Identification of genetic determinants of a tick-borne flavivirus associated with host-specific adaptation and pathogenicity

Mitzel, Dana N.; Best, Sonja M.; Masnick, Max; Porcella, Stephen F.; Wolfinbarger, James B.; Bloom, Marshall E.

doi:10.1016/j.virol.2008.08.030

Cited by 30 publications

(29 citation statements)

References 39 publications

(57 reference statements)

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“…These results confirm the results of the authors' previous studies (20,26) as well as other studies that showed replication of highly virulent strains of TBEV starting from 12 h pi by using different cell cultures (31,35,45,52).…”

Section: Dynamics Of Infection Of Donors' Blood Cells By Tbev Strainssupporting

confidence: 92%

“…The key to understanding how these viruses are able to evade the host's immune response and make their way from the site of infection to the central nervous system and the brain is studying viral-host cell interactions. Mutational analyses of the flaviviral envelope E protein, which is critical for cellular infectivity, have demonstrated a striking ability of flaviviruses to adapt to different cells and receptors (2,11,31). In this study, the interaction between TBEV and human blood leukocytes was examined, since it is known that these cells could differently contribute to the protective and pathogenic manifestations of flavivirus infections (4,28,32,37).…”

Section: Introductionmentioning

confidence: 99%

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Molecular Mechanisms of Interaction Between Human Immune Cells and Far Eastern Tick-Borne Encephalitis Virus Strains

2015

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Although studies have established that immune mechanisms are important in controlling tick-borne encephalitis virus (TBEV) infection, the interactions of different TBEV strains with cells of innate and adaptive immunity are not well understood. In this study, the ability of two Far Eastern subtype TBEV strains (Dal'negorsk and Primorye-183) with various degrees of pathogenicity for humans to modulate the expression of membrane molecules differently on human immune cells were investigated using a whole-blood flow cytometry-based assay. The whole-blood samples (from 10 healthy donors) were infected with TBEV strains and analyzed for the virus binding to the blood cells, as well as expression of adhesion (CD11b and ICAM-1) and activation (CD69, CD25, CD95) molecules on the surfaces of monocytes, granulocytes, natural killer (NK) cells, and T-lymphocytes (CD4+, CD8+) at selected times (3, 6, and 24 h post-infection). It was found that the highly pathogenic Dal'negorsk strain penetrated rapidly and was actively replicated in the blood cells, inducing downregulation of CD11b, ICAM-1, and CD69 on monocytes and a significant decrease of NK cells expressing CD69, CD25, CD95, and CD8 T-lymphocytes expressing CD69 compared with the mock-infected cells. The nonpathogenic Primorye-183 strain penetrated slowly and was replicated in the blood cells, but caused a significant increase in the adhesion and activation of molecule expression to trigger innate defense mechanisms and enable the rapid elimination of the virus from the organism. Thus, TBEV-induced activation or suppression of adhesion and activation receptors expression form an essential part of fundamental virus properties, that is, virulence and pathogenicity.

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Section: Dynamics Of Infection Of Donors' Blood Cells By Tbev Strainssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of Interaction Between Human Immune Cells and Far Eastern Tick-Borne Encephalitis Virus Strains

2015

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“…Langat virus has a low virulence for humans, although it shares more than 74% nucleotide identity with TBEV. Experimental models on LGTV in mice have been reported (19,20).…”

Section: Discussionmentioning

confidence: 99%

“…The pathogenicity of LGTV is in part determined by genetic determinants of the virus that are involved in mechanisms of host adaptation (19). Genetic determinants of the host, for example, genes of the tlr family, may also control virus infection in neurons, possibly by regulating neuroinflammatory responses (20).…”

