The highest levels of proinflammatory cytokines/chemokines (IFN, CCL3/MIP-1, CCL2/MCP-1, IP-10) (after s.c. (-)-DHMEQ relation to the host genetic background was (-)-DHMEQ 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. Conclusions Our 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. Keywords: Tick-borne encephalitis, Flavivirus encephalitis, Neuroinflammation, Antibody production Background Flaviviruses, a group of small, enveloped, positive-sense, single-stranded RNA viruses, include several medically very important pathogens. Especially Japanese encephalitis virus, yellow fever virus, West Nile virus, dengue virus, Murray Valley encephalitis virus and tick-borne encephalitis virus (TBEV) are responsible for large outbreaks of fatal encephalitis or hemorrhagic fevers at diverse geographical regions around the world. Tick-borne encephalitis (TBE), a disease caused by TBEV, represents one of the most important and serious neuroinfections in Europe and northeastern Asia. More than 13,000 clinical cases of TBE, including numerous deaths, are reported annually. Despite the medical importance of this disease, some crucial steps in the development of encephalitis remain poorly understood. In humans, TBEV may produce a variety of clinical symptoms, from an asymptomatic disease (70-90% of cases) to a fever and acute or chronic progressive encephalitis. This is influenced by a variety of factors, e.g., the inoculation dose Rabbit Polyclonal to CDCA7 and virulence of the virus [1], the age, sex and immune status of the host [2], and also susceptibility based on the hosts genetic background. Studies of animal models and epidemiological studies in humans have shown that many apparently nonhereditary diseases, including infectious diseases, develop predominantly in genetically predisposed individuals and that this predisposition is caused by multiple genes [3]. In humans, a functional Toll-like receptor 3 gene may be a risk factor for TBEV infection [4]. A deletion within the chemokine receptor CCR5 (CCR532), which plays an important role in leukocyte transmigration across the bloodCbrain barrier, is significantly more frequent in patients with TBE than in TBE-na?ve patients with (-)-DHMEQ aseptic meningitis [5]. Moreover, the severity and outcome of TBE is associated with variability in the 2′-5′-oligoadenylate synthetase gene cluster (family members are interferon-induced 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 gene [7]. This gene encodes dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN), a C-type lectin pathogen-recognition receptor expressed on the surface of dendritic cells and some types of macrophages [7]. Taken together, polymorphism in various genes may largely influence the sensitivity of the host to the infection and determine the severity of this disease. While in humans involvement of genetic factors in the control of the susceptibility to TBEV infection is quite difficult to investigate, mice provide a useful small animal model for such a kind of study [8]. Mice are suitable animal models of infection with TBEV because they can reproduce symptoms and physiopathological markers as observed in severe cases in humans. A high susceptibility of most laboratory mouse strains to flavivirus infection has been genetically mapped to a stop codon mutation in the coding region of the 2-5-oligoadenylate synthetase gene gene. We analyzed the sensitivity to TBEV in CcS/Dem (CcS) recombinant congenic (RC) strains of mice [10] derived.