Bengert Brooke, Mehri Samaneh, Holliday Madeline, Lennemann Nicholas J
bioRxiv. 2025 Jun 25:2025.06.25.661519. doi: 10.1101/2025.06.25.661519.
Human astroviruses (HAstV) are major cause of acute, non-bacterial gastroenteritis and have been implicated in severe infections of the nervous system. Despite global prevalence, there are no established treatments for HAstVs due to a lack of understanding of the fundamental biology of infection, including mechanisms of viral replication. Like all positive-stranded RNA (+ssRNA) viruses, infection induces remodeling of host membranes into replication organelles (ROs). However, the intracellular membrane source and viral proteins involved in the coordination of HAstV ROs remain poorly defined. Using immunofluorescence microscopy, we determined that HAstV1 infection drives extensive restructuring of the endoplasmic reticulum (ER) to concentrate RNA replication and virus packaging. Long-term, time-lapse imaging of the ER and time point transmission electron microscopy revealed that temporal manipulation of ER membrane corresponds with the emergence of ER-contiguous double membrane vesicles (DMV). The co-expression of transmembrane nonstructural proteins nsp1a/1 and nsp1a/2 established similar DMV networks in the absence of an active infection. Further, super resolution microscopy revealed the organization of these two viral proteins in RO-like arrangements within the perinuclear region of infected cells. Together, these findings enhance our understanding of HAstV1-induced RO biogenesis, highlighting nsp1a/1 and nsp1a/2 as exploitable targets for the design of antivirals restricting astrovirus replication.
Human astroviruses (HAstV) are understudied, globally prevalent pathogens capable of causing potentially fatal infections of the central nervous system in children, the elderly, and immunocompromised individuals. Despite the capacity to cause devastating disease, there are no established vaccines, antivirals, or therapeutics available combat HAstV infections, in part due to a lack of knowledge for the functions of several viral proteins. This study furthers our understanding of HAstV manipulation of the host cell by identification of the viral proteins responsible for the biogenesis of virus-induced double membrane vesicles, which are a hallmark of replication.
人星状病毒（HAstV）是急性非细菌性肠胃炎的主要病因，并且与严重的神经系统感染有关。尽管在全球广泛流行，但由于对感染的基础生物学，包括病毒复制机制缺乏了解，目前尚无针对HAstV的既定治疗方法。与所有正链RNA（+ssRNA）病毒一样，感染会诱导宿主膜重塑为复制细胞器（RO）。然而，参与HAstV RO协调的细胞内膜来源和病毒蛋白仍不清楚。通过免疫荧光显微镜，我们确定HAstV1感染会驱动内质网（ER）的广泛重组，以集中RNA复制和病毒包装。对ER的长期延时成像和时间点透射电子显微镜显示，ER膜的时间操纵与ER相邻的双膜囊泡（DMV）的出现相对应。跨膜非结构蛋白nsp1a/1和nsp1a/2的共表达在没有活跃感染的情况下建立了类似的DMV网络。此外，超分辨率显微镜揭示了这两种病毒蛋白在受感染细胞核周区域内以RO样排列的组织方式。总之，这些发现增强了我们对HAstV1诱导的RO生物发生的理解，突出了nsp1a/1和nsp1a/2作为设计限制星状病毒复制的抗病毒药物的可利用靶点。
人星状病毒（HAstV）是研究不足、全球流行的病原体，能够在儿童、老年人和免疫功能低下的个体中引起潜在致命的中枢神经系统感染。尽管有能力引起毁灭性疾病，但目前尚无既定的疫苗、抗病毒药物或治疗方法来对抗HAstV感染，部分原因是对几种病毒蛋白的功能缺乏了解。这项研究通过鉴定负责病毒诱导的双膜囊泡生物发生的病毒蛋白，进一步加深了我们对HAstV对宿主细胞操纵的理解，而双膜囊泡是复制的标志。
