Estes M K, Kang G, Zeng C Q, Crawford S E, Ciarlet M
Division of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
Novartis Found Symp. 2001;238:82-96; discussion 96-100. doi: 10.1002/0470846534.ch6.
The outcome of intestinal infection with rotaviruses is more complex than initially appreciated, and it is affected by a complex interplay of host and viral factors. Rotaviruses infect intestinal enterocytes, and the early events in infection are mediated by virus-epithelial cell interactions. Diarrhoea may be caused by several mechanisms including (i) malabsorption that occurs secondary to the destruction of enterocytes, (ii) villus ischaemia and activation of the enteric nervous system that may be evoked by release of a vasoactive agent from infected epithelial cells in the absence of significant pathologic lesions or enterocyte damage, and (iii) intestinal secretion stimulated by the intracellular or extracellular action of the rotavirus non-structural protein, NSP4, a novel enterotoxin and secretory agonist with pleiotropic properties. New studies of rotavirus infection of polarized intestinal epithelial cells show that rotaviruses infect cells differently depending on whether or not they require sialic acid for initial binding, and infection alters epithelial cell functions. NSP4 also affects epithelial cell function and interactions. NSP4 (i) induces an age- and dose-dependent diarrhoeal response in young rodents that is similar to virus-induced disease, (ii) stimulates a Ca(2+)-dependent cell permeability where the secretory response is age-dependent, and (iii) alters epithelial cell integrity. Antibody to NSP4 protects mouse pups from diarrhoea induced by homotypic and heterotypic viruses. These data support a new mechanism of rotavirus-induced diarrhoea whereby a viral enterotoxin triggers a signal transduction pathway that alters epithelial cell permeability and chloride secretion. This new information about how a gastrointestinal virus causes disease demonstrates common pathogenic mechanisms for viral and bacterial pathogens not previously appreciated. These results also suggest new approaches to prevent or treat rotavirus-induced diarrhoea.
轮状病毒肠道感染的结果比最初认为的更为复杂，它受到宿主和病毒因素复杂相互作用的影响。轮状病毒感染肠道肠上皮细胞，感染的早期事件由病毒与上皮细胞的相互作用介导。腹泻可能由多种机制引起，包括：（i）肠上皮细胞破坏继发的吸收不良；（ii）在无明显病理病变或肠上皮细胞损伤的情况下，感染的上皮细胞释放血管活性物质可能诱发的绒毛缺血和肠神经系统激活；（iii）轮状病毒非结构蛋白NSP4的细胞内或细胞外作用刺激肠道分泌，NSP4是一种具有多效性的新型肠毒素和分泌激动剂。对极化肠道上皮细胞轮状病毒感染的新研究表明，轮状病毒根据其初始结合是否需要唾液酸而以不同方式感染细胞，且感染会改变上皮细胞功能。NSP4也会影响上皮细胞功能和相互作用。NSP4（i）在幼鼠中诱导年龄和剂量依赖性的腹泻反应，类似于病毒诱导的疾病；（ii）刺激Ca（2+）依赖性细胞通透性，其中分泌反应具有年龄依赖性；（iii）改变上皮细胞完整性。NSP4抗体可保护幼鼠免受同型和异型病毒诱导的腹泻。这些数据支持一种轮状病毒诱导腹泻的新机制，即病毒肠毒素触发信号转导途径，改变上皮细胞通透性和氯化物分泌。关于一种胃肠道病毒如何致病的这一新信息揭示了病毒和细菌病原体以前未被认识的共同致病机制。这些结果还提示了预防或治疗轮状病毒诱导腹泻的新方法。
