scholarly journals Fas Ligand Interactions Contribute to CD8+ T-Cell-Mediated Control of West Nile Virus Infection in the Central Nervous System

2007 ◽  
Vol 81 (21) ◽  
pp. 11749-11757 ◽  
Author(s):  
Bimmi Shrestha ◽  
Michael S. Diamond
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
West Nile Virus ◽  
T Cell ◽  
Fas Ligand ◽  
Lymphoid Tissues ◽  
Control Mechanisms ◽  
West Nile ◽  
Specific Priming

ABSTRACT West Nile virus (WNV) is a neurotropic flavivirus that causes encephalitis, most frequently in elderly and immunocompromised humans. Previous studies demonstrated that CD8+ T cells utilize perforin-dependent cytolytic mechanisms to limit WNV infection. Nonetheless, the phenotype of perforin-deficient CD8+ T cells was not as severe as that of an absence of CD8+ T cells, suggesting additional effector control mechanisms. In this study, we evaluated the contribution of Fas-Fas ligand (FasL) interactions to CD8+ T-cell-mediated control of WNV infection. Notably, the cell death receptor Fas was strongly upregulated on neurons in culture and in vivo after WNV infection. gld mice that were functionally deficient in FasL expression showed increased susceptibility to lethal WNV infection. Although antigen-specific priming of CD8+ T cells in peripheral lymphoid tissues was normal in gld mice, increased central nervous system (CNS) viral burdens and delayed clearance were observed. Moreover, the adoptive transfer of WNV-primed wild-type but not gld CD8+ T cells to recipient CD8−/− or gld mice efficiently limited infection in the CNS and enhanced survival rates. Overall, our data suggest that CD8+ T cells also utilize FasL effector mechanisms to contain WNV infection in Fas-expressing neurons in the CNS.

scholarly journals Neuronal CXCL10 Directs CD8+ T-Cell Recruitment and Control of West Nile Virus Encephalitis

2005 ◽  
Vol 79 (17) ◽  
pp. 11457-11466 ◽  
Author(s):  
Robyn S. Klein ◽  
Eugene Lin ◽  
Bo Zhang ◽  
Andrew D. Luster ◽  
Judy Tollett ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
West Nile Virus ◽  
T Cell ◽  
Cell Trafficking ◽  
New Paradigm ◽  
West Nile ◽  
West Nile Virus Encephalitis ◽  
The Central Nervous System

ABSTRACT The activation and entry of antigen-specific CD8+ T cells into the central nervous system is an essential step towards clearance of West Nile virus (WNV) from infected neurons. The molecular signals responsible for the directed migration of virus-specific T cells and their cellular sources are presently unknown. Here we demonstrate that in response to WNV infection, neurons secrete the chemokine CXCL10, which recruits effector T cells via the chemokine receptor CXCR3. Neutralization or a genetic deficiency of CXCL10 leads to a decrease in CXCR3+ CD8+ T-cell trafficking, an increase in viral burden in the brain, and enhanced morbidity and mortality. These data support a new paradigm in chemokine neurobiology, as neurons are not generally considered to generate antiviral immune responses, and CXCL10 may represent a novel neuroprotective agent in response to WNV infection in the central nervous system.

scholarly journals The Interferon-Stimulated GeneIfitm3Restricts West Nile Virus Infection and Pathogenesis

2016 ◽  
Vol 90 (18) ◽  
pp. 8212-8225 ◽  
Author(s):  
Matthew J. Gorman ◽  
Subhajit Poddar ◽  
Michael Farzan ◽  
Michael S. Diamond
Keyword(s):  
Central Nervous System ◽  
Cell Culture ◽  
T Cells ◽  
Nervous System ◽  
West Nile Virus ◽  
Transmembrane Protein ◽  
Viral Pathogenesis ◽  
West Nile ◽  
The Brain

