Table_5_Comparative Metabolomics and Proteomics Reveal Vibrio parahaemolyticus Targets Hypoxia-Related Signaling Pathways of Takifugu obscurus.xls

Coronavirus disease 2019 (COVID-19) raises the issue of how hypoxia destroys normal physiological function and host immunity against pathogens. However, there are few or no comprehensive omics studies on this effect. From an evolutionary perspective, animals living in complex and changeable marine environments might develop signaling pathways to address bacterial threats under hypoxia. In this study, the ancient genomic model animal Takifugu obscurus and widespread Vibrio parahaemolyticus were utilized to study the effect. T. obscurus was challenged by V. parahaemolyticus or (and) exposed to hypoxia. The effects of hypoxia and infection were identified, and a theoretical model of the host critical signaling pathway in response to hypoxia and infection was defined by methods of comparative metabolomics and proteomics on the entire liver. The changing trends of some differential metabolites and proteins under hypoxia, infection or double stressors were consistent. The model includes transforming growth factor-β1 (TGF-β1), hypoxia-inducible factor-1α (HIF-1α), and epidermal growth factor (EGF) signaling pathways, and the consistent changing trends indicated that the host liver tended toward cell proliferation. Hypoxia and infection caused tissue damage and fibrosis in the portal area of the liver, which may be related to TGF-β1 signal transduction. We propose that LRG (leucine-rich alpha-2-glycoprotein) is widely involved in the transition of the TGF-β1/Smad signaling pathway in response to hypoxia and pathogenic infection in vertebrates as a conserved molecule.

2019冠状病毒病（COVID-19）提出了低氧如何破坏机体正常生理功能以及宿主抗病原体免疫能力这一科学问题。然而，目前针对该效应的全面组学研究仍寥寥无几，甚至尚未有相关报道。从进化视角来看，栖息于复杂多变海洋环境中的动物，或许演化出了应对低氧条件下细菌威胁的信号通路。本研究选取古老的基因组模式动物暗纹东方鲀（Takifugu obscurus）以及广泛分布的副溶血性弧菌（Vibrio parahaemolyticus），针对该效应展开研究。研究人员对暗纹东方鲀分别进行副溶血性弧菌攻毒、低氧暴露以及二者联合胁迫处理。通过对全肝组织进行比较代谢组学与蛋白质组学分析，本研究明确了低氧与感染各自的生物学效应，并构建了宿主应对低氧与感染的关键信号通路理论模型。部分差异代谢物与蛋白质在低氧、感染或联合胁迫下的变化趋势保持一致。该模型涵盖转化生长因子-β1（transforming growth factor-β1, TGF-β1）、缺氧诱导因子-1α（hypoxia-inducible factor-1α, HIF-1α）以及表皮生长因子（epidermal growth factor, EGF）信号通路，上述一致的变化趋势表明宿主肝脏呈现细胞增殖倾向。低氧与感染可导致肝脏门管区出现组织损伤与纤维化，该现象可能与TGF-β1信号转导通路相关。本研究提出，富含亮氨酸α2糖蛋白（leucine-rich alpha-2-glycoprotein, LRG）作为一类保守分子，广泛参与脊椎动物体内TGF-β1/Smad信号通路响应低氧与病原体感染的调控过程。