role of NK cells during in vivo flavivirus infection [31,42], it has been reported that NK cells can’t be fully depleted in all WNV- infected tissues [36]. …”