Protection Against CTL Escape and Clinical Disease in a Murine Model of Virus Persistence (original) (raw)
Related papers
Microbial Pathogenesis, 1987
The presence of maternal antibodies protected suckling C57BL/6 mice from the clinical manifestations of the acute encephalomyelitis caused by mouse hepatitis virus, strain JHM (MHV-JHM), a coronavirus, even though histological evidence of encephalomyelitis was found at early times after inoculation. 100% of infected suckling mice developed a fatal disease in the absence of maternal antibody. By 14 days after inoculation, the brains of all antibody-protected mice examined were nearly normal on histological examination. At 3-8 weeks post-inoculation, approximately 40% of the antibody-protected mice developed a neurological disease characterized by hindlimb paralysis and wasting. Evidence of inflammation and demyelination was apparent in the spinal cord and brainstem. The mice that remained asymptomatic at this time showed few signs of inflammation and none developed clinical disease over the following 9 months. Viral antigen could be detected in most of the mice examined at all times after inoculation, whether symptomatic or not, and was particularly evident in the animals with hindlimb paralysis. MHV-JHM could be consistently cultured from the mice with hindlimb paralysis. These results show that maternal immune factors can completely protect susceptible mice from the acute, fatal, clinical encephalomyelitis caused by MHV-JHM, but cannot prevent the establishment of a latent state and subsequent development of virus-induced, clinically evident, demyelinating disease. This model will be useful for studying the virus and host factors important for the development of MHV-JHM latency and subsequent virus-induced demyelination .
Localization of Virus and Antibody Response in Mice Infected Persistently with MHV-JHM
Advances in Experimental Medicine and Biology, 1990
Suckling mice infected intranasally with MHV-JHM and nursed by immunized dams develop a late onset demyelinating encephalomyelitis. Analysis by in situ hybridization revealed that MHV-JHM entered the central nervous system (CNS) via the olfactory and trigeminal nerves and spread over the next two weeks to the spinal cord, prior to amplification at this site. Serial measurements of neutralizing antibody titers showed that the late onset disease developed in some mice at levels of antibody which protected mice from the fatal, acute encephalitis, supporting the notion that cell-mediated and not humoral immunity is important in protecting mice from MHV-JHM persistence.
Cytotoxic T Cell?Resistant Variants Are Selected in a Virus-Induced Demyelinating Disease
Immunity, 1996
mice infected with lymphocytic choriomeningitis virus ‡ Neuroscience Program (LCMV). In C57Bl/6 (B6) mice, three LCMV-specific epi-University of Iowa topes are recognized by CD8 ϩ T cells. Infection with Iowa City, Iowa 52242 virus in which either two (Moskophidis and Zinkernagel, 1995) or three (Lewicki et al., 1995) of these epitopes have been mutated so that they are no longer recognized Summary by CD8 ϩ T cells results in a delay in kinetics until the virus is eliminated. Similar results have been obtained C57Bl/6 mice infected with mouse hepatitis virus, by in vivo selection of LCMV escape mutants (Pircher strain JHM (MHV-JHM) develop a chronic demyelinatet al., 1990). In these experiments, mice transgenic for ing encephalomyelitis. Infectious virus can be isolated a virus-specific T cell receptor were used since selection only from symptomatic mice. In C57Bl/6 mice, two for LCMV CTL escape mutants occurs infrequently in CD8 ؉ T cell epitopes within the MHV-JHM surface glymice with a normal immune system. This example procoprotein were previously identified. Here, we show vides the only evidence for a clear correlation between, that mutations in the RNA encoding the immunodomion the one hand, the development of CTL escape munant of the epitopes are present in nearly all virus tants and, on the other hand, increased viral replication samples isolated from these mice. Mutations are not during the course of a natural infection. present in sequences flanking this epitope or in other Mouse hepatitis virus, strain JHM (MHV-JHM) causes CD8 ؉ or CD4 ؉ T cell epitopes. Furthermore, analysis acute encephalitis and acute and chronic demyelinating of five peptides corresponding to variant epitopes in encephalomyelitis in susceptible rodents (Kyuwa and direct ex vivo cytotoxicity assays showed that each Stohlman, 1990; Wege, 1995). The CD8 ϩ T cell response mutation caused a loss of epitope recognition. These to MHV is important for virus control and clearance. results suggest that escape from CD8 ؉ T cell recogni-Depletion of CD8 ϩ T cells results in decreased virus tion is necessary for enhanced virus replication and clearance in MHV-infected mice (Pearce et al., 1994; development of clinical disease in these MHV-JHM-Williamson and Stohlman, 1990). 2-microglobulin infected mice. (Ϫ/Ϫ) mice, defective in major histocompatibility complex (MHC) class I antigen presentation, are exquisitely sensitive to infection with the mildly neurotropic A59
