Neutrophil Apoptosis Induction by Tick-Borne Encephalitis Virus

Плехова, Н. Г.; Сомова, Л. М.; Lyapun, I. N.; Крылова, Н. В.; Леонова, Г Н

doi:10.1007/s10517-012-1655-2

Cited by 6 publications

(7 citation statements)

References 12 publications

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“…While astrocytes can also become infected, these cells appear to be primarily involved in cytokine production and do not undergo morphological changes or apoptosis (63, 64). We do show that LGTV antigen co-localized to areas of apoptotic cells, and based on previous literature, these infected cells may be primarily neurons and/or neutrophils (35, 59–62). Our study also does not address the mechanism by which neutrophils function within the CNS.…”

Section: Discussionsupporting

confidence: 85%

“…Support for this model comes from our data showing that increased neutrophils in the CNS correlate with greater viral replication and apoptosis in the brain tissue, a phenotype that is reversed following neutrophil depletion. This model is supported by another published report showing that neutrophils are cellular targets for infection with TBEV and also undergo apoptosis following infection (35). Similarly, neutrophils are readily infected ex vivo by the related virus, WNV, and may serve as an important reservoir of virus replication in vivo (57).…”

Section: Discussionsupporting

confidence: 71%

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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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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 71%

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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“…WNV replicates in neutrophils at high levels and is likely disseminated via neutrophils [37]. A similar mechanism appears possible for TBEV, since it has been shown to infect neutrophils [38], [39], although in the present study immunohistology did not detect virus in infiltrating neutrophils in the early stage of infection when there was evidence of cell recruitment into the brain parenchyma. Like in humans, viral antigen was mainly observed in intact and only rarely in dying, apoptotic neurons which further confirms that the virus is not likely to have a direct neuropathic effect and that direct activation of the apoptotic cascade is not a prominent mode of cell death in TBE [36].…”

Section: Discussionsupporting

confidence: 39%

The Three Subtypes of Tick-Borne Encephalitis Virus Induce Encephalitis in a Natural Host, the Bank Vole (Myodes glareolus)

et al. 2013

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Tick-borne encephalitis virus (TBEV) infects bank voles (Myodes glareolus) in nature, but the relevance of rodents for TBEV transmission and maintenance is unclear. We infected colonized bank voles subcutaneously to study and compare the infection kinetics, acute infection, and potential viral persistence of the three known TBEV subtypes: European (TBEV-Eur), Siberian (TBEV-Sib) and Far Eastern (TBEV-FE). All strains representing the three subtypes were infective and highly neurotropic. They induced (meningo)encephalitis in some of the animals, however most of the cases did not present with apparent clinical symptoms. TBEV-RNA was cleared significantly slower from the brain as compared to other organs studied. Supporting our earlier findings in natural rodent populations, TBEV-RNA could be detected in the brain for up to 168 days post infection, but we could not demonstrate infectivity by cell culture isolation. Throughout all time points post infection, RNA of the TBEV-FE was detected significantly more often than RNA of the other two strains in all organs studied. TBEV-FE also induced prolonged viremia, indicating distinctive kinetics in rodents in comparison to the other two subtypes. This study shows that bank voles can develop a neuroinvasive TBEV infection with persistence of viral RNA in brain, and mount an anti-TBEV IgG response. The findings also provide further evidence that bank voles can serve as sentinels for TBEV endemicity.

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“…IL-8 is also known to attract T cells and neutrophils to the site of infection. With the ability of TBEV to infect neutrophils ( Plekhova et al., 2012 ) and a tendency toward positive association of IL-8 levels with total pleocytosis and CSF neutrophil counts observed in VBT patients, IL-8 expression could significantly contribute to virus dissemination and CNS immunopathology during TBE in patients previously vaccinated against this disease. Also, an observed higher expression of IL-8 and GRO-α/CXCL1 in convalescent sera of VBT patients compared to serum levels of healthy controls, point to a lengthened disruption of BBB, preventing CSF hemostasis and disease remission.…”

Section: Discussionmentioning

confidence: 99%

Upregulated Intrathecal Expression of VEGF-A and Long Lasting Global Upregulation of Proinflammatory Immune Mediators in Vaccine Breakthrough Tick-Borne Encephalitis

Pavletič

Korva

Knap

et al. 2021

Front. Cell. Infect. Microbiol.

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Although anti-TBE vaccines are highly effective, vaccine breakthrough (VBT) cases have been reported. With increasing evidence for immune system involvement in TBE pathogenesis, we characterized the immune mediators reflecting innate and adaptive T and B cell responses in neurological and convalescent phase in VBT TBE patients. At the beginning of the neurological phase, VBT patients have significantly higher serum levels of several innate and adaptive inflammatory cytokines compared to healthy donors, reflecting a global inflammatory state. The majority of cytokines, particularly those associated with innate and Th1 responses, are highly concentrated in CSF and positively correlate with intrathecal immune cell counts, demonstrating the localization of Th1 and proinflammatory responses in CNS, the site of disease in TBE. Interestingly, compared to unvaccinated TBE patients, VBT TBE patients have significantly higher CSF levels of VEGF-A and IFN-β and higher systemic levels of neutrophil chemoattractants IL-8/CXCL8 and GROα/CXCL1 on admission. Moreover, serum levels of IL-8/CXCL8 and GROα/CXCL1 remain elevated for two months after the onset of neurological symptoms, indicating a prolonged systemic immune activation in VBT patients. These findings provide the first insights into the type of immune responses and their dynamics during TBE in VBT patients. An observed systemic upregulation of neutrophil derived inflammation in acute and convalescent phase of TBE together with highly expressed VEGF-A could contribute to BBB disruption that facilitates the entry of immune cells and supports the intrathecal localization of Th1 responses observed in VBT patients.

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Neutrophil Apoptosis Induction by Tick-Borne Encephalitis Virus

Cited by 6 publications

References 12 publications

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

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

The Three Subtypes of Tick-Borne Encephalitis Virus Induce Encephalitis in a Natural Host, the Bank Vole (Myodes glareolus)

Upregulated Intrathecal Expression of VEGF-A and Long Lasting Global Upregulation of Proinflammatory Immune Mediators in Vaccine Breakthrough Tick-Borne Encephalitis

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