Section: Introductionmentioning

confidence: 99%

A Tick-Borne Encephalitis Model in Infant Rats Infected With Langat Virus

Maffioli

Grandgirard

Engler

et al. 2014

J Neuropathol Exp Neurol

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Tick-borne encephalitis virus (TBEV) is the causative agent of human TBE, a severe infection that can cause long-lasting neurologic sequelae. Langat virus (LGTV), which is closely related to TBEV, has a low virulence for human hosts and has been used as a live vaccine against TBEV. Tick-borne encephalitis by natural infection of LGTV in humans has not been described, but one of 18,500 LGTV vaccinees developed encephalitis. The pathogenetic mechanisms of TBEV are poorly understood and, currently, no effective therapy is available. We developed an infant rat model of TBE using LGTV as infective agent. Infant Wistar rats were inoculated intracisternally with 10 focus-forming units of LGTV and assessed for clinical disease and neuropathologic findings at Days 2, 4, 7, and 9 after infection. Infection with LGTV led to gait disturbance, hypokinesia, and reduced weight gain or weight loss. Cerebrospinal fluid concentrations of RANTES, interferon-γ, interferon-β, interleukin-6, and monocyte chemotactic protein-1 were increased in infected animals. The brains of animals with LGTV encephalitis exhibited characteristic perivascular inflammatory cuffs and glial nodules; immunohistochemistry documented the presence of LGTV in the thalamus, hippocampus, midbrain, frontal pole, and cerebellum. Thus, LGTV meningoencephalitis in infant rats mimics important clinical and histopathologic features of human TBE. This new model provides a tool to investigate disease mechanisms and to evaluate new therapeutic strategies against encephalitogenic flaviviruses.

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“…A control replicon construct with NS5 catalytic aspartate residue deletions was transfected in parallel as a negative control. At 3,6,12,24,48,72,96, and 120 h posttransfection, the medium was removed and cells were washed with phosphate-buffered saline and lysed with 100 l of 1ϫ Renilla lysis buffer from the Renilla Luciferase Assay System (Promega, Madison, WI). The lysates were stored at Ϫ80°C.…”

mentioning

confidence: 99%

Protein Kinase G Phosphorylates Mosquito-Borne Flavivirus NS5

Bhattacharya

Mayuri

Best

et al. 2009

J Virol

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Serine/threonine phosphorylation of the nonstructural protein 5 (NS5) is a conserved feature of flaviviruses, but the kinase(s) responsible and function(s) remain unknown. Mass spectrometry was used to compare the phosphorylation sites of the NS5 proteins of yellow fever virus (YFV) and dengue virus (DENV), two flaviviruses transmitted by mosquitoes. Seven DENV phosphopeptides were identified, but only one conserved phosphoacceptor site (threonine 449 in DENV) was identified in both viruses. This site is predicted to be a protein kinase G (PKG) recognition site and is a strictly conserved serine/threonine phosphoacceptor site in mosquito-borne flaviviruses. In contrast, in tick-borne flaviviruses, this residue is typically a histidine. A DENV replicon engineered to have the tick-specific histidine residue at this position is replication defective. We show that DENV NS5 purified from Escherichia coli is a substrate for PKG in vitro and facilitates the autophosphorylation of PKG as seen with cellular substrates. Phosphorylation in vitro by PKG also occurs at threonine 449. Activators and inhibitors of PKG modulate DENV replication in cell culture but not replication of the tick-borne langat virus. Collectively, these data argue that PKG mediates a conserved serine/threonine phosphorylation event specifically for flaviviruses spread by mosquitoes.The flavivirus genus contains many medically important species, including dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), and tick-borne encephalitis virus (TBEV). More than 2 billion people are at risk of infection by DENV alone, leading to an estimated 50 million cases annually, which may increase further as the range of the mosquito vector expands with urbanization (24). While disease from mosquito-borne flaviviruses is particularly common, there are other flaviviral human pathogens that exist with transmission cycles that do not involve mosquitoes. Tick-borne transmission is the other well-described route, but non-arthropodborne routes also exist (for example, bats). It is likely that each transmission route has genetic adaptations that facilitate that route, but such changes are not yet understood (7).Serine/threonine phosphorylation is a conserved feature across all three genera of the family Flaviviridae, including the genus flavivirus (the others genera being pestivirus and hepacivirus). Among the features of Flaviviridae, the most-studied examples are the multiple phosphorylations of nonstructural protein 5A (NS5A) of hepatitis C virus, which exists in both basal (termed p56) and hyperphosphorylated (termed p58) states mediated by multiple kinases that both are necessary for and limit replication (14,18,23). Phosphorylation of NS5B, the RNA-dependent RNA polymerase (RdRP), has also been shown to affect replicon activity (10). In the genus flavivirus, several mosquito-borne viruses (DENV, WNV, and YFV) and at least one tick-borne encephalitis virus are known to have phosphorylated forms of nonstructural protein NS5 (2,9,11,13,19). In the genus...

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Identification of genetic determinants of a tick-borne flavivirus associated with host-specific adaptation and pathogenicity

Cited by 30 publications

References 39 publications

Molecular Mechanisms of Interaction Between Human Immune Cells and Far Eastern Tick-Borne Encephalitis Virus Strains

Molecular Mechanisms of Interaction Between Human Immune Cells and Far Eastern Tick-Borne Encephalitis Virus Strains

A Tick-Borne Encephalitis Model in Infant Rats Infected With Langat Virus

Protein Kinase G Phosphorylates Mosquito-Borne Flavivirus NS5

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