BACKGROUND: Tick-borne encephalitis (TBE) is the most common tick-borne viral infection in Eurasia. Outcomes range from asymptomatic infection to fatal encephalitis, with host genetics likely playing a role. BALB/c mice have intermediate susceptibility to TBE virus (TBEV) and STS mice are highly resistant, whereas the recombinant congenic strain CcS-11, which carries 12.5% of the STS genome on the BALB/c background, is more susceptible than BALB/c mice. In the present study, we employed these genetically distinct mouse models to investigate the host response to TBEV infection in both peripheral macrophages, one of the initial target cell populations, and the brain, the terminal target organ of the virus. METHODS: TBEV growth and the production of key cytokines and chemokines were measured and compared in macrophages derived from BALB/c, CcS-11, and STS mice. In addition, brains from these TBEV-infected mouse strains underwent in-depth transcriptomic analysis. RESULTS: Virus production in BALB/c and CcS-11 macrophages exhibited similar kinetics 24 and 48 h post-infection (hpi), but CcS-11 macrophages yielded significantly higher titers 72 hpi. Macrophages from both sensitive strains demonstrated elevated chemokine and proinflammatory cytokine production upon infection, whereas the resistant strain, STS, showed no cytokine/chemokine activation. Transcriptomic analysis of brain tissue demonstrated that the genetic background of the mouse strains dictated their transcriptional response to infection. The resistant strain exhibited a more robust cell-mediated immune response, whereas both sensitive strains showed a less effective cell-mediated response but increased cytokine signaling and signs of demyelination, with loss of oligodendrocytes. CONCLUSIONS: Our findings suggest that variations in susceptibility linked to host genetic background correspond with distinct host responses, both in the periphery upon virus entry into the organism and in the brain, the target organ of the virus. These results provide insights into the influence of host genetics on the clinical trajectory of TBE.

Department of Cellular Neurophysiology Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

Department of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic

Department of Medical Genetics Faculty of Medicine Charles University 3rd Prague Czech Republic

Department of Molecular and Cellular Biology Roswell Park Comprehensive Cancer Center Buffalo NY USA

Faculty of Science Charles University Prague Czech Republic

Faculty of Science University of South Bohemia Ceske Budejovice Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague Czechia

Laboratory of Arbovirology Institute of Parasitology Biology Centre of the Czech Academy of Sciences Ceske Budejovice Czech Republic

Laboratory of Emerging Viral Diseases Veterinary Research Institute Brno Czech Republic

Laboratory of Gene Expression Institute of Biotechnology of the Czech Academy of Sciences Vestec Czech Republic

Laboratory of Molecular and Cellular Immunology Institute of Molecular Genetics Czech Academy of Sciences Prague Czech Republic

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