Immunologic Research, 2007
Infection of mice with variants of mouse hepatitis virus, strain JHM (MHV-JHM), provide models of acute and chronic viral infection of the central nervous system (CNS). Through targeted recombination and reverse genetic manipulation, studies of infection with MHV-JHM variants have identified phenotypic differences and examined the effects of these differences on viral pathogenesis and anti-viral host immune responses. Studies employing recombinant viruses with a modified spike (S) glycoprotein of MHV-JHM have identified the S gene as a major determinant of neurovirulence. However, the association of S gene variation and neurovirulence with host ability to generate anti-viral CD8 T cell responses is not completely clear. Partially protective anti-viral immune responses may result in persistent infection and chronic demyelinating disease characterized by myelin removal from axons of the CNS and associated with dense macrophage/ microglial infiltration. Demyelinating disease during MHV-JHM infection is immunemediated, as mice that lack T lymphocytes fail to develop disease despite succumbing to encephalitis with high levels of infectious virus in the CNS. However, the presence of T lymphocytes or anti-viral antibody can induce disease in infected immunodeficient mice. The mechanisms by which these immune effectors induce demyelination share an ability to activate and recruit macrophages and microglia, thus increasing the putative role of these cells in myelin destruction.
CD8 T cells protect adult naive mice from JEV-induced morbidity via lytic function
PLoS neglected tropical diseases, 2017
Following Japanese encephalitis virus (JEV) infection neutralizing antibodies are shown to provide protection in a significant proportion of cases, but not all, suggesting additional components of immune system might also contribute to elicit protective immune response. Here we have characterized the role of T cells in offering protection in adult mice infected with JEV. Mice lacking α/β-T cells (TCRβ-null) are highly susceptible and die over 10-18 day period as compared to the wild-type (WT) mice which are resistant. This is associated with high viral load, higher mRNA levels of proinflammatory cytokines and breach in the blood-brain-barrier (BBB). Infected WT mice do not show a breach in BBB; however, in contrast to TCRβ-null, they show the presence of T cells in the brain. Using adoptive transfer of cells with specific genetic deficiencies we see that neither the presence of CD4 T cells nor cytokines such as IL-4, IL-10 or interferon-gamma have any significant role in offering pr...
Journal of Virology, 1998
C57BL/6 mice infected with mouse hepatitis virus strain JHM (MHV-JHM) develop a chronic demyelinating encephalomyelitis several weeks after inoculation. Previously, we showed that mutations in the immunodominant CD8 T-cell epitope (S-510-518) could be detected in nearly all samples of RNA and virus isolated from these mice. These mutations abrogated recognition by T cells harvested from the central nervous systems of infected mice in direct ex vivo cytotoxicity assays. These results suggested that cytotoxic T-lymphocyte (CTL) escape mutants contributed to virus amplification and the development of clinical disease in mice infected with wild-type virus. In the present study, the importance of these mutations was further evaluated by infecting naive mice with MHV-JHM variants isolated from infected mice and in which epitope S-510-518 was mutated. Compared to mice infected with wild-type virus, variant virus-infected animals showed higher mortality and morbidity manifested by decreased...
Journal of Virology, 2005
ABSTRACTThe immunodominant CD8+T-cell epitope of a highly neurovirulent strain of mouse hepatitis virus (MHV), JHM, is thought to be essential for protection against virus persistence within the central nervous system. To test whether abrogation of this H-2Db-restricted epitope, located within the spike glycoprotein at residues S510 to 518 (S510), resulted in delayed virus clearance and/or virus persistence we selected isogenic recombinants which express either the wild-type JHM spike protein (RJHM) or spike containing the N514S mutation (RJHMN514S), which abrogates the response to S510. In contrast to observations in suckling mice in which viruses encoding inactivating mutations within the S510 epitope (epitope escape mutants) were associated with persistent virus and increased neurovirulence (Pewe et al., J Virol. 72:5912-5918, 1998), RJHMN514Swas not more virulent than the parental, RJHM, in 4-week-old C57BL/6 (H-2b) mice after intracranial injection. Recombinant viruses expressi...