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In the Kurgan region, the Siberian subtype of the tick-borne encephalitis virus (TBEV) is dominant. The vaccines prepared from Far-Eastern TBEV subtype are used in this area. Among TBE patients in 2007-2011, 23.79% were vaccinated according to complete or incomplete course. 76.9% of persons were vaccinated with Encevir vaccine, Tomsk. An unusual focal form of TBE with fulminant disease with lethal outcome was developed in a patient who was vaccinated 6 times with heterotype vaccines produced using the strains of the Far-Eastern TBE subtype. Inoculation of immunoglobulin in hospital produced aggravation of clinical symptoms, development of convulsions, brain oedema, and respiratory distress syndrome. The disease continues only 55 hours from first symptoms to fatal outcome. Siberian subtype of TBEV was isolated from patient spinal cord (Kurgan-118-2010 strain). Possible mechanisms of this disease are discussed.

Aim: Study of macrophage migration inhibiting factor (MIF) effect after intracerebral administration on the course of experimental infection induced in mice by tick borne encephalitis virus (TEV), and study of sodium polyprenyl phosphate (PPP) and/or antibodies against MIF on the course of this infection against the background of MIF administration., Materials and Methods: Phosprenil preparation was used as a source of PPP. PPP was administered intracerebrally. MIF--human recombinant (R&D, USA), mice--Balb/c line., Results: In the sera of mice infected with TEV, MIF production stimulation was detected at days 8 through 10 after the infection--against the background of clinical signs presentation of tick borne encephalitis (TE). Administration of PPP to infected mice, on the contrary, resulted in MIF production suppression at the specified period. After administration of 20 ng of MIF to mice, lethality increased by 40% and average life span decreased by 2.3 days. Thus, MIF at high doses caused an increase of infection course severity, induced by TEV in mice, and administration of 60 microg of PPP resulted in the protection from infection in 100% of cases. Intracerebral administrationto mice of antibodies against MIF resulted in a decrease of lethality indicator up to 26% as compared with control and an increase of averagelife span by 5.5 days. During simultaneous administration into the brain of infected mice of MIF, PPP and antibodies against MIF, prevention of MIF-induced increase of TE course severity was registered., Conclusion: The data obtained allow to conclude that MIF may serve as an indicator of TE course severity, and possible prognostic indicator of meningo-encephalitic form development in humans.

An experiment with BALB/c mice, infected with a lethal dosage of the virus of tick-borne encephalitis (TE), strain 205, was accompanied by pronounced growing concentrations of the IL-1 beta, IL-6, IL-10 and TNF alpha cytokines in the blood serum of animals. The maximum values of the above cytokines were determined at the infection terminal stage. A reliably less pronounced growth of concentrations of IL-1 beta, TNF alpha and IL-10 was found in animals infected with a non-lethal TE dosage. The concentration of IL-6 in the blood serum of animals, infected with a non-lethal dosage of the virus, changed during the whole observation period. The dynamics of cytokines in the blood serum of mice, infected with a lethal dosage of the TE virus, suggests the development of SIRS at the infection terminal stage.

Efficacy of drug therapy of Omsk hemorrhagic fever (OHF) was tested experimentally using cell culture and laboratory animals infected with the OHF virus strain Ondatra. Screening tests showed that high concentrations of Virazol or interferon inducers Larifan and Rifastin caused moderately pronounced suppression of virus reproduction in cell culture. Realdiron was found to be a high-efficacy preparation causing complete inhibition of virus reproduction in cell. Larifan demonstrated the highest antiviral efficacy against OHF virus in experiments with laboratory animals. This drug prevented the death of 65% infected mice and significantly decreased infection process severity in rabbits.

Narrow-skulled voles (Microtus gregalis) were inoculated with tick-borne encephalitis (TBE) and rabies (RV) viruses isolated in the steppe zone of West Siberia. TBE infection was asymptomatic and nonlethal in all voles. The virus was eliminated from the voles between days 14 and 60 postinoculation. Only 1 of 26 tested animals produced anti-TBE antibodies in titer 1:20. RV infection was acute and lethal. All sick animals contained RV in the brain, 42.1% in salivary glands, 5.3% in the lungs and kidneys. The voles which survived RV inoculation had no RV. The voles inoculated with RV after TBE were less sensitive and had a longer incubation period in comparison with the animals challenged with RV alone. The differences augmented from day 0 to day 14 after TBE inoculation and became statistically significant on day 14. Later, 21 day after challenge with TBE virus, the differences almost disappeared. The role of possible interference in the evolution of virus-host interaction of Lyssaviruses is discussed.

