Pulmonary edema is a fatal complication of EV71-associated hand, foot, and mouth disease (HFMD). The pathogenesis of EV71-induced pulmonary edema remains largely unclear. In this study, we aimed to explore the roles of the capsid protein VP1 in the occurrence of EV71-induced pulmonary edema. The intranasal inoculation of recombinant VP1 protein caused lung inflammation with an elevation of inflammatory cytokines and neutrophils infiltration. Moreover, neutrophil extracellular traps (NETs) were observed in the lung parenchyma of the mice treated with VP1. VP1 directly induced the formation of NETs, which depended on PAD4. VP1 also damaged the lung barrier via the reduction of the tight junction protein occludin. Moreover, the EV71 attachment receptor vimentin was increased upon VP1 administration. In contrast, NETs decreased vimentin levels, suggesting a novel role for NETs in viral immune defense. These results evidenced a direct role of VP1 in EV71-induced pulmonary edema and demonstrated that NETs may be both harmful and beneficial in EV71 infection.

肺水肿是与EV71相关的手足口病（HFMD）的致命并发症。EV71引起的肺水肿的发病机理仍不清楚。在这项研究中，我们旨在探讨衣壳蛋白VP1在EV71诱导的肺水肿发生中的作用。鼻内接种重组VP1蛋白会引起肺部炎症，并伴有炎症细胞因子和中性粒细胞浸润的增加。此外，在用VP1处理的小鼠的肺实质中观察到嗜中性白细胞胞外陷阱（NETs）。VP1直接诱导依赖于PAD4的NET的形成。VP1还通过减少紧密连接蛋白occludin破坏了肺屏障。此外，EV71附着受体波形蛋白在VP1给药后增加。相反，NETs降低波形蛋白水平，提示NETs在病毒免疫防御中具有新作用。这些结果证明了VP1在EV71引起的肺水肿中的直接作用，并证明NETs在EV71感染中可能既有害又有益。