Sin Jon, McIntyre Laura, Stotland Aleksandr, Feuer Ralph, Gottlieb Roberta A
The Cedars-Sinai Heart Institute and the Barbra Streisand Women's Heart Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
The Institute for Immunology and the Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, California, USA.
J Virol. 2017 Nov 30;91(24). doi: 10.1128/JVI.01347-17. Print 2017 Dec 15.
Coxsackievirus B (CVB) is a common enterovirus that can cause various systemic inflammatory diseases. Because CVB lacks an envelope, it has been thought to be inherently cytolytic, wherein CVB can escape from the infected host cell only by causing it to rupture. In recent years, however, we and others have observed that various naked viruses, such as CVB, can trigger the release of infectious extracellular microvesicles (EMVs) that contain viral material. This mode of cellular escape has been suggested to allow the virus to be masked from the adaptive immune system. Additionally, we have previously reported that these viral EMVs have LC3, suggesting that they originated from autophagosomes. We now report that CVB-infected cells trigger DRP1-mediated fragmentation of mitochondria, which is a precursor to autophagic mitochondrial elimination (mitophagy). However, rather than being degraded by lysosomes, mitochondrion-containing autophagosomes are released from the cell. We believe that CVB localizes to mitochondria, induces mitophagy, and subsequently disseminates from the cell in an autophagosome-bound mitochondrion-virus complex. Suppressing the mitophagy pathway in HL-1 cardiomyocytes with either small interfering RNA (siRNA) or Mdivi-1 caused marked reduction in virus production. The findings in this study suggest that CVB subverts mitophagy machinery to support viral dissemination in released EMVs. Coxsackievirus B (CVB) can cause a number of life-threatening inflammatory diseases. Though CVB is well known to disseminate via cytolysis, recent reports have revealed a second pathway in which CVB can become encapsulated in host membrane components to escape the cell in an exosome-like particle. Here we report that these membrane-bound structures derive from mitophagosomes. Blocking various steps in the mitophagy pathway reduced levels of intracellular and extracellular virus. Not only does this study reveal a novel mechanism of picornaviral dissemination, but also it sheds light on new therapeutic targets to treat CVB and potentially other picornaviral infections.
柯萨奇病毒B（CVB）是一种常见的肠道病毒，可引起各种全身性炎症性疾病。由于CVB没有包膜，一直被认为具有内在的细胞溶解性，即CVB只能通过使受感染的宿主细胞破裂才能从其中逃逸。然而，近年来，我们和其他人观察到，各种无包膜病毒，如CVB，可触发含有病毒物质的传染性细胞外微泡（EMV）的释放。有人提出，这种细胞逃逸模式可使病毒躲避适应性免疫系统。此外，我们之前曾报道，这些病毒EMV含有LC3，表明它们起源于自噬体。我们现在报告，CVB感染的细胞会触发由动力相关蛋白1（DRP1）介导的线粒体分裂，这是自噬性线粒体清除（线粒体自噬）的前奏。然而，含有线粒体的自噬体并非被溶酶体降解，而是从细胞中释放出来。我们认为，CVB定位于线粒体，诱导线粒体自噬，随后以与自噬体结合的线粒体-病毒复合物形式从细胞中传播。用小干扰RNA（siRNA）或Mdivi-1抑制HL-1心肌细胞中的线粒体自噬途径，可显著降低病毒产生。本研究结果表明，CVB会破坏线粒体自噬机制，以支持病毒在释放的EMV中传播。柯萨奇病毒B（CVB）可引发多种危及生命的炎症性疾病。尽管众所周知CVB通过细胞溶解进行传播，但最近的报告揭示了另一种途径，即CVB可被包裹在宿主膜成分中，以类似外泌体的颗粒形式从细胞中逃逸。我们在此报告，这些膜结合结构源自线粒体自噬体。阻断线粒体自噬途径的各个步骤可降低细胞内和细胞外病毒水平。这项研究不仅揭示了小核糖核酸病毒传播的新机制，还为治疗CVB及潜在的其他小核糖核酸病毒感染提供了新的治疗靶点。
