scholarly journals CD8+ T Cells Require Perforin To Clear West Nile Virus from Infected Neurons

2006 ◽  
Vol 80 (1) ◽  
pp. 119-129 ◽  
Author(s):  
Bimmi Shrestha ◽  
Melanie A. Samuel ◽  
Michael S. Diamond
Keyword(s):  
New York ◽  
T Cells ◽  
West Nile Virus ◽  
Fas Ligand ◽  
Wild Type ◽  
West Nile ◽  
Necrosis Factor Alpha ◽  
Mediated Effects ◽  
The Central Nervous System ◽  
Deficient Mice

ABSTRACT Injury to neurons after West Nile virus (WNV) infection is believed to occur because of viral and host immune-mediated effects. Previously, we demonstrated that CD8+ T cells are required for the resolution of WNV infection in the central nervous system (CNS). CD8+ T cells can control infection by producing antiviral cytokines (e.g., gamma interferon or tumor necrosis factor alpha) or by triggering death of infected cells through perforin- or Fas ligand-dependent pathways. Here, we directly evaluated the role of perforin in controlling infection of a lineage I New York isolate of WNV in mice. A genetic deficiency of perforin molecules resulted in higher viral burden in the CNS and increased mortality after WNV infection. In the few perforin-deficient mice that survived initial challenge, viral persistence was observed in the CNS for several weeks. CD8+ T cells required perforin to control WNV infection as adoptive transfer of WNV-primed wild-type but not perforin-deficient CD8+ T cells greatly reduced infection in the brain and spinal cord and enhanced survival of CD8-deficient mice. Analogous results were obtained when wild-type or perforin-deficient CD8+ T cells were added to congenic primary cortical neuron cultures. Taken together, our data suggest that despite the risk of immunopathogenesis, CD8+ T cells use a perforin-dependent mechanism to clear WNV from infected neurons.

scholarly journals CD4+ T-Cell Responses Are Required for Clearance of West Nile Virus from the Central Nervous System

2006 ◽  
Vol 80 (24) ◽  
pp. 12060-12069 ◽  
Author(s):  
Elizabeth M. Sitati ◽  
Michael S. Diamond
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
West Nile Virus ◽  
T Cell ◽  
Wild Type ◽  
Cell Responses ◽  
The Central Nervous System ◽  
Deficient Mice

ABSTRACT Although studies have established that innate and adaptive immune responses are important in controlling West Nile virus (WNV) infection, the function of CD4+ T lymphocytes in modulating viral pathogenesis is less well characterized. Using a mouse model, we examined the role of CD4+ T cells in coordinating protection against WNV infection. A genetic or acquired deficiency of CD4+ T cells resulted in a protracted WNV infection in the central nervous system (CNS) that culminated in uniform lethality by 50 days after infection. Mice surviving past day 10 had high-level persistent WNV infection in the CNS compared to wild-type mice, even 45 days following infection. The absence of CD4+ T-cell help did not affect the kinetics of WNV infection in the spleen and serum, suggesting a role for CD4-independent clearance mechanisms in peripheral tissues. WNV-specific immunoglobulin M (IgM) levels were similar to those of wild-type mice in CD4-deficient mice early during infection but dropped ∼20-fold at day 15 postinfection, whereas IgG levels in CD4-deficient mice were ∼100- to 1,000-fold lower than in wild-type mice throughout the course of infection. WNV-specific CD8+ T-cell activation and trafficking to the CNS were unaffected by the absence of CD4+ T cells at day 9 postinfection but were markedly compromised at day 15. Our experiments suggest that the dominant protective role of CD4+ T cells during primary WNV infection is to provide help for antibody responses and sustain WNV-specific CD8+ T-cell responses in the CNS that enable viral clearance.

scholarly journals CD8+ T cell-mediated immune responses in West Nile virus (Sarafend strain) encephalitis are independent of gamma interferon

2006 ◽  
Vol 87 (12) ◽  
pp. 3599-3609 ◽  
Author(s):  
Yang Wang ◽  
Mario Lobigs ◽  
Eva Lee ◽  
Aulikki Koskinen ◽  
Arno Müllbacher
Keyword(s):  
T Cells ◽  
West Nile Virus ◽  
Surface Expression ◽  
Gamma Interferon ◽  
Cell Surface Expression ◽  
Wild Type ◽  
Survival Times ◽  
West Nile ◽  
Antiviral Function ◽  
Pleiotropic Functions

