Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, 59840, USA.
Medical Research Council Laboratory of Molecular Biology, Cambridge, CB20QH, UK.
Nat Commun. 2024 Oct 25;15(1):9236. doi: 10.1038/s41467-024-53362-7.
Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a negative-sense RNA virus spread by Hyalomma genus ticks across Europe, Asia, and Africa. CCHF disease begins as a non-specific febrile illness which may progress into a severe hemorrhagic disease with no widely approved or highly efficacious interventions currently available. Recently, we reported a self-replicating, alphavirus-based RNA vaccine that expresses the CCHFV nucleoprotein and is protective against lethal CCHFV disease in mice. This vaccine induces high titers of non-neutralizing anti-NP antibodies and we show here that protection does not require Fc-gamma receptors or complement. Instead, vaccinated mice deficient in the intracellular Fc-receptor TRIM21 were unable to control the infection despite mounting robust CCHFV-specific immunity. We also show that passive transfer of NP-immune sera confers significant TRIM21-dependent protection against lethal CCHFV challenge. Together our data identifies TRIM21-mediated mechanisms as the Fc effector function of protective antibodies against the CCHFV NP and provides mechanistic insight into how vaccines against the CCHFV NP confer protection.
克里米亚-刚果出血热病毒（CCHFV）是一种负义 RNA 病毒，通过在欧洲、亚洲和非洲的革螨属传播。CCHF 疾病最初表现为非特异性发热性疾病，可能进展为严重出血性疾病，目前尚无广泛批准或高度有效的干预措施。最近，我们报道了一种自我复制的、基于甲病毒的 RNA 疫苗，该疫苗表达 CCHFV 核蛋白，可预防小鼠致命的 CCHFV 疾病。该疫苗诱导高水平的非中和性抗 NP 抗体，我们在这里表明，保护不需要 Fc-γ 受体或补体。相反，缺乏细胞内 Fc 受体 TRIM21 的接种小鼠尽管产生了强烈的 CCHFV 特异性免疫，但无法控制感染。我们还表明，NP 免疫血清的被动转移可赋予针对致命性 CCHFV 挑战的显著依赖于 TRIM21 的保护。我们的数据共同确定了 TRIM21 介导的机制作为针对 CCHFV NP 的保护性抗体的 Fc 效应功能，并为 CCHFV NP 疫苗如何提供保护提供了机制见解。
