Genetic polymorphisms in innate immunity genes influence predisposition to tick-borne encephalitis.

Tick-borne encephalitis (TBE) is a neuroviral disease that ranges in severity from a mild febrile illness to a severe and life-threatening meningoencephalitis or encephalomyelitis. There is increasing evidence that susceptibility to tick-borne encephalitis virus (TBEV)-induced disease and its severity are largely influenced by host genetic factors, in addition to other virus- and host-related factors. In this study, we investigated the contribution of selected single nucleotide polymorphisms (SNPs) in innate immunity genes to predisposition to TBE in humans. More specifically, we investigated a possible association between SNPs rs304478 and rs303212 in the gene Interferon Induced Protein With Tetratricopeptide Repeats 1 (IFIT1), rs7070001 and rs4934470 in the gene Interferon Induced Protein With Tetratricopeptide Repeats 2 (IFIT2), and RIG-I (Retinoic acid-inducible gene I) encoding gene DDX58 rs311795343, rs10813831, rs17217280 and rs3739674 SNPs with predisposition to TBE in population of the Czech Republic, where TBEV is highly endemic. Genotypic and allelic frequencies for these SNPs were analyzed in 247 nonimmunized TBE patients and compared with 204 control subjects. The analysis showed an association of IFIT1 rs304478 SNP and DDX58 rs3739674 and rs17217280 SNPs with predisposition to TBE in the Czech population indicating novel risk factors for clinical TBE but not for disease severity. These results also highlight the role of innate immunity genes in TBE pathogenesis.

Serum matrix metalloproteinase-9 (MMP-9) as a biomarker in paediatric and adult tick-borne encephalitis patients.

Matrix metalloproteinases (MMPs) play an important role in central nervous system infections. We analysed the levels of 8 different MMPs in the cerebrospinal fluid (CSF) of 89 adult patients infected with tick-borne encephalitis (TBE) virus and compared them with the levels in a control group. MMP-9 was the only MMP that showed significantly increased CSF levels in TBE patients. Serum MMP-9 levels were subsequently measured in 101 adult TBE patients at various time points during the neurological phase of TBE and at follow-up. In addition, serum MMP-9 was analysed in 37 paediatric TBE patients. Compared with control levels, both paediatric and adult TBE patients had significantly elevated serum MMP-9 levels. In most adult patients, serum MMP-9 levels peaked at hospital admission, with higher serum MMP-9 levels observed in patients with encephalitis than in patients with meningitis. Elevated serum MMP-9 levels were observed throughout hospitalisation but decreased to normal levels at follow-up. Serum MMP-9 levels correlated with clinical course, especially in patients heterozygous for the single-nucleotide polymorphism rs17576 (A/G; Gln279Arg) in the MMP9 gene. The results highlight the importance of MMP-9 in the pathogenesis of TBE and suggest that serum MMP-9 may serve as a promising bioindicator of TBE in both paediatric and adult TBE patients.

A matrix metalloproteinase 9 (MMP9) gene single nucleotide polymorphism is associated with predisposition to tick-borne encephalitis virus-induced severe central nervous system disease.

The progression of infectious diseases depends on causative agents, the environment and the host's genetic susceptibility. To date, human genetic susceptibility to tick-borne encephalitis (TBE) virus-induced disease has not been sufficiently studied. We have combined whole-exome sequencing with a candidate gene approach to identify genes that are involved in the development of predisposition to TBE in a Russian population. Initially, six exomes from TBE patients with severe central nervous system (CNS) disease and seven exomes from control individuals were sequenced. Despite the small sample size, two nonsynonymous single nucleotide polymorphisms (SNPs) were significantly associated with TBE virus-induced severe CNS disease. One of these SNPs is rs6558394 (G/A, Pro422Leu) in the scribbled planar cell polarity protein (SCRIB) gene and the other SNP is rs17576 (A/G, Gln279Arg) in the matrix metalloproteinase 9 (MMP9) gene. Subsequently, these SNPs were genotyped in DNA samples of 150 non-immunized TBE patients with different clinical forms of the disease from two cities and 228 control randomly selected samples from the same populations. There were no statistically significant differences in genotype and allele frequencies between the case and control groups for rs6558394. However, the frequency of the rs17576 G allele was significantly higher in TBE patients with severe CNS diseases such as meningo-encephalitis (43.5%) when compared with TBE patients with milder meningitis (26.3%; P = 0.01), as well as with the population control group (32.5%; P = 0.042). The results suggest that the MMP9 gene may affect genetic predisposition to TBE in a Russian population.

Single nucleotide polymorphism rs1800872 in the promoter region of the IL10 gene is associated with predisposition to chronic hepatitis C in Russian population.

Previously, we studied an association of two IL28B gene single nucleotide polymorphisms (SNPs) and three IL10 gene SNPs with predisposition to tick-borne encephalitis in a Russian population. In this study, a possible involvement of these SNPs in the development of predisposition to chronic hepatitis C (caused by structurally similar, related virus from the Flaviviridae family) was investigated in the same population. Only the IL10 promoter rs1800872 SNP was associated with predisposition to chronic hepatitis C. This SNP seems to be a common genetic marker of predisposition to two diseases caused by hepatitis C and tick-borne encephalitis viruses in Russian population.

Association of IL28B and IL10 gene polymorphism with predisposition to tick-borne encephalitis in a Russian population.