The flavivirus West Nile virus (WNV) can cause fatal encephalitis in humans and mice. It has recently been demonstrated, in an experimental model using WNV strain Sarafend and C57BL/6 mice, that both virus- and immune-mediated pathology is involved in WNV encephalitis, with CD8+ T cells being the dominant subpopulation of lymphocyte infiltrates in the brain. Here, the role of activated WNV-immune CD8+ T cells in mouse WNV encephalitis was investigated further. Passive transfer of WNV-immune CD8+ T cells reduced mortality significantly and prolonged survival times of mice infected with WNV. Early infiltration of WNV-immune CD8+ T cells into infected brains is shown, suggesting a beneficial contribution of these lymphocytes to recovery from encephalitis. This antiviral function was not markedly mediated by gamma interferon (IFN-γ), as a deficiency in IFN-γ did not affect mortality to two strains of WNV (Sarafend and Kunjin) or brain virus titres significantly. The cytolytic potential, as well as precursor frequency, of WNV-immune CD8+ T cells were not altered by the absence of IFN-γ. This was reflected in transfer experiments of WNV-immune CD8+ T cells from IFN-γ −/− mice into WNV-infected wild-type mice, which showed that IFN-γ-deficient T cells were as effective as those from WNV-immune wild-type mice in ameliorating disease outcome. It is speculated here that one of the pleiotropic functions of IFN-γ is mimicked by WNV-Sarafend-mediated upregulation of cell-surface expression of major histocompatibility complex antigens, which may explain the lack of phenotype of IFN-γ −/− mice in response to WNV.

scholarly journals A Critical Role for Induced IgM in the Protection against West Nile Virus Infection

2003 ◽  
Vol 198 (12) ◽  
pp. 1853-1862 ◽  
Author(s):  
Michael S. Diamond ◽  
Elizabeth M. Sitati ◽  
Lindzy D. Friend ◽  
Stephen Higgs ◽  
Bimmi Shrestha ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
West Nile Virus ◽  
Critical Role ◽  
West Nile Virus Infection ◽  
The Elderly ◽  
Wild Type ◽  
West Nile ◽  
Lethal Infection ◽  
The Central Nervous System

In humans, the elderly and immunocompromised are at greatest risk for disseminated West Nile virus (WNV) infection, yet the immunologic basis for this remains unclear. We demonstrated previously that B cells and IgG contributed to the defense against disseminated WNV infection (Diamond, M.S., B. Shrestha, A. Marri, D. Mahan, and M. Engle. 2003. J. Virol. 77:2578–2586). In this paper, we addressed the function of IgM in controlling WNV infection. C57BL/6J mice (sIgM−/−) that were deficient in the production of secreted IgM but capable of expressing surface IgM and secreting other immunoglobulin isotypes were vulnerable to lethal infection, even after inoculation with low doses of WNV. Within 96 h, markedly higher levels of infectious virus were detected in the serum of sIgM−/− mice compared with wild-type mice. The enhanced viremia correlated with higher WNV burdens in the central nervous system, and was also associated with a blunted anti-WNV IgG response. Passive transfer of polyclonal anti-WNV IgM or IgG protected sIgM−/− mice against mortality, although administration of comparable amounts of a nonneutralizing monoclonal anti-WNV IgM provided no protection. In a prospective analysis, a low titer of anti-WNV IgM antibodies at day 4 uniformly predicted mortality in wild-type mice. Thus, the induction of a specific, neutralizing IgM response early in the course of WNV infection limits viremia and dissemination into the central nervous system, and protects against lethal infection.

scholarly journals CD40-CD40 Ligand Interactions Promote Trafficking of CD8+ T Cells into the Brain and Protection against West Nile Virus Encephalitis

2007 ◽  
Vol 81 (18) ◽  
pp. 9801-9811 ◽  
Author(s):  
Elizabeth Sitati ◽  
Erin E. McCandless ◽  
Robyn S. Klein ◽  
Michael S. Diamond
Keyword(s):  
T Cells ◽  
West Nile Virus ◽  
T Cell ◽  
Cd40 Ligand ◽  
Affinity Maturation ◽  
Immunoglobulin M ◽  
Lymphoid Tissues ◽  
Cell Trafficking ◽  
Wild Type ◽  
West Nile

