Rotavirus (RV) accounts for 19.11% of global diarrheal deaths. Though GAVI assisted vaccine introduction has curtailed RV induced mortality, factors like RV strain diversity, differential infantile gut microbiome, malnutrition, interference from maternal antibodies and other administered vaccines, etc. often compromise vaccine efficacy. Herein emerges the need of antivirals which can be administered adjunct to vaccination to curb the socio-economic burden stemming from frequent RV infection. Cognisance of pathogen-perturbed host cellular physiology has revolutionized translational research and aided precision-based therapy, particularly for viruses, with no metabolic machinery of their own. To date there has been limited exploration of the host cellular metabolome in context of RV infection. In this study, we explored the endometabolomic landscape of human intestinal epithelial cells (HT-29) on RV-SA11 infection. Significant alteration of host cellular metabolic pathways like the nucleotide biosynthesis pathway, alanine, aspartate and glutamate metabolism pathway, the host citric acid cycle was observed in RV-SA11 infection scenario. Detailed study further revealed that RV replication is exclusively dependent on glutamine metabolism for their propagation in host cells. Glutamine metabolism generates glutamate, aspartate, and asparagine which facilitates virus infection. Abrogation of aspartate biogenesis from glutamine by use of Aminooxyacetic acid (AOAA), significantly curbed RV-SA11 infection in-vitro and in-vivo. Overall, the study improves our understanding of host-rotavirus interactome and recognizes host glutamine metabolism pathway as a suitable target for effective therapeutic intervention against RV infection.

中文翻译：

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轮状病毒将宿主细胞代谢途径重新连接到谷氨酰胺分解代谢，以实现有效的病毒感染。


轮状病毒 （RV） 占全球腹泻死亡人数的 19.11%。尽管 GAVI 辅助疫苗的引入降低了 RV 诱导的死亡率，但 RV 菌株多样性、婴儿肠道微生物组差异、营养不良、母体抗体和其他接种疫苗的干扰等因素通常会损害疫苗的疗效。因此，需要抗病毒药物，这些药物可以作为疫苗接种的辅助药物，以遏制因频繁的 RV 感染而产生的社会经济负担。对病原体扰乱的宿主细胞生理学的认识彻底改变了转化研究，并有助于基于精准的治疗，特别是对于没有自身代谢机制的病毒。迄今为止，在 RV 感染的情况下对宿主细胞代谢组的探索有限。在这项研究中，我们探讨了 RV-SA11 感染后人肠上皮细胞 （HT-29） 的内代谢组学景观。在 RV-SA11 感染情况下观察到宿主细胞代谢途径（如核苷酸生物合成途径、丙氨酸、天冬氨酸和谷氨酸代谢途径）的显着改变，宿主柠檬酸循环。详细的研究进一步揭示了 RV 复制完全依赖于谷氨酰胺代谢在宿主细胞中的繁殖。谷氨酰胺代谢产生谷氨酸、天冬氨酸和天冬酰胺，从而促进病毒感染。通过使用氨基氧乙酸 （AOAA） 消除谷氨酰胺中的天冬氨酸生物发生，在体外和体内显着抑制了 RV-SA11 感染。总体而言，该研究提高了我们对宿主-轮状病毒相互作用组的理解，并认识到宿主谷氨酰胺代谢途径是针对 RV 感染的有效治疗干预的合适靶点。