Mice provide a useful tool for study of human TBE, since they recapitulate the pathological and pathophysiological processes seen in severe human TBE cases. However, biological and virological markers indicating the severity of TBE in mice as well as in humans remain unclear. The severity of TBE can be influenced by a variety of factors, e.g., the inoculation dose and virulence of the virus [
1], the age, sex and immune status of the host [
2], and susceptibility based on the host’s genetic background. Generally, age of the host is the most common host risk factor identified for severe forms of flavivirus encephalitis [
29]. However, genetic host risk factors play an important role in the development of severe flaviviral neurological diseases as well. Several genetic host factors associated with the severe forms of flavivirus encephalitis have been identified. These include polymorphisms in
HLA-A and
HLA-B, polymorphism located in the promoter region of the human
CD209 gene [
7] and functional Toll-like receptor 3 gene [
4], deletion in
CCR5[
5] and variability in 2´-5´-oligoadenylate synthetase gene cluster [
6]. In our study, we developed a new mouse model of hosts differing in the susceptibility to TBEV infection based on CcS/Dem RC mouse strains. We observed clearly different patterns in the susceptibility of the CcS/Dem RC strains to s.c. infection with TBEV. Out of the eight strains tested, one (STS) exhibited low susceptibility, five intermediate susceptibility (CcS-3, CcS-7, CcS-9, CcS-16 and BALB/c) and two strains (CcS-11 and CcS-15) high susceptibility (Additional file
1: Figure S1). Differences in MST between the strains CcS-11, BALB/c and STS were also observed after i.c. inoculation of TBEV, i.e., CcS-11 mice had the shortest MST, BALB/c medium MST and STS the longest MST and higher survival (Figure
1C). These differences indicate the presence of TBEV susceptibility genes. Different susceptibility to virus infection in recombinant inbred strains between BALB/c and STS mice was also observed in case of infection with murine coronavirus [
30]. After i.c. inoculation of 100 pfu of murine coronavirus, all BALB/c mice were highly susceptible and died; in contrast, STS mice were shown to be partially resistant, with a mortality rate of 30%, longer survival times and lower rates of virus production [
30]. In our study, RC strain CcS-11, which contains approximately 12.5% genes of the donor strain STS and 87.5% genes of the background strain BALB/c, was more sensitive to TBEV infection than both parental strains BALB/c and STS. The observations of progeny having a phenotype beyond the range of the phenotype of its parents are not rare in traits controlled by multiple genes [
18]. Such an observation may be due to multiple gene-gene interactions of quantitative trait loci, which in new combinations of these genes in RC or chromosomal substitution can lead to the appearance of new phenotypes that exceed their range in parental strains [
18]. Another possibility is when some progeny receives predominantly susceptible alleles from both parents. These susceptible alleles are distinct from genes
H2,
Cd209,
Tlr3,
Ccr5 and
Oas1b, which are involved in genetic control of susceptibility to flavivirus encephalitis (see above), because these genes are in CcS-11 localized on segments derived from the background BALB/c strain [Figure
1A and Mouse Genome Informatics (
http://www.informatics.jax.org/)]. We also cannot exclude the possibility of a spontaneous mutation appearing during inbreeding and causing the unique phenotype [
18]. Similarly to our study, CcS-11 mice were more susceptible to infection with
Leishmania tropica[
18] and to
Trypanosoma brucei brucei[
31] than both parental mouse strains. However, CcS-11 is more resistant to
L. major than BALB/c [
32].