Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
Integrated Program of Biomedical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
PLoS Pathog. 2022 Apr 22;18(4):e1009716. doi: 10.1371/journal.ppat.1009716. eCollection 2022 Apr.
Human astroviruses (HAstV), positive sense single-stranded RNA viruses, are one of the leading causes of diarrhea worldwide. Despite their high prevalence, the cellular mechanisms of astrovirus pathogenesis remain ill-defined. Previous studies showed HAstV increased epithelial barrier permeability by causing a re-localization of the tight junction protein, occludin. In these studies, we demonstrate that HAstV replication induces epithelial-mesenchymal transition (EMT), by upregulating the transcription of EMT-related genes within 8 hours post-infection (hpi), followed by the loss of cell-cell contacts and disruption of polarity by 24 hpi. While multiple classical HAstV serotypes, including clinical isolates, induce EMT, the non-classical genotype HAstV-VA1 and two strains of reovirus are incapable of inducing EMT. Unlike the re-localization of tight junction proteins, HAstV-induced EMT requires productive replication and is dependent transforming growth factor-β (TGF-β) activity. Finally, inhibiting TGF-β signaling and EMT reduces viral replication, highlighting its importance in the viral life cycle. This finding puts classical strains of HAstV-1 in an exclusive group of non-oncogenic viruses triggering EMT.
人类星状病毒（HAstV）是正链单股 RNA 病毒，是全球范围内导致腹泻的主要病原体之一。尽管它们的流行率很高，但星状病毒发病机制的细胞机制仍未明确。先前的研究表明，HAstV 通过引起紧密连接蛋白紧密连接蛋白（occludin）的重新定位来增加上皮屏障通透性。在这些研究中，我们证明 HAstV 复制通过在感染后 8 小时内上调 EMT 相关基因的转录来诱导上皮-间充质转化（EMT），随后在 24 小时内失去细胞-细胞接触并破坏极性。虽然包括临床分离株在内的多种经典 HAstV 血清型可诱导 EMT，但非经典基因型 HAstV-VA1 和两种轮状病毒株则不能诱导 EMT。与紧密连接蛋白的重新定位不同，HAstV 诱导的 EMT 需要有效的复制，并且依赖转化生长因子-β（TGF-β）活性。最后，抑制 TGF-β 信号转导和 EMT 可减少病毒复制，这突出了其在病毒生命周期中的重要性。这一发现将经典的 HAstV-1 株置于引发 EMT 的非致癌病毒的独特群体中。
