Megakaryocyte regulation by the gut microbiome

肠道微生物组对巨核细胞的调节

• 批准号: 10720081
• 负责人: Melody Y Zeng
• 金额: $ 67.8万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720081
• 关键词: 2019-nCoV; ACE2; Antibiotics; Autoimmune Diseases; Bacteria; Biological Markers; Blood Platelets; Blood coagulation; Blood flow; Bone Marrow; Bone Marrow Cells; COVID-19 pandemic; COVID-19 patient; Cancer Patient; Coagulation Process; Data; Diet; Disease; Fermentation; Fiber; Germ-Free; Goals; Hamsters; Heterogeneity; Histone Deacetylase; Homeostasis; Human; Impairment; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Knowledge; Life; Ligands; Link; Long COVID; Lung; Mediating; Megakaryocytes; Megakaryocytopoieses; Microscopic; Middle East Respiratory Syndrome; Morbidity - disease rate; Mus; Oxygen; Pathway interactions; Patients; Pectins; Predisposition; Probiotics; Regulation; Reporting; Rheumatoid Arthritis; Risk Reduction; Role; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Shapes; Signal Transduction; Systemic Lupus Erythematosus; Testing; Thrombosis; