Intra-tick and intra-host infection dynamics of a tick-borne bunyavirus

项目概要和摘要 严重发热伴血小板减少综合征（SFTS）是一种由蜱传疾病引起的新发疾病， 布尼亚病毒，SFTS病毒（SFTSV）。SFTSV由长角血蜱传播， 但最近在美国建立了入侵种群，并继续扩大， 地理范围。SFTS病例在亚洲的发病率不断上升，缺乏具体的治疗策略， 死亡率和蜱虫媒介的全球范围扩张使SFTS成为公共卫生问题。作为一个蜱传 SFTSV不同于单宿主病毒，因为它必须在脊椎动物和哺乳动物中复制和存活， 无脊椎动物宿主目前，迫切需要阐明蜱内和宿主内感染动力学 使布尼亚病毒能够感染、传播并在蜱虫的不同环境中持续存在， 脊椎动物宿主获得这些基本知识对于开发新的预防策略至关重要。 SFTSV传输。本研究提案是对NIH RFA-AI-21-046“促进 Bunyavirales基础科学研究。总体目标是确定SFTSV感染的动力学， 传播和蜱媒介内的细胞嗜性，以及蜱到宿主的传播时间轴和初始 SFTSV-皮肤中的宿主相互作用。中心假设是与H.长角的 生活周期促进蜱内SFTSV传播到蜕皮后的唾液腺，这反过来又使 蜱迅速传播SFTSV到下一个脊椎动物宿主，同时创造一个免疫学 在蜱虫取食的皮肤部位的特殊微环境。中心假设将通过以下两个方面进行检验： 具体目的：1）表征SFTSV感染、传播和在体内的跨stadial存活的动态。 H. longicornis蜱;和，2）定义SFTSV和早期宿主的最小蜱到宿主传播时间 皮肤对SFTSV感染蜱虫的免疫反应。这些目标的完成将定义感染 SFTSV在蜱媒介中跨多个生命阶段和在皮肤内的动力学和细胞嗜性 脊椎动物宿主拟议的研究将是第一次集体检查蜱内和宿主内感染 蜱传本扬病毒的动力学阐明了H.长角线虫-SFTSV-脊椎动物宿主 相互作用将使未来的工作朝着发展合理的干预措施，破坏病毒的生存 以及蜱虫和脊椎动物宿主之间的传播。

PROJECT SUMMARY & ABSTRACT Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease caused by the bunyavirus, SFTS virus (SFTSV). SFTSV is transmitted by the Haemaphysalis longicornis tick, which is native to East Asia but recently established invasive populations in the United States and continues to expand in geographic range. The rising incidence of SFTS cases in Asia, lack of specific treatment strategies, high case fatality rates, and global range expansion of the tick vector make SFTS a public health concern. As a tick-borne virus, SFTSV is unique from single-host viruses because it must replicate and survive in both vertebrate and invertebrate hosts. Currently, there is a critical need to elucidate the intra-tick and intra-host infection dynamics that enable bunyaviruses to infect, disseminate, and persist within the distinct environments of the tick and vertebrate host. Acquiring this fundamental knowledge is paramount to developing novel strategies that prevent SFTSV transmission. This research proposal is in direct response to NIH RFA-AI-21-046, “Promoting Bunyavirales Basic Science Research.” The overall objective is to define the dynamics of SFTSV infection, dissemination, and cell tropism within the tick vector, as well as the tick-to-host transmission timeline and initial SFTSV–host interactions in the skin. The central hypothesis is that biotic factors associated with H. longicornis’ life cycle facilitate intra-tick SFTSV dissemination to the salivary glands after molting, which in turn enables the tick to rapidly transmit SFTSV to the next vertebrate host on which it feeds while creating an immunologically privileged microenvironment at the skin site of tick feeding. The central hypothesis will be tested by pursuing two specific aims: 1) Characterize the dynamics of SFTSV infection, dissemination, and transstadial survival within H. longicornis ticks; and, 2) Define the minimum tick-to-host transmission time of SFTSV and the early host cutaneous immune response to SFTSV-infected tick feeding. Completion of these aims will define the infection kinetics and cell tropism of SFTSV within the tick vector across multiple life stages and within the skin of the vertebrate host. The proposed studies will be the first to collectively examine the intra-tick and intra-host infection dynamics of a tick-borne bunyavirus. Elucidating the fundamental H. longicornis–SFTSV–vertebrate host interactions will enable future work towards the development of rational interventions that disrupt virus survival within, and transmission between, the tick and vertebrate host.