Emerging Viruses, Inflammation and Therapeutics Group, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia.
Global Virus Network (GVN) Centre of Excellence in Arboviruses, Griffith University, Gold Coast, Queensland, Australia.
mBio. 2023 Apr 25;14(2):e0058823. doi: 10.1128/mbio.00588-23. Epub 2023 Apr 10.
Arthritogenic alphaviruses such as Ross River virus (RRV) and Chikungunya virus (CHIKV) are responsible for large-scale epidemics that cause debilitating acute and chronic musculoskeletal diseases. MXRA8 was recently discovered as an entry receptor for multiple alphaviruses including CHIKV, RRV, Mayaro virus (MAYV), and O'nyong-nyong virus (ONNV). However, the role of MXRA8 in the development of alphavirus-induced musculoskeletal inflammation has not yet been fully studied. Here, we attempt to fully characterize the contribution of MXRA8 to RRV disease in an established mouse model. MXRA8 knockout (MXRA8) mice generated on a C57BL/6J background, showed abrogated disease signs and reduced viral replication, which correlated with lower viral load, diminished proinflammatory cytokines, and limited cell infiltrates in inflamed tissues. Immunomodulation genes were upregulated to higher levels in RRV-infected wild-type (WT) mice than in MXRA8 mice. Intriguingly, and genes in blood and CD127/IL7RA, CD45, BatF3, IFNGR, Ly6G/Ly6C, CD40, CD127, F4/80, and MHC-II genes in quadriceps were found to be upregulated in RRV-infected MXRA8 mice compared to WT mice. Our results showed an essential role of MXRA8 in the immune response of mice infected with RRV and, more importantly, demonstrated novel changes in immunomodulation genes, which shed light on the immunopathogenesis of alphavirus-induced disease. Previous studies have shown the importance of the cell surface protein MXRA8 as an entry receptor for several different prominent alphaviruses such as CHIKV, RRV, MAYV, and ONNV. In particular, the role of MXRA8 in the tissue tropism, viral pathogenesis, and immune response of a CHIKV mouse model have already been briefly characterized. However, the role of MXRA8 warrants further characterization in RRV disease background, since there are noticeable differences in the disease profile between CHIKV and RRV. For example, patients infected with CHIKV are usually affected by sudden onset of severe arthritis and fever, whereas RRV-infected patients generally only have minor joint pain and mild fever. Here, we characterized the role of MXRA8 in RRV disease and assessed several key mechanisms of MXRA8 that may contribute to the disease progression.
关节炎性甲病毒，如罗斯河病毒（RRV）和基孔肯雅病毒（CHIKV），可引发大规模流行，导致衰弱性急性和慢性肌肉骨骼疾病。MXRA8 最近被发现是多种甲病毒的进入受体，包括 CHIKV、RRV、马亚罗病毒（MAYV）和奥尼昂-尼昂病毒（ONNV）。然而，MXRA8 在甲病毒引起的肌肉骨骼炎症发展中的作用尚未得到充分研究。在这里，我们试图在已建立的小鼠模型中充分表征 MXRA8 对 RRV 疾病的贡献。在 C57BL/6J 背景下生成的 MXRA8 敲除（MXRA8）小鼠表现出疾病迹象减轻和病毒复制减少，这与病毒载量降低、促炎细胞因子减少以及炎症组织中的细胞浸润减少相关。与 MXRA8 小鼠相比，RRV 感染的野生型（WT）小鼠中的免疫调节基因上调到更高水平。有趣的是，与 WT 小鼠相比，RRV 感染的 MXRA8 小鼠的血液和 CD127/IL7RA、CD45、BatF3、IFNGR、Ly6G/Ly6C、CD40、CD127、F4/80 和 MHC-II 基因上调。我们的研究结果表明，MXRA8 在 RRV 感染的小鼠免疫反应中起着至关重要的作用，更重要的是，发现了免疫调节基因的新变化，这为甲病毒引起的疾病的免疫发病机制提供了线索。以前的研究表明，细胞表面蛋白 MXRA8 作为几种不同的主要甲病毒（如 CHIKV、RRV、MAYV 和 ONNV）的进入受体具有重要意义。特别是，MXRA8 在 CHIKV 小鼠模型中的组织嗜性、病毒发病机制和免疫反应中的作用已经得到了简要描述。然而，鉴于 CHIKV 和 RRV 之间的疾病谱存在明显差异，因此 MXRA8 在 RRV 疾病背景下的作用需要进一步表征。例如，感染 CHIKV 的患者通常会出现突发性严重关节炎和发热，而感染 RRV 的患者通常只有轻微的关节疼痛和轻度发热。在这里，我们对 MXRA8 在 RRV 疾病中的作用进行了表征，并评估了可能导致疾病进展的 MXRA8 的几个关键机制。
