The role of chemokines in the pathogenesis of neurotropic flaviviruses

Bardina, Susana V.; Lim, Jean K.

doi:10.1007/s12026-012-8333-3

Cited by 44 publications

(56 citation statements)

References 102 publications

(129 reference statements)

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“…Fatal infections were associated with weak systemic immune responses and a subsequent failure to clear virus from the periphery, and onset of clinical disease correlated with high viral RNA loads and infiltration of activated T cells in the CNS. Interestingly, depletion of T cells did not improve survival, suggesting that in contrast to other encephalitic viruses [26], [27], that RVFV neurologic disease is not immune-mediated. These results provide important insights into the pathogenesis of severe RVFV infection that could inform the development of therapies targeted towards treating or preventing RVFV mediated encephalitis.…”

Section: Introductionmentioning

confidence: 80%

“…Although there were no overt alterations in BBB permeability, it was possible that T cell infiltration and associated upregulation of inflammatory cytokines alone might have enhanced neurovirulence, as seen in other models of viral encephalitis [26], [27], [48]. Induction of these cytokines and chemokines amplify the antiviral response and recruit leukocytes, but if left unchecked, can have destructive effects.…”

Section: Discussionmentioning

confidence: 99%

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Rift Valley Fever Virus Encephalitis Is Associated with an Ineffective Systemic Immune Response and Activated T Cell Infiltration into the CNS in an Immunocompetent Mouse Model

et al. 2014

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BackgroundRift Valley fever virus (RVFV) causes outbreaks of severe disease in livestock and humans throughout Africa and the Arabian Peninsula. In people, RVFV generally causes a self-limiting febrile illness but in a subset of individuals, it progresses to more serious disease. One manifestation is a delayed-onset encephalitis that can be fatal or leave the afflicted with long-term neurologic sequelae. In order to design targeted interventions, the basic pathogenesis of RVFV encephalitis must be better understood.Methodology/Principal FindingsTo characterize the host immune responses and viral kinetics associated with fatal and nonfatal infections, mice were infected with an attenuated RVFV lacking NSs (ΔNSs) that causes lethal disease only when administered intranasally (IN). Following IN infection, C57BL/6 mice developed severe neurologic disease and succumbed 7–9 days post-infection. In contrast, inoculation of ΔNSs virus subcutaneously in the footpad (FP) resulted in a subclinical infection characterized by a robust immune response with rapid antibody production and strong T cell responses. IN-inoculated mice had delayed antibody responses and failed to clear virus from the periphery. Severe neurological signs and obtundation characterized end stage-disease in IN-inoculated mice, and within the CNS, the development of peak virus RNA loads coincided with strong proinflammatory responses and infiltration of activated T cells. Interestingly, depletion of T cells did not significantly alter survival, suggesting that neurologic disease is not a by-product of an aberrant immune response.Conclusions/SignificanceComparison of fatal (IN-inoculated) and nonfatal (FP-inoculated) ΔNSs RVFV infections in the mouse model highlighted the role of the host immune response in controlling viral replication and therefore determining clinical outcome. There was no evidence to suggest that neurologic disease is immune-mediated in RVFV infection. These results provide important insights for the future design of vaccines and therapeutic options.

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Section: Introductionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Rift Valley Fever Virus Encephalitis Is Associated with an Ineffective Systemic Immune Response and Activated T Cell Infiltration into the CNS in an Immunocompetent Mouse Model

et al. 2014

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“…Unfortunately, our model was limited by the fact that BeH 355964 was unable to cause disease in adult immunocompetent mice when injected peripherally. By injecting virus i.c., we skip initial phases of infection at the skin and lymphoid tissues, which are believed to precede flavivirus invasion of the CNS [45]. Therefore, we consider our animal model to better represent SLEV-induced severe disease, where SLEV has already invaded the CNS, and causes meningoencephalitis.…”

