Berankova Michaela, Holoubek Jiri, Hönig Vaclav, Matusova Zuzana, Palus Martin, Salat Jiri, Krayem Imtissal, Vojtiskova Jarmila, Svoboda Pavel, Pranclova Veronika, Valihrach Lukas, Demant Peter, Lipoldova Marie, Ruzek Daniel
Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
Laboratory of Arbovirology, Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Ceske Budejovice, Czech Republic.
J Neuroinflammation. 2025 Jan 28;22(1):22. doi: 10.1186/s12974-025-03354-1.
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.
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.
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.
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.
蜱传脑炎（TBE）是欧亚大陆最常见的蜱传病毒感染。其结局从无症状感染到致命性脑炎不等，宿主基因可能发挥了作用。BALB/c小鼠对TBE病毒（TBEV）具有中等易感性，而STS小鼠具有高度抗性，而在BALB/c背景上携带12.5% STS基因组的重组近交系CcS-11比BALB/c小鼠更易感。在本研究中，我们采用这些基因不同的小鼠模型来研究宿主在初始靶细胞群体之一的外周巨噬细胞以及病毒的终末靶器官脑内对TBEV感染的反应。
对源自BALB/c、CcS-11和STS小鼠的巨噬细胞中TBEV的生长以及关键细胞因子和趋化因子的产生进行了测量和比较。此外，对这些感染TBEV的小鼠品系的脑进行了深入的转录组分析。
BALB/c和CcS-11巨噬细胞在感染后24小时和48小时表现出相似的病毒产生动力学，但CcS-11巨噬细胞在感染后72小时产生的病毒滴度显著更高。两种敏感品系的巨噬细胞在感染后趋化因子和促炎细胞因子的产生均增加，而抗性品系STS未表现出细胞因子/趋化因子激活。脑组织的转录组分析表明，小鼠品系的遗传背景决定了它们对感染的转录反应。抗性品系表现出更强的细胞介导免疫反应，而两种敏感品系的细胞介导反应效果较差，但细胞因子信号传导增加和脱髓鞘迹象明显，少突胶质细胞丢失。
我们的研究结果表明，与宿主遗传背景相关的易感性差异与不同的宿主反应相对应，无论是在病毒进入机体时的外周还是在病毒的靶器官脑内。这些结果为宿主基因对TBE临床病程的影响提供了见解。
