CD8 T cells protect adult naive mice from JEV-induced morbidity via lytic function (original) (raw)
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Immunomodulatory Cytokines Determine the Outcome of Japanese Encephalitis Virus Infection in Mice
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-g. 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. J. Med. Virol. 82:304– 310, 2010. 2009 Wiley-Liss, Inc. KEY WORDS: Japanese encephalitis; microarray; adoptive transfer; splenocytes INTRODUCTION Japanese encephalitis (JE) is a flaviviral disease of great medical importance. Japanese encephalitis virus (JEV) infection occurs throughout most of Asia and is also spreading to new geographical areas like Australia. Children are at greatest risk of infection in endemic areas [Ruben and Gajanana, 1997]. Factors governing the establishment of JEV infection in the central nervous system (CNS) are poorly understood. The course of disease in humans can effectively be replicated in laboratory rodents. Young mice are susceptible to extraneural inoculation with JEV and succumb to infection soon after the establishment of infection in the CNS [Johnson et al., 1985; Hase et al., 1990]. The adoptive transfer ofJEVimmunesplenocytes into these young mice has been shown to confer protection against subsequent lethal challenge with JEV, thus demonstrating a role for cellular immunity in JEV infection [Biswas et al., 2009]. Differential expression profiling of genes using high throughput system enables the identification of critical genes responsible for modulation of infection and a subsequent understanding of the cellular and molecular pathways associated with disease progression. Most gene profiling studies in flavivirus infection have been carried out using permissive cell lines. Microarray analysis of human glioblastoma cells infected with West Nile Virus revealed the differential expression of 173 cellular genes, of which 23 were identified that might play a role in cellular neuro-degeneration [Koh and Ng, 2005]. Apoptosis was identified as the mechanism of cell death induced by JEV replication in several neuronal and non-neuronal cell lines [Liao et al., 1997]. In addition, activation of tumor necrosis factor receptor 1 (TNFR1) and signaling through the TNFR-associated death domain (TRADD) following JEV infection was assumed to trigger downstream apoptotic cascades in mouse and human neuroblastoma cell lines [Swarup et al., 2007a
Host Defence Mechanisms Against Japanese Encephalitis Virus Infection in Mice
Journal of General Virology, 1983
The role of antibody and cell-mediated immunity in the resistance to Japanese encephalitis virus (JEV) infection was studied in adult mice. Passively transferred antibodies obtained up to 2 weeks after primary infection protected the recipient mice against a challenge infection with JEV. Antibody obtained at 4 or 5 weeks failed to protect despite the presence of high titres of neutralizing antibody. Protection was abrogated by pretreatment of the early serum with 2-mercaptoethanol to remove ]gM. Similarly, adoptive transfer of immune spleen cells obtained up to 2 weeks after immunization provided protection. The protective effect was abolished by pretreatment of the immune spleen cells with anti-Thy 1.2 antiserum and complement. These findings suggest a role of T lymphocytes and IgM antibody in recovery from JEV infection.
Journal of Biosciences, 1997
have been generated specifically against JEV in our laboratory and these CTL have been shown to protect mice against lethal challenge with JEV. Virus replication was found to be inhibited in the brains of animals that were adoptively transferred with JEV specific CTL as revealed by immunohistological staining as well as viral plaque assays. We further show that virus specific CTL could be recovered from such protected mice as long as 45 days after adoptive transfer.
PloS one, 2013
Japanese encephalitis virus (JEV) causes acute central nervous system (CNS) disease in humans, in whom the clinical symptoms vary from febrile illness to meningitis and encephalitis. However, the mechanism of severe encephalitis has not been fully elucidated. In this study, using a mouse model, we investigated the pathogenetic mechanisms that correlate with fatal JEV infection. Following extraneural infection with the JaOArS982 strain of JEV, infected mice exhibited clinical signs ranging from mild to fatal outcome. Comparison of the pathogenetic response between severe and mild cases of JaOArS982-infected mice revealed increased levels of TNF-α in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-α KO mice was significantly increased compared with that of WT mice, indicating that TNF-α plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-α KO mice. However, exagge...
Human T cell responses to Japanese encephalitis virus in health and disease
The Journal of Experimental Medicine, 2016
Japanese encephalitis (JE) virus (JEV) is an important cause of encephalitis in children of South and Southeast Asia. However, the majority of individuals exposed to JEV only develop mild symptoms associated with long-lasting adaptive immunity. The related flavivirus dengue virus (DENV) cocirculates in many JEV-endemic areas, and clinical data suggest cross-protection between DENV and JEV. To address the role of T cell responses in protection against JEV, we conducted the first full-breadth analysis of the human memory T cell response using a synthetic peptide library. Ex vivo interferon-γ (IFN-γ) responses to JEV in healthy JEV-exposed donors were mostly CD8 + and targeted nonstructural (NS) proteins, whereas IFN-γ responses in recovered JE patients were mostly CD4 + and targeted structural proteins and the secreted protein NS1. Among patients, a high quality, polyfunctional CD4 + T cell response was associated with complete recovery from JE. T cell responses from healthy donors sh...