ABSTRACT Recent studies have established a protective role for T cells during primary West Nile virus (WNV) infection. Binding of CD40 by CD40 ligand (CD40L) on activated CD4+ T cells provides an important costimulatory signal for immunoglobulin class switching, antibody affinity maturation, and priming of CD8+ T-cell responses. We examined here the function of CD40-dependent interactions in limiting primary WNV infection. Compared to congenic wild-type mice, CD40−/− mice uniformly succumbed to WNV infection. Although CD40−/− mice produced low levels of WNV-specific immunoglobulin M (IgM) and IgG, viral clearance from the spleen and serum was not altered, and CD8+ T-cell priming in peripheral lymphoid tissues was normal. Unexpectedly, CD8+ T-cell trafficking to the central nervous system (CNS) was markedly impaired in CD40−/− mice, and this correlated with elevated WNV titers in the CNS and death. In the brains of CD40−/− mice, T cells were retained in the perivascular space and did not migrate into the parenchyma, the predominant site of WNV infection. In contrast, in wild-type mice, T cells trafficked to the site of infection in neurons. Beside its role in maturation of antibody responses, our experiments suggest a novel function of CD40-CD40L interactions: to facilitate T-cell migration across the blood-brain barrier to control WNV infection.

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 Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

2017 ◽  
Vol 91 (10) ◽  
Author(s):  
Susana V. Bardina ◽  
Julia A. Brown ◽  
Daniela Michlmayr ◽  
Kevin W. Hoffman ◽  
Janet Sum ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Node ◽  
West Nile Virus ◽  
West Nile ◽  
Viral Loads ◽  
West Nile Virus Encephalitis ◽  
Draining Lymph Node ◽  
The Brain ◽  
Deficient Mice

ABSTRACT West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the central nervous system (CNS). Despite an excess of virus-specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates than wild-type animals. Mechanistically, the elevated trafficking of infected myeloid cells into the brain in Ccr7-deficient mice resulted in increased levels of WNV in the CNS, thereby effectively contributing to neuroinflammation and lowering viral clearance. Combined, our experiments suggest that during WNV infection, Ccr7 is a gatekeeper for nonspecific viral transference to the brain. IMPORTANCE In this study, we show that Ccr7 is required for the sufficient migration of dendritic cells and T cells into the draining lymph node immediately following infection and for the restriction of leukocyte migration into the brain. Further, the severe loss of dendritic cells in the draining lymph node had no impact on viral replication in this organ, suggesting that WNV may migrate from the skin into the lymph node through another mechanism. Most importantly, we found that the loss of Ccr7 results in a significant leukocytosis, leading to hypercellularity within the CNS, where monocytes/macrophages contribute to CNS viremia, neuroinflammation, and increased mortality. Together, our data point to Ccr7 as a critical host defense restriction factor limiting neuroinflammation during acute viral infection.

Theiler’s Virus Infection of Perforin-Deficient Mice

1998 ◽  
Vol 72 (5) ◽  
pp. 4515-4519 ◽  
Author(s):  
Claudia Pena Rossi ◽  
Andrés McAllister ◽  
Myriam Tanguy ◽  
David Kägi ◽  
Michel Brahic
Keyword(s):  
T Cells ◽  
Fas Ligand ◽  
Cytotoxic T Cells ◽  
Viral Rna ◽  
Theiler's Virus ◽  
Nervous Systems ◽  
Central Nervous Systems ◽  
The Central Nervous System ◽  
Infected Cells ◽  
Deficient Mice

ABSTRACT Theiler’s virus, a murine picornavirus, infects the central nervous systems of C57BL/6 mice and is cleared after approximately 10 days by a process which requires CD8+ cytotoxic T cells. We used perforin-deficient C57BL/6 mice to test the role of this protein in viral clearance. Perforin-deficient mice died from viral encephalomyelitis between days 12 and 18 postinoculation. They had high levels of viral RNA in their central nervous systems until the time of death. In contrast, viral RNA had disappeared by day 11 postinoculation in wild-type C57BL/6 mice. Cytotoxic T cells can kill infected cells by two main mechanisms: the secretion of the pore-forming protein perforin or the interaction of the Fas ligand with the apoptosis-inducing Fas molecule on the target cell. Our results demonstrate that clearance of Theiler’s virus from the central nervous system in C57BL/6 mice is perforin dependent.

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.

CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Jean-Christophe Deschemin ◽  
Mireille Viguier ◽  
Matthias Mack ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Wild Type ◽  
Experimental Cerebral Malaria ◽  
Pathologic Features ◽  
Th1 Cytokine ◽  
The Brain ◽  
Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

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