Abstract
BackgroundThe clinical course of tick-borne encephalitis (TBE), a disease caused by TBE virus, ranges from asymptomatic or mild influenza-like infection to severe debilitating encephalitis or encephalomyelitis. Despite the medical importance of this disease, some crucial steps in the development of encephalitis remain poorly understood. In particular, the basis of the disease severity is largely unknown.MethodsTBE virus growth, neutralizing antibody response, key cytokine and chemokine mRNA production and changes in mRNA levels of cell surface markers of immunocompetent cells in brain were measured in mice with different susceptibilities to TBE virus infection.ResultsAn animal model of TBE based on BALB/c-c-STS/A (CcS/Dem) recombinant congenic mouse strains showing different severities of the infection in relation to the host genetic background was developed. After subcutaneous inoculation of TBE virus, BALB/c mice showed medium susceptibility to the infection, STS mice were resistant, and CcS-11 mice were highly susceptible. The resistant STS mice showed lower and delayed viremia, lower virus production in the brain and low cytokine/chemokine mRNA production, but had a strong neutralizing antibody response. The most sensitive strain (CcS-11) failed in production of neutralizing antibodies, but exhibited strong cytokine/chemokine mRNA production in the brain. After intracerebral inoculation, all mouse strains were sensitive to the infection and had similar virus production in the brain, but STS mice survived significantly longer than CcS-11 mice. These two strains also differed in the expression of key cytokines/chemokines, particularly interferon gamma-induced protein 10 (IP-10/CXCL10) and monocyte chemotactic protein-1 (MCP-1/CCL2) in the brain.ConclusionsOur data indicate that the genetic control is an important factor influencing the clinical course of TBE. High neutralizing antibody response might be crucial for preventing host fatality, but high expression of various cytokines/chemokines during TBE can mediate immunopathology and be associated with more severe course of the infection and increased fatality.
Highlights
The clinical course of tick-borne encephalitis (TBE), a disease caused by TBE virus, ranges from asymptomatic or mild influenza-like infection to severe debilitating encephalitis or encephalomyelitis
The severity and outcome of TBE is associated with variability in the 2'-5'-oligoadenylate synthetase gene cluster [6] and with the rs2287886 single nucleotide polymorphism located in the promoter region of the human CD209 gene [7]
CcS/Dem recombinant congenic (RC) mouse strains show diverse susceptibilities to infection with tick-borne encephalitis virus (TBEV) To study the susceptibility of mice to TBEV, we infected females of the strains BALB/c, STS and RC strains CcS3, CcS-7, CcS-9, CcS-11, CcS-15 and CcS-16 s.c. with
Summary
The clinical course of tick-borne encephalitis (TBE), a disease caused by TBE virus, ranges from asymptomatic or mild influenza-like infection to severe debilitating encephalitis or encephalomyelitis. The severity and outcome of TBE is associated with variability in the 2'-5'-oligoadenylate synthetase gene cluster (family members are interferoninduced antiviral proteins that play an important role in the endogenous antiviral pathway) [6] and with the rs2287886 single nucleotide polymorphism located in the promoter region of the human CD209 gene [7]. This gene encodes dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN), a C-type lectin pathogenrecognition receptor expressed on the surface of dendritic cells and some types of macrophages [7]. Polymorphism in various genes may largely influence the sensitivity of the host to the infection and determine the severity of this disease
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