Japanese Encephalitis Virus Generated Neurovirulence, Antigenicity, and Host Immune Responses
ISRN Virology, 2013
In response to a JE virus attack, infected body cells start secretion of different cytokines and activate innate immune response. Virus starts neuronal invasion by entering into nerve cells and inflecting the central nervous system. It avoids exposure of body's natural immunity and generates neurotrophic effects. Virus causes acute susceptibility to CNS and establishes encephalitis syndrome that results in very high fatality in children. In survivors, JEV inhibits the growth and proliferation of NCPs and imposes permanent neuronal disorders like cognitive, motor, and behavioral impairments. However, body cells start TCR mediated interactions, to recognize viral antigens with class I MHC complex on specific target cells, and operate mass killing of virus infected cells by increased CTL activity. Thus, both cell mediated and antibody interactions plays a central role in protection against JEV. In the present review article virus generated neurovirulence, antigenicity, and host immune responses are described in detail. More emphasis is given on diagnosis, clinical care, and active immunization with well-designed potential antiflavivirus vaccines. Further, for achieving an elite success against JEV, global eradication strategies are to be needed for making vaccination program more responsible and effective in endemic areas.
Role of regulatory T cells in coronavirus-induced acute encephalitis
Virology, 2009
C57BL/6 mice infected with mouse hepatitis virus, strain JHM (JHMV) develop a rapidly fatal acute encephalitis. Previously, we showed that this disease is partially CD4 T cell-mediated since infection with a recombinant JHMV (rJ) mutated in only a single immunodominant CD4 T cell epitope (epitope M133, rJ. M Y135Q) results in a nonlethal disease. Increased mortality correlated with a greater number of JHMV-specific CD4 T cells in the brains of rJ compared to rJ.M Y135Q-infected mice. Here, we extend these results to show that the diminished number of virus-specific T cells correlates with a reduced cytokine/chemokine response in the infected brain. We also show that regulatory CD4 T cells (Tregs) are critical for mild disease in rJ.M Y135Qinfected mice because their depletion results in increased mortality. Further, a relative paucity of Tregs characterizes lethal infection because adoptive transfer of Tregs into rJ-infected mice increases survival from 0% to 50%. These results support the notion that clinical disease in coronavirus-induced acute encephalitis results from a balance between factors critical for virus clearance, such as virus-specific effector T cells and anti-inflammatory elements, such as Tregs. These findings also show that unlike chronic infections, in which an excessive number of Tregs contributes to pathogen persistence, Tregs in the setting of acute encephalitis may help to limit immunopathological disease without delaying virus clearance.
Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection
2021
Japanese Encephalitis Virus (JEV) is a mosquito borne flavivirus infection. Transmission of JEV starts with the infected mosquito bite where human dermis layer act as the primary site of infection. Once JEV makes its entry into blood, it infects monocytes wherein the viral replication peaks up without any cell death and results in production of TNF-α. One of the most characteristics pathogenesis of JEV is the breaching of blood brain barrier (BBB). JEV propagation occurs in neurons that results in neuronal cell death as well as dissemination of virus into astrocytes and microglia leading to overexpression of proinflammatory cytokines. JEV infection results in host cells mediated secretion of various types of cytokines including type-1 IFN along with TNF-α and IFN-γ. Molecule like nitrous oxide (NO) exhibits antiviral activities against JEV infection and helps in inhibiting the viral replication by blocking protein synthesis and viral RNA and also in virus infected cells clearance. I...
Journal of Neuroinflammation, 2014
Background: Theiler's murine encephalomyelitis virus (TMEV) infection represents a commonly used infectious animal model to study various aspects of the pathogenesis of multiple sclerosis (MS). In susceptible SJL mice, dominant activity of Foxp3 + CD4 + regulatory T cells (Tregs) in the CNS partly contributes to viral persistence and progressive demyelination. On the other hand, resistant C57BL/6 mice rapidly clear the virus by mounting a strong antiviral immune response. However, very little is known about the role of Tregs in regulating antiviral responses during acute encephalitis in resistant mouse strains. Methods: In this study, we used DEREG mice that express the diphtheria toxin (DT) receptor under control of the foxp3 locus to selectively deplete Foxp3 + Tregs by injection of DT prior to infection and studied the effect of Treg depletion on the course of acute Theiler's murine encephalomyelitis (TME).
European Journal of Immunology, 2014
The mechanisms underlying Japanese encephalitis virus (JEV) pathogenesis need to be thoroughly explored to delineate therapeutic approaches. It is believed that JEV manipulates the innate and adaptive compartments of the host's immune system to evade immune response and cross the blood-brain barrier. The present study was thus designed to investigate the functional modulation of DCs after exposure to JEV and to assess the consequences on CD4 + T-lymphocyte functions. Human monocyte-derived DCs were either infected with 1 MOI of live virus, UV-inactivated virus, or were mock-infected. Replication-competent JEV induced a significant increase in the expression of maturation markers 48 h postinfection, along with that of programmed cell death 1 ligand 1 (PD-L1; also called B7-H1 and CD274). JEV-infected DCs expanded the Treg cells in allogenic mixed lymphocyte reactions. The expansion of Treg cells by JEV-infected DCs was significantly reduced upon blocking PD-L1 using an antagonist. In addition, JEV-infected DCs significantly altered the proliferation and reduced the polarization of Th cells toward the Th1-cell phenotype. The results, for the first time, suggest that JEV evades the host's immune system by modulating the crosstalk between DCs and T lymphocytes via the PD-L1 axis.