The action of information stress for 14 days leads to the development of immunosuppression, which is manifested by the suppression of humoral response to sheep red blood cells (SRBC) and the decrease of resistance to Langat virus having low pathogenicity. As shown in this investigation, an immunomodifier, purified staphylococcal toxoid (PST), protects experimental animals from the immunosuppressive effect of information stress. After the injection of PST to stress-affected mice in doses of 15 or 1.5 binding units per animal on days 9, 11 and 13 of the experiment their humoral response to SRBC and resistance to Langat virus are partially restored (by 45-60%).

Experimentally, two aspects protective and damaging, of the immune response were demonstrated in the course of development of infection in mice inoculated with tickborne encephalitis (TBE) virus, Langat, yellow fever, dengue type 2 or West Nile viruses. The experiments were carried out in animals in which the functions of T- and B-lymphocytes, were temporarily inhibited with cyclophosphane (CP). It was demonstrated that the protective or damaging role of the immune response depended on the method of inoculation of the animals, the virus properties, and characteristics of the mouse strain. The conditions optimal for the development of immunopathological reactions in one infection (TBE) were not identical for those in another infection even when caused by an antigenically related virus (LANGAT). In mice of the AKR strain the possibility of producing a therapeutic effect upon treatment with CP of the animals inoculated with TBE virus was demonstrated.

The graft versus host reaction (GVHR) under conditions of two-way incompatibility was shown to increase average longevity (AL) of mice with experimental tick-borne encephalitis (TBE) and to activate asymptomatic infection caused by Langat virus. Experiments with TBE virus demonstrated participation of viable T lymphocytes in GVHR. Inhibition of function of both humoral and cellular immunity was shown to occur in GVHR. The assumption that the increase in the average longevity in TBE is associated with the inhibition of the damaging function of cellular immunity is experimentally substantiated.

Stress factors of different nature activate antigen-nonspecific suppressors inhibiting different mechanisms of immune response in mice. The adoptive transfer of the population of immunocompetent cells containing stress-induced suppressors to mice infected with Langat virus has been found to lead to the activation of asymptomatic infection. The data obtained in this investigation indicate that the above-mentioned mechanism of the development of antigen-nonspecific immune deficiency is of importance in the pathogenesis of viral infections in man and it explains the onset of diseases (or their aggravation) under the conditions of stress.

Persistent infection with tick-borne encephalitis virus (TBE) was established in experimentally infected continuous lymphoblastoid human cell lines Raji, L-101 (of B-origin) and 1387 (T-origin) and with Venezuelan equine encephalomyelitis (VEE) virus in Raji and 1387 lines. The persistently infected lines produced infectious virus, the cells showed specific fluorescence in immunofluorescent tests, and electron microscopic examinations revealed TBE and VEE virions in sections.

Certain parameters of humoral and cellular immunity induced by attenuated tick-borne encephalitis (TBE) and Langat virus strains were studied in monkeys. The immunogenic activity of the strains inoculated subcutaneously and intracerebrally was manifested by two processes: synthesis of specific antibody and cellular immune response. The highest titers of humoral immunity in N, HI, and CF tests were observed to homologous viruses. The immune response to both homologous and heterologous viruses could be optimized by increasing the number of antigenic stimulations. The sequence of antibody synthesis of the macro- and microglobulin series was similar in monkeys infected with virulent and attenuated strains. Cellular immunity reactions were detected and changes in the quantity and functional activity of T- and B-lymphocytes were determined. Most marked immunological changes were observed with the virulent TBE virus strain as compared with naturally and experimentally attenuated Langat virus strains.

A comparative analysis of tryptic hydrolysates of virus-specific proteins NV5, V3 and NV3 of the tick-borne encephalitis complex viruses showed proteins NV5 to have considerable regions of similar amino acid sequences, V3 proteins to have significantly differing primary structures, and NV3 proteins to have different amino acid sequences.

The precursors of autoreactive T-lymphocytes (PARTL) have been detected in the spleen of mice infected with Langat virus. When introduced into syngeneic recipients, PARTL differentiate in their lymph nodes into autoreactive T-lymphocytes (ARTL) causing a fatal autoimmune disease in the syngeneic recipients in vivo and capable of destroying syngeneic cell cultures in vitro. In the thymus of mice infected with Langat virus T-suppressors (TS) inhibiting the differentiation of PARTL into ARTL have been detected. The serum of intact mice has been shown to contain the serum blocking factor (SBF) which suppresses the differentiation of PARTL and the activity of TS from donors having common H-2 haplotypes of the gene complex with serum donors. In the course of viral infection the decrease of SBF activity and, simultaneously, the activation of PARTL and TS occur. The activation of PARTL and TS in infected mice may be suppressed by the injection of the serum of intact donors identical in H-2 haplotypes. The injection of ARTL induced by Langat virus into syngeneic recipients infected with this virus provokes the transformation of asymptomatic infection into acute infection, while TS and SBF blocking the differentiation of PARTL protect the animals from death.