ABSTRACTThe interferon-induced transmembrane protein (IFITM) family of proteins inhibit infection of several different enveloped viruses in cell culture by virtue of their ability to restrict entry and fusion from late endosomes. As few studies have evaluated the importance ofIfitm3 in vivoin restricting viral pathogenesis, we investigated its significance as an antiviral gene against West Nile virus (WNV), an encephalitic flavivirus, in cells and mice.Ifitm3−/−mice were more vulnerable to lethal WNV infection, and this was associated with greater virus accumulation in peripheral organs and central nervous system tissues. As no difference in viral burden in the brain or spinal cord was observed after direct intracranial inoculation, Ifitm3 likely functions as an antiviral protein in nonneuronal cells. Consistent with this,Ifitm3−/−fibroblasts but not dendritic cells resulted in higher yields of WNV in multistep growth analyses. Moreover, transcomplementation experiments showed that Ifitm3 inhibited WNV infection independently of Ifitm1, Ifitm2, Ifitm5, and Ifitm6. Beyond a direct effect on viral infection in cells, analysis of the immune response in WNV-infectedIfitm3−/−mice showed decreases in the total number of B cells, CD4+T cells, and antigen-specific CD8+T cells. Finally, bone marrow chimera experiments demonstrated that Ifitm3 functioned in both radioresistant and radiosensitive cells, as higher levels of WNV were observed in the brain only when Ifitm3 was absent from both compartments. Our analyses suggest that Ifitm3 restricts WNV pathogenesis likely through multiple mechanisms, including the direct control of infection in subsets of cells.IMPORTANCEAs part of the mammalian host response to viral infections, hundreds of interferon-stimulated genes (ISGs) are induced. The inhibitory activity of individual ISGs varies depending on the specific cell type and viral pathogen. Among ISGs, the genes encoding interferon-induced transmembrane protein (IFITM) have been reported to inhibit multiple families of viruses in cell culture. However, few reports have evaluated the impact ofIFITMgenes on viral pathogenesisin vivo. In this study, we characterized the antiviral activity of Ifitm3 against West Nile virus (WNV), an encephalitic flavivirus, using mice with a targeted gene deletion ofIfitm3. Based on extensive virological and immunological analyses, we determined that Ifitm3 protects mice from WNV-induced mortality by restricting virus accumulation in peripheral organs and, subsequently, in central nervous system tissues. Our data suggest that Ifitm3 restricts WNV pathogenesis by multiple mechanisms and functions in part by controlling infection in different cell types.

scholarly journals Role of CD8+ T Cells in Control of West Nile Virus Infection

2004 ◽  
Vol 78 (15) ◽  
pp. 8312-8321 ◽  
Author(s):  
Bimmi Shrestha ◽  
Michael S. Diamond
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
West Nile Virus ◽  
Immunoglobulin M ◽  
Target Cells ◽  
West Nile ◽  
Class I Mhc ◽  
Increased Risk

ABSTRACT Infection with West Nile virus (WNV) causes fatal encephalitis more frequently in immunocompromised humans than in those with a healthy immune system. Although a complete understanding of this increased risk remains unclear, experiments with mice have begun to define how different components of the adaptive and innate immune response function to limit infection. Previously, we demonstrated that components of humoral immunity, particularly immunoglobulin M (IgM) and IgG, have critical roles in preventing dissemination of WNV infection to the central nervous system. In this study, we addressed the function of CD8+ T cells in controlling WNV infection. Mice that lacked CD8+ T cells or classical class Ia major histocompatibility complex (MHC) antigens had higher central nervous system viral burdens and increased mortality rates after infection with a low-passage-number WNV isolate. In contrast, an absence of CD8+ T cells had no effect on the qualitative or quantitative antibody response and did not alter the kinetics or magnitude of viremia. In the subset of CD8+-T-cell-deficient mice that survived initial WNV challenge, infectious virus was recovered from central nervous system compartments for several weeks. Primary or memory CD8+ T cells that were generated in vivo efficiently killed target cells that displayed WNV antigens in a class I MHC-restricted manner. Collectively, our experiments suggest that, while specific antibody is responsible for terminating viremia, CD8+ T cells have an important function in clearing infection from tissues and preventing viral persistence.

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