Genetic predisposition to tick-borne encephalitis (TBE) is rather poorly studied in human populations. Human genes encoding crucial components of antiviral immune response are most likely involved in protective mechanisms against TBE virus. Previously, several single nucleotide polymorphisms (SNPs) located in interleukin 28B (IL28B) and interleukin 10 (IL10) genes were associated with predisposition to chronic hepatitis C (caused by a structurally similar virus from the same Flaviviridae family) in a number of human populations. The aim of the present study was to estimate a possible association of the IL28B gene rs8103142 and rs12980275 SNPs and IL10 gene rs1800872, rs3021094, and rs3024498 SNPs with predisposition to TBE in a Russian population. Genotypic and allelic frequencies for these SNPs were analyzed in 132 non-immunized TBE patients (34 with fever, 60 with meningitis, and 38 with severe central nervous system disease) and compared with the population control (221 Novosibirsk citizens). The results obtained suggest that both studied IL28B gene SNPs, as well as the IL10 gene rs1800872 SNP are associated with predisposition to TBE in Russian population.

Association between polymorphisms in OAS2 and CD209 genes and predisposition to chronic hepatitis C in Russian population.

Chronic hepatitis C is a severe liver disease caused by positive-strand RNA virus. Previously, we reported an association between seven single nucleotide polymorphisms (SNPs) in four innate immunity genes (OAS2, OAS3, CD209, and TLR3) and human predisposition to tick-borne encephalitis, caused by a virus from the same Flaviviridae family, in a Russian population. Currently, genotype and allele frequencies for these SNPs were analyzed in 75 chronic hepatitis C patients and compared with the population control (269 Novosibirsk citizens). Data obtained suggest that the OAS2 rs1293762 and CD209 rs2287886 SNPs are associated with predisposition to chronic hepatitis C in Russian population.

Association of single nucleotide polymorphism rs3775291 in the coding region of the TLR3 gene with predisposition to tick-borne encephalitis in a Russian population.

Tick-borne encephalitis (TBE) is a central nervous system (CNS) disease caused by the neurotropic, positive-sense RNA virus, tick-borne encephalitis virus (TBEV). A possible association between predisposition to TBE in a Russian population and two polymorphisms, a 32bp deletion in the coding region of the chemokine receptor CCR5 gene and the rs3775291 single nucleotide polymorphism (SNP) (G/A, Leu412Phe) in exon 4 of the toll-like receptor TLR3 gene, was investigated. The genotypic and allelic frequencies of these polymorphisms were analyzed in 137 non-immunized TBE patients with different clinical manifestations, including fever (35), meningitis (62), and severe CNS disease (40), as well as in a control population (269 randomly selected Novosibirsk citizens). The frequencies of the TLR3 G allele and G/G homozygotes were significantly higher among the patients with TBE compared with the control group (P=0.029 and 0.037, respectively), especially among patients with severe disease (P=0.018 and 0.017, respectively). These results indicate that the G allele (within the G/G homozygous genotype) of the TLR3 rs3775291 SNP is associated with predisposition to TBE in the Russian population.

Single nucleotide polymorphism in the promoter region of the CD209 gene is associated with human predisposition to severe forms of tick-borne encephalitis.

Tick-borne encephalitis virus (TBEV) is a neurotropic, positive-sense RNA virus of the genus Flavivirus (family Flaviviridae) which can cause a variety of clinical manifestations in humans. Previously the severity and outcome of dengue fever and hepatitis C (diseases caused by viruses from the family Flaviviridae) were associated with the rs4804803 single nucleotide polymorphism (SNP) located in the promoter region of the human CD209 gene. 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. In the current study, a possible association between two SNPs in the promoter region of the CD209 gene (rs4804803 and rs2287886) and predisposition to severe forms of TBEV-induced disease was investigated. The genotypic, allelic and haplotypic frequencies of these SNPs were analyzed in 136 non-immunized Russian patients with different clinical manifestations of tick-borne encephalitis (TBE) and in a control group. An increase in the frequency of the rs2287886 SNP AA homozygotes and the A allele was detected among patients with severe central nervous system disease compared with the group of patients with meningitis (P=0.003 and 0.019), or a combined group of patients with mild forms (fever and meningitis) (P=0.003 and 0.026), or the control group (P=0.007 and 0.035). Thus, our results suggest that the CD209 gene promoter region rs2287886 SNP is associated with predisposition to severe forms of TBE in the Russian population.

Variability in the 2'-5'-oligoadenylate synthetase gene cluster is associated with human predisposition to tick-borne encephalitis virus-induced disease.

The 2'-5'-oligoadenylate synthetase (2'-5'-OAS) family members are interferon-induced antiviral proteins. Twenty-three single nucleotide polymorphisms located within the OAS1, OAS2, OAS3, and OASL genes were analyzed in 142 patients with Russian tick-borne encephalitis. Statistically significant differences in genotype, allele, and haplotype frequencies for 3 OAS2 single nucleotide polymorphisms (rs1293762, rs15895, and rs1732778) and 2 OAS3 single nucleotide polymorphisms (rs2285932 and rs2072136) were detected between patients with central nervous system disease and both those with fever and/or meningitis and the control group. The data suggest a possible association between these 5 OAS single nucleotide polymorphisms and the outcome of tick-borne encephalitis virus infection in a Russian population.