Lethal Experimental Tick-Borne Encephalitis Infection: Influence of Two Strains with Similar Virulence on the Immune Response

Abstract

Tick-borne encephalitis virus (TBEV) is a tick-transmitted arbovirus that causes serious diseases in humans in Europe and Northern Asia. About 6000–10,000 cases are registered annually, and one-third of them lead to sequela with different degrees of severity. Two TBEV strains (Absettarov and EK-328) similar in virulence rate in laboratory mice were used to study pathogenesis and immune response upon lethal infection in mice. The strains differed in the dynamics of appearance of virus, IFNs and other cytokines in blood of mice, and ability to induce a cytokine storm in the terminal stages of disease and a non-sterile immunity. Moreover, the TBEV strains differed in characteristics of their interactions with DCs: level of reproduction in these cells, virus dose triggering IFN-α production, and impact on DCs' maturation. Infection of DCs with Absettarov strain led to IFN-α induction only at high multiplicity of infection (MOI), and an increased amount of the mature DCs with high adhesion activity and low-level of MHCII positive cells. While reproduction of the EK-328 strain in DCs was less efficient, a low dose of the virus induced IFN-α production and stimulated maturation of DCs with relatively low adhesive capacity, but with the high percentage of cells expressing MHCII molecules. Thus, the studied strains differed significantly in the impact on DCs' maturation and antigen presentation to CD4+ lymphocytes. Injection of low (103 PFU) and high (106 PFU) doses of both TBEV strains caused a lethal infection in mice. At the same time, the dose of the virus in the inoculum, regardless of the strain properties, affected the following virulence characteristics: the time of virus appearance in brain (day 4–5 vs. day 1 p.i.), time of IFN-α appearance in blood (10 h vs. 5 h p.i.), concentration of IFN-α in blood, and induction of IFN-α during infection of DCs. Therefore, virulent TBEV strains during lethal infection can interact differently with the host immune system, and the infectious dose has an impact on both: virus spread in the infected organism and immune response activation.

Experimental Evaluation of the Protective Efficacy of Tick-Borne Encephalitis (TBE) Vaccines Based on European and Far-Eastern TBEV Strains in Mice and in Vitro

“…TBEV strains (Table 1 ) were described previously (Gritsun et al, 1997 ; Romanova et al, 2007 ; Zlobin et al, 2007 ; Kozlovskaya et al, 2010 ; Vorovitch et al, 2015 ; Chernokhaeva et al, 2016b ; Shevtsova et al, 2016 ). The viruses were stored at −70°C as a 10% mouse brain suspension or a culture supernate (CS) of infected PEK cells.…”

Experimental Assessment of Possible Factors Associated with Tick-Borne Encephalitis Vaccine Failure

“…We also assessed several virus-related factors that could lead to TBE breakthrough infections. The differences in the vaccine efficacy against various TBEV strains can be explained by several reasons, including high virulence of a particular strain [70], features of the interaction of different strains with the immune system [39], and genetic [71,72] or structural heterogeneity of the virus sample. It was previously shown that the vaccine efficacy can be associated with the properties of the virulent virus and, probably, with its antigenic structure [59].…”

“…Such factors as the infection dose of the virus, its virulence, reproduction rate, route of inoculation, etc. were shown to influence the severity of the disease and the immune response [39].…”

Histone deacetylase 3 promotes innate antiviral immunity through deacetylation of TBK1

“…As a critical kinase involved in innate immunity, the activity of TBK1 is tightly regulated to maintain immune homeostasis. K63-linked polyubiquitination of TBK1 at Lys30 and Lys401 and autophosphorylation of TBK1 at Ser172 were shown to be critical for its activation (Wang et al, 2009 ; Li et al, 2011 ; Ma et al, 2012 ; Tu et al, 2013 ; Shevtsova et al, 2016 ). Modification of TBK1 at Lys694 by the small ubiquitin-like modifier SUMO contributes to the ability of TBK1 to bind to adaptors for the transduction of IFN signaling (Saul et al, 2015 ).…”