Virus Host Interaction Team, Leeds Institute of Medical Research, School of Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS9 7TF, UK.
Institute of Infection, Immunology and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
Sci Transl Med. 2020 Jan 22;12(527). doi: 10.1126/scitranslmed.aax2421.
Arthropod-borne viruses (arboviruses) are important human pathogens for which there are no specific antiviral medicines. The abundance of genetically distinct arbovirus species, coupled with the unpredictable nature of their outbreaks, has made the development of virus-specific treatments challenging. Instead, we have defined and targeted a key aspect of the host innate immune response to virus at the arthropod bite that is common to all arbovirus infections, potentially circumventing the need for virus-specific therapies. Using mouse models and human skin explants, we identify innate immune responses by dermal macrophages in the skin as a key determinant of disease severity. Post-exposure treatment of the inoculation site by a topical TLR7 agonist suppressed both the local and subsequent systemic course of infection with a variety of arboviruses from the , , and genera. Clinical outcome was improved in mice after infection with a model alphavirus. In the absence of treatment, antiviral interferon expression to virus in the skin was restricted to dermal dendritic cells. In contrast, stimulating the more populous skin-resident macrophages with a TLR7 agonist elicited protective responses in key cellular targets of virus that otherwise proficiently replicated virus. By defining and targeting a key aspect of the innate immune response to virus at the mosquito bite site, we have identified a putative new strategy for limiting disease after infection with a variety of genetically distinct arboviruses.
虫媒病毒（arboviruses）是重要的人类病原体，目前尚无特效抗病毒药物。大量具有不同遗传特征的虫媒病毒物种，加上其爆发的不可预测性，使得开发针对病毒的治疗方法具有挑战性。相反，我们已经确定并针对节肢动物叮咬时宿主固有免疫反应的一个关键方面进行了靶向治疗，该方面对所有虫媒病毒感染都是共同的，可能避免了对病毒特异性治疗的需求。使用小鼠模型和人皮肤外植体，我们发现皮肤中的真皮巨噬细胞的固有免疫反应是疾病严重程度的关键决定因素。在接种部位进行局部 TLR7 激动剂治疗，可抑制多种属（Flavivirus、Togavirus 和 Bunyavirus）的虫媒病毒的局部和随后的全身感染过程。在感染模型甲病毒后，小鼠的临床预后得到改善。在没有治疗的情况下，皮肤中的抗病毒干扰素表达仅限于真皮树突状细胞。相比之下，用 TLR7 激动剂刺激数量更多的皮肤常驻巨噬细胞，可在病毒的关键细胞靶标中引发保护性反应，而这些靶标原本能够有效地复制病毒。通过确定和针对节肢动物叮咬部位宿主对病毒固有免疫反应的一个关键方面，我们已经确定了一种针对多种具有不同遗传特征的虫媒病毒感染后限制疾病的潜在新策略。