Section: Discussionmentioning

confidence: 99%

Development of a model of Saint Louis encephalitis infection and disease in mice

Marques

Sarto

Rocha

et al. 2017

J Neuroinflammation

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BackgroundFlaviviruses are a genre of closely related viral pathogens which emerged in the last decades in Brazil and in the world. Saint (St.) Louis encephalitis virus (SLEV) is a neglected flavivirus that can cause a severe neurological disease that may lead to death or sequelae. St. Louis encephalitis pathogenesis is poorly understood, which hinders the development of specific treatment or vaccine.MethodsTo address this problem, we developed a model of SLEV infection in mice to study mechanisms involved in the pathogenesis of severe disease. The model consists in the intracranial inoculation of the SLEV strain BeH 355964, a strain isolated from a symptomatic human patient in Brazil, in adult immunocompetent mice.ResultsInoculated mice presented SLEV replication in the brain, accompanied by tissue damage, disease signs, and mortality approximately 7 days post infection. Infection was characterized by the production of proinflammatory cytokines and interferons and by leukocyte recruitment to the brain, composed mainly by neutrophils and lymphocytes. In vitro experiments indicated that SLEV is able to replicate in both neurons and glia and caused neuronal death and cytokine production, respectively.ConclusionsAltogether, intracranial SLEV infection leads to meningoencephalitis in mice, recapitulating several aspects of St. Louis encephalitis in humans. Our study indicates that the central nervous system (CNS) inflammation is a major component of SLEV-induced disease. This model may be useful to identify mechanisms of disease pathogenesis or resistance to SLEV infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0837-2) contains supplementary material, which is available to authorized users.

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“…A hallmark of viral encephalitis is the accumulation of leukocytes in the infected CNS, which is essential for viral clearance but can also lead to neuroimmunopathology (8) (9). Leukocyte migration into infected tissues is guided, in part, by chemokines produced during inflammation, with their receptors found on circulating leukocytes.…”

Section: Introductionmentioning

confidence: 99%

Dual Function of Ccr5 during Langat Virus Encephalitis: Reduction in Neutrophil-Mediated Central Nervous System Inflammation and Increase in T Cell–Mediated Viral Clearance

Michlmayr

Bardina

Rodriguez

et al. 2016

The Journal of Immunology

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Tick-borne encephalitis virus (TBEV) is a vector-transmitted flavivirus that causes potentially fatal neurological infection. There are thousands of cases reported annually, and despite the availability of an effective vaccine, the incidence of TBEV is increasing worldwide. Importantly, up to thirty percent of affected individuals will develop long-term neurologic sequelae. We investigated the role of chemokine receptor Ccr5 in a mouse model of TBEV infection using the naturally attenuated tick-borne flavivirus, Langat virus (LGTV). Ccr5-deficient mice presented with an increase in viral replication within the CNS and decreased survival during LGTV encephalitis when compared to wild type (WT) controls. This enhanced susceptibility was due to the temporal lag in lymphocyte migration into the CNS. Adoptive transfer of WT T cells, but not Ccr5-deficient T cells, was able to significantly improve survival outcome in LGTV-infected Ccr5-deficient mice. Concomitantly, a significant increase in neutrophil migration into the CNS in LGTV-infected Ccr5−/− mice was documented at the late stage of infection. Antibody-mediated depletion of neutrophils in Ccr5−/− mice resulted in a significant improvement in mortality, a decrease in viral load, and a decrease in overall tissue damage in the CNS when compared to isotype control-treated mice. Ccr5 is crucial in not only directing T cells towards the LGTV-infected brain, but also in suppressing neutrophil-mediated inflammation within the CNS.

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The role of chemokines in the pathogenesis of neurotropic flaviviruses

Cited by 44 publications

References 102 publications

Rift Valley Fever Virus Encephalitis Is Associated with an Ineffective Systemic Immune Response and Activated T Cell Infiltration into the CNS in an Immunocompetent Mouse Model

Rift Valley Fever Virus Encephalitis Is Associated with an Ineffective Systemic Immune Response and Activated T Cell Infiltration into the CNS in an Immunocompetent Mouse Model

Development of a model of Saint Louis encephalitis infection and disease in mice

Dual Function of Ccr5 during Langat Virus Encephalitis: Reduction in Neutrophil-Mediated Central Nervous System Inflammation and Increase in T Cell–Mediated Viral Clearance

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