Patil Ketki, Ayyar B Vijayalakshmi, Hayes Nicole M, Neill Frederick H, Bode Lars, Estes Mary K, Atmar Robert L, Ramani Sasirekha
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
Department of Pediatrics, Larsson-Rosenquist Foundation Mother-Milk-Infant Center of Research Excellence (MOMI CORE), and the Human Milk Institute (HMI), University of California San Diego, La Jolla, California, USA.
J Virol. 2025 Feb 25;99(2):e0093824. doi: 10.1128/jvi.00938-24. Epub 2025 Jan 10.
Human noroviruses (HuNoVs) are the leading cause of acute gastroenteritis worldwide. Currently, there are no targeted antivirals for the treatment of HuNoV infection. Histo-blood group antigens (HBGAs) on the intestinal epithelium are cellular attachment factors for HuNoVs; molecules that block the binding of HuNoVs to HBGAs thus have the potential to be developed as antivirals. Human milk oligosaccharides (HMOs) are glycans in human milk with structures analogous to HBGAs. HMOs have been shown to act as decoy receptors to prevent the attachment of multiple enteric pathogens to host cells. Previous X-ray crystallography studies have demonstrated the binding of HMO 2'-fucosyllactose (2'FL) in the same pocket as HBGAs for some HuNoV strains. We evaluated the effect of 2'FL on the replication of a globally dominant GII.4 Sydney [P16] HuNoV strain using human intestinal enteroids (HIEs) from adults and children. A significant reduction in GII.4 Sydney [P16] replication was seen in duodenal and jejunal HIEs from multiple adult donors, all segments of the small intestine from an adult organ donor, and in two pediatric duodenal HIEs. However, 2'FL did not inhibit HuNoV replication in two infant jejunal HIEs that had significantly lower expression of α1-2-fucosylated glycans. 2'FL can be synthesized in large scale, and safety and tolerance have been assessed previously. Our data suggest that 2'FL has the potential to be developed as a therapeutic for HuNoV gastroenteritis.
Human noroviruses infect the gastrointestinal tract and are a leading cause of acute gastroenteritis worldwide. Common symptoms of norovirus include diarrhea, vomiting, and stomach cramps. Virus shedding and symptoms are prolonged and debilitating in immunocompromised patients. Currently, there are no approved vaccines or targeted antivirals for treating human norovirus infection. Human intestinal enteroids derived from intestinal stem cells allow the successful replication of norovirus in the laboratory and can be used as a physiologically relevant model system to evaluate antivirals. We discovered that 2'-fucosyllactose (2'FL), an oligosaccharide naturally occurring in human milk, inhibits GII.4 norovirus replication in HIEs from multiple donors and thus has the potential to be developed as a therapeutic for human norovirus. These findings have high translational potential since 2'FL from several manufacturers has a "generally recognized as safe" status and can be synthesized on a large scale for immediate application.
人诺如病毒（HuNoVs）是全球急性胃肠炎的主要病因。目前，尚无针对HuNoV感染的靶向抗病毒药物。肠道上皮细胞上的组织血型抗原（HBGAs）是HuNoVs的细胞附着因子；因此，能够阻断HuNoVs与HBGAs结合的分子有潜力被开发为抗病毒药物。人乳寡糖（HMOs）是母乳中的聚糖，其结构与HBGAs类似。HMOs已被证明可作为诱饵受体，防止多种肠道病原体附着于宿主细胞。先前的X射线晶体学研究表明，对于某些HuNoV毒株，HMO 2'-岩藻糖基乳糖（2'FL）与HBGAs结合于同一口袋。我们使用来自成人和儿童的人肠道类器官（HIEs）评估了2'FL对全球流行的GII.4悉尼[P16]HuNoV毒株复制的影响。在来自多个成人供体的十二指肠和空肠HIEs、一名成人器官供体的小肠所有节段以及两个儿科十二指肠HIEs中，均观察到GII.4悉尼[P16]复制显著减少。然而，2'FL并未抑制两个α1-2-岩藻糖基化聚糖表达显著较低的婴儿空肠HIEs中的HuNoV复制。2'FL可以大规模合成，并且之前已经评估了其安全性和耐受性。我们的数据表明，2'FL有潜力被开发为治疗HuNoV胃肠炎的药物。
人诺如病毒感染胃肠道，是全球急性胃肠炎的主要病因。诺如病毒的常见症状包括腹泻、呕吐和胃痉挛。在免疫功能低下的患者中，病毒排出和症状会持续较长时间且使人虚弱。目前，尚无批准的疫苗或靶向抗病毒药物用于治疗人诺如病毒感染。源自肠道干细胞的人肠道类器官能够使诺如病毒在实验室中成功复制，并且可作为评估抗病毒药物的生理相关模型系统。我们发现，2'-岩藻糖基乳糖（2'FL），一种天然存在于母乳中的寡糖，可抑制来自多个供体的HIEs中GII.4诺如病毒的复制，因此有潜力被开发为治疗人诺如病毒的药物。这些发现具有很高的转化潜力，因为来自几家制造商的2'FL具有“一般认为安全”的地位，并且可以大规模合成以便立即应用。
