Defensin-driven viral evolution.
Defensin-driven viral evolution.
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DOI：
10.1371/journal.ppat.1009018
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发表时间：
2020-11
期刊：
影响因子：
6.7
通讯作者：
Smith JG
中科院分区：
文献类型：
--
作者：
Diaz K;Hu CT;Sul Y;Bromme BA;Myers ND;Skorohodova KV;Gounder AP;Smith JG
肠道α-防御素是先天免疫的有效效应物，在小肠中大量表达。某些肠道细菌和病毒对防御素有抗性，甚至可以利用它们来增强感染，尽管它们可以中和密切相关的微生物。因此，我们假设，防御素施加选择性压力，在粪口传播。在存在人防御素的情况下，将腺病毒的防御素敏感血清型传代后，主要衣壳蛋白六邻体中的突变积累。相反，先前的研究确定顶点蛋白作为防御素抗病毒活性的重要决定因素。感染和生化分析表明，增加的细胞结合和下游之间的平衡块介导的细胞内运输防御素与所有的主要衣壳蛋白的相互作用决定了感染的结果。这些结果广泛修订了我们的理解之间的相互作用防御素和无包膜病毒。此外，它们为防御素塑造病毒进化提供了可行的理论基础，导致密切相关病毒的感染表型差异。防御素是存在于人体粘膜表面的有效抗菌肽，可以直接中和病毒。它们在小肠中大量存在，小肠不断受到摄入的病毒病原体的挑战。有趣的是，感染胃肠道系统的无包膜病毒，如腺病毒，不受防御素的影响，甚至可以利用防御素来增强其感染。相反，呼吸道腺病毒被相同的防御素中和。肠道病毒如何克服防御素中和作用还不清楚。我们的研究首次表明防御素可以驱动无包膜病毒的进化。此外，我们确定了人类腺病毒中决定防御素敏感性的重要成分。这种对防御素-病毒相互作用的新见解为我们了解病毒感染的粘膜免疫提供了信息。
Enteric alpha-defensins are potent effectors of innate immunity that are abundantly expressed in the small intestine. Certain enteric bacteria and viruses are resistant to defensins and even appropriate them to enhance infection despite neutralization of closely related microbes. We therefore hypothesized that defensins impose selective pressure during fecal-oral transmission. Upon passaging a defensin-sensitive serotype of adenovirus in the presence of a human defensin, mutations in the major capsid protein hexon accumulated. In contrast, prior studies identified the vertex proteins as important determinants of defensin antiviral activity. Infection and biochemical assays suggest that a balance between increased cell binding and a downstream block in intracellular trafficking mediated by defensin interactions with all of the major capsid proteins dictates the outcome of infection. These results extensively revise our understanding of the interplay between defensins and non-enveloped viruses. Furthermore, they provide a feasible rationale for defensins shaping viral evolution, resulting in differences in infection phenotypes of closely related viruses. Defensins are potent antimicrobial peptides that are found on human mucosal surfaces and can directly neutralize viruses. They are abundant in the small intestine, which is constantly challenged by ingested viral pathogens. Interestingly, non-enveloped viruses, such as adenovirus, that infect the gastrointestinal system are unaffected by defensins or can even appropriate defensins to enhance their infection. In contrast, respiratory adenoviruses are neutralized by the same defensins. How enteric viruses overcome defensin neutralization is not well understood. Our studies are the first to show that defensins can drive the evolution of non-enveloped viruses. Furthermore, we identify important components within human adenovirus that dictate sensitivity to defensins. This new insight into defensin-virus interactions informs our understanding of mucosal immunity to viral infections.
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影响因子：
9.8
作者：
McQuin C;Goodman A;Chernyshev V;Kamentsky L;Cimini BA;Karhohs KW;Doan M;Ding L;Rafelski SM;Thirstrup D;Wiegraebe W;Singh S;Becker T;Caicedo JC;Carpenter AE
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作者：
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