Hantaviruses: crossing the species barrier of natural hosts

汉坦病毒（布尼亚病毒科）是引起两种人类人畜共患病，即肾综合征出血热和汉坦病毒心肺综合征的新出现病毒，因其与宿主（主要是啮齿动物）密切相关而闻名。然而，所谓的非宿主动物的溢出感染在自然界中发生，可能为汉坦病毒物种屏障机制和病毒宿主转换过程提供重要见解。该建议的重点是对德国存在的三种汉坦病毒的自然感染和外溢感染进行比较分析；银行田鼠（Myodes glareolus）携带Puumala病毒（PUUV），条纹田鼠（黑线姬鼠）携带DOBV，普通田鼠（Microtus arvalis）及其亲缘种鼠携带图拉病毒（TULV）。结合对自然发生的啮齿动物物种（包括水库和非水库物种）的研究和体外实验，可以在生态和细胞水平上研究宿主物种的屏障。在德国“啮齿动物传播的病原体”网络活动框架内收集了所需的组织标本，可用于所需的实验。实地资料研究将提供自然界汉坦病毒外溢感染的发生、频率和致病后果的原始数据。同时进行的体外实验将侧重于受体分子和先天免疫成分作为汉坦病毒宿主范围的预期分子决定因素。该方法包括对天然汉坦病毒宿主的基因组和转录组进行具体分析。为了进一步确定在细胞水平上决定物种屏障的因素，这些有针对性的调查将与受感染的啮齿动物来源的细胞的比较转录组分析相结合，作为一种“开放观点”策略。总而言之，提出的生态实地研究与最新分子和病毒学研究的独特结合代表了第一个关注汉坦病毒外溢感染的综合研究。已建立的工具和获得的数据不仅可以对汉坦病毒的物种屏障提供有价值的见解，而且还可能在总体上显著推进啮齿动物传播的病原体领域。该项目将在申请者的长期互动中进行，包括博士生的共同监督。此外，将与优先规划内的其他项目伙伴交流思想、方法和标本。

Hantaviruses (Bunyaviridae family), emerging viruses causing two human zoonoses, hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome, are well known for their strict association with their reservoir hosts, mainly rodents. However, so called spillover infections of non-reservoir animals occur in nature and might provide crucial insights into the mechanisms of hantavirus species barriers and processes of the virus host switch. This proposal is focused on comparative analyses of natural and spillover infections of the three hantaviruses present in Germany; Puumala virus (PUUV) carried by bank vole (Myodes glareolus), Dobrava-Belgrade virus (DOBV) carried by the striped field mouse (Apodemus agrarius), and Tula virus (TULV) carried by the common vole (Microtus arvalis) and related Microtus species.The combination of studies on syntopically occurring rodent species (including reservoir and non-reservoir species) and in vitro experiments will allow studying the host species barriers on the ecological as well as cellular level. The required tissue specimens were collected before in frame of the activities of the German network “„Rodent-borne pathogens“ and can be used for the desired experiments. Studies of field materials will provide original data on occurrence, frequency, and pathogenetic consequences of hantavirus spillover infections in nature. In vitro experiments conducted in parallel will focus on receptor molecules and innate immunity components as anticipated molecular determinants of the hantavirus host range. The approach includes a specific analysis of the genome and transcriptome of natural hantavirus hosts. In order to identify further factors determining the species barrier on the cellular level, these targeted investigations will be combined with comparative transcriptome analysis of the infected rodent-derived cells as an “open view” strategy.In summary, the proposed unique combination of ecologic field studies with state-of-theart molecular and virological investigations represents the first comprehensive study focusing on hantavirus spillover infections. The established tools and obtained data will not only allow valuable insights into the hantavirus species barriers but might also significantly advance the field of rodent-borne pathogens in general.The project will be performed in permanent interaction of the applicants which includes joint supervision of the Ph.D. students. In addition, an exchange of ideas, methods, and specimens will be established with other project partners within the Priority Programme.