Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
Cell Host Microbe. 2012 Mar 15;11(3):298-305. doi: 10.1016/j.chom.2012.01.014.
Autophagy protects against many infections by inducing the lysosomal-mediated degradation of invading pathogens. However, previous in vitro studies suggest that some enteroviruses not only evade these protective effects but also exploit autophagy to facilitate their replication. We generated Atg5(f/f)/Cre(+) mice, in which the essential autophagy gene Atg5 is specifically deleted in pancreatic acinar cells, and show that coxsackievirus B3 (CVB3) requires autophagy for optimal infection and pathogenesis. Compared to Cre(-) littermates, Atg5(f/f)/Cre(+) mice had an ∼2,000-fold lower CVB3 titer in the pancreas, and pancreatic pathology was greatly diminished. Both in vivo and in vitro, Atg5(f/f)/Cre(+) acinar cells had reduced intracellular viral RNA and proteins. Furthermore, intracellular structural elements induced upon CVB3 infection, such as compound membrane vesicles and highly geometric paracrystalline arrays, which may represent viral replication platforms, were infrequently observed in infected Atg5(f/f)/Cre(+) cells. Thus, CVB3-induced subversion of autophagy not only benefits the virus but also exacerbates pancreatic pathology.
自噬通过诱导溶酶体介导的入侵病原体降解来保护免受许多感染。然而，先前的体外研究表明，一些肠道病毒不仅逃避这些保护作用，还利用自噬来促进其复制。我们生成了 Atg5(f/f)/Cre(+) 小鼠，其中必需的自噬基因 Atg5 特异性地在胰腺腺泡细胞中缺失，并表明柯萨奇病毒 B3 (CVB3) 为了最佳感染和发病机制需要自噬。与 Cre(-) 同窝仔相比，Atg5(f/f)/Cre(+) 小鼠的胰腺中 CVB3 滴度低约 2000 倍，胰腺病理大大减少。在体内和体外，Atg5(f/f)/Cre(+) 腺泡细胞中的细胞内病毒 RNA 和蛋白质减少。此外，在感染 CVB3 后诱导的细胞内结构元素，如复合膜泡和高度几何准晶阵列，可能代表病毒复制平台，在感染的 Atg5(f/f)/Cre(+) 细胞中很少观察到。因此，CVB3 诱导的自噬功能丧失不仅有利于病毒，还会加重胰腺病理。
