*Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany; †BioDoc, Hannover, Germany; ‡Department of Physiology, University of Veterinary Medicine Hannover, Hannover, Germany; §Institute for Clinical Biochemistry, Hannover Medical School, Hannover, Germany; ‖Medical Clinic 1, Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany; ¶Institute of Pharmacology, Hannover Medical School, Hannover, Germany; **Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany; and ††Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
Inflamm Bowel Dis. 2014 Mar;20(3):431-43. doi: 10.1097/01.MIB.0000441346.86827.ed.
Infection may trigger clinically overt mucosal inflammation in patients with predisposition for inflammatory bowel disease. However, the impact of particular enteropathogenic microorganisms is ill-defined. In this study, the influence of murine norovirus (MNV) infection on clinical, histopathological, and immunological features of mucosal inflammation in the IL10-deficient (Il10) mouse model of inflammatory bowel disease was examined.
C57BL/6J and C3H/HeJBir wild-type and Il10 mice kept under special pathogen-free conditions and devoid of clinical and histopathological signs of mucosal inflammation were monitored after MNV infection for structural and functional intestinal barrier changes by in situ MNV reverse transcription PCR, transgene reporter gene technology, histology, flux measurements, quantitative real-time PCR, immunohistology, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. In addition, the influence of the enteric microbiota was analyzed in MNV-infected germfree Il10 mice.
Although MNV-infected wild-type mice remained asymptomatic, mucosal inflammation was noted in previously healthy Il10 mice 2 to 4 weeks after infection. MNV-induced changes in Il10 mice included increased paracellular permeability indicated by increased mucosal mannitol flux, reduced gene expression of tight junction molecules, and an enhanced rate of epithelial apoptosis. MNV-induced reduction of tight junction protein expression and inflammatory lesions were absent in germfree Il10 mice, whereas epithelial apoptosis was still observed.
Despite its subclinical course in wild-type animals, MNV causes epithelial barrier disruption in Il10 animals representing a potent colitogenic stimulus that largely depends on the presence of the enteric microbiota. MNV might thus trigger overt clinical disease in individuals with a nonsymptomatic predisposition for inflammatory bowel disease by impairment of the intestinal mucosa.
感染可能会引发具有炎症性肠病易感性的患者出现临床明显的黏膜炎症。然而，特定肠致病性微生物的影响仍不清楚。在这项研究中，研究了鼠诺如病毒（MNV）感染对炎症性肠病 IL10 缺陷（Il10）小鼠模型中黏膜炎症的临床、组织病理学和免疫学特征的影响。
在无病原体条件下饲养的 C57BL/6J 和 C3H/HeJBir 野生型和 Il10 小鼠，在没有黏膜炎症的临床和组织病理学迹象的情况下，通过原位 MNV 逆转录 PCR、转基因报告基因技术、组织学、通量测量、定量实时 PCR、免疫组织化学和末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记分析，监测 MNV 感染后结构和功能肠屏障变化。此外，还分析了 MNV 感染无菌 Il10 小鼠时肠内微生物群的影响。
尽管感染 MNV 的野生型小鼠无症状，但在感染后 2 至 4 周，先前健康的 Il10 小鼠出现了黏膜炎症。MNV 诱导 Il10 小鼠发生的变化包括增加了黏膜甘露糖醇通量，表明细胞旁通透性增加，紧密连接分子的基因表达减少，以及上皮细胞凋亡率增加。在无菌 Il10 小鼠中，MNV 诱导的紧密连接蛋白表达减少和炎症病变不存在，而上皮细胞凋亡仍然存在。
尽管在野生型动物中其病程呈亚临床，但 MNV 会导致 Il10 动物的上皮屏障破坏，这是一种潜在的结肠炎刺激因素，在很大程度上依赖于肠内微生物群的存在。因此，MNV 可能通过损害肠道黏膜，引发具有炎症性肠病亚临床易感性的个体出现明显的临床疾病。
