Hameed Muddassar, Solomon Norman A, Weger-Lucarelli James
Department of Biomedical Sciences and Pathobiology, VA-MD Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA.
Center for Zoonotic and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA.
bioRxiv. 2024 Aug 3:2024.07.31.606106. doi: 10.1101/2024.07.31.606106.
Arthritogenic alphaviruses, including chikungunya virus (CHIKV), Mayaro virus (MAYV), Ross River virus (RRV), and O'nyong nyong virus (ONNV) are emerging and reemerging viruses that cause disease characterized by fever, rash, and incapacitating joint swelling. Alphavirus infection induces robust immune responses in infected hosts, leading to the upregulation of several cytokines and chemokines, including chemokine C ligand 4 (CCL4). CCL4 is a chemoattractant for immune cells such as T cells, natural killer cells, monocytes/macrophages, and dendritic cells, recruiting these cells to the site of infection, stimulating the release of proinflammatory mediators, and inducing T cell differentiation. CCL4 has been found at high levels in both the acute and chronic phases of chikungunya disease; however, the role of CCL4 in arthritogenic alphavirus disease development remains unexplored. Here, we tested the effect of CCL4 on MAYV infection in mice through antibody depletion and treatment with recombinant mouse CCL4. We observed no differences in mice depleted of CCL4 or treated with recombinant CCL4 in terms of disease progression such as weight loss and footpad swelling or the development of viremia. CCL4 uses the G protein-coupled receptor C-C chemokine receptor type 5 (CCR5). To determine whether CCR5 deficiency would alter disease outcomes or virus replication in mice, we inoculated CCR5 knockout (CCR5) mice with MAYV and observed no effect on disease development and immune cell profile of blood and footpads between CCR5 and wild type mice. These studies failed to identify a clear role for CCL4 or its receptor CCR5 in MAYV infection.
致关节炎甲病毒，包括基孔肯雅病毒（CHIKV）、马亚罗病毒（MAYV）、罗斯河病毒（RRV）和奥尼永尼永病毒（ONNV），是正在出现和再次出现的病毒，它们引起的疾病特征为发热、皮疹和使人丧失能力的关节肿胀。甲病毒感染在受感染宿主中诱导强烈的免疫反应，导致包括趋化因子C配体4（CCL4）在内的多种细胞因子和趋化因子上调。CCL4是T细胞、自然杀伤细胞、单核细胞/巨噬细胞和树突状细胞等免疫细胞的趋化剂，将这些细胞招募到感染部位，刺激促炎介质的释放，并诱导T细胞分化。在基孔肯雅病的急性期和慢性期均发现CCL4水平很高；然而，CCL4在致关节炎甲病毒疾病发展中的作用仍未得到探索。在这里，我们通过抗体清除和用重组小鼠CCL4处理来测试CCL4对小鼠MAYV感染的影响。我们观察到，在疾病进展方面，如体重减轻、足垫肿胀或病毒血症的发展，CCL4缺失或用重组CCL4处理的小鼠没有差异。CCL4使用G蛋白偶联受体C-C趋化因子受体5型（CCR5）。为了确定CCR5缺陷是否会改变小鼠的疾病结局或病毒复制，我们用MAYV接种CCR5基因敲除（CCR5）小鼠，并未观察到CCR5小鼠和野生型小鼠在疾病发展以及血液和足垫免疫细胞谱方面有任何影响。这些研究未能确定CCL4或其受体CCR5在MAYV感染中的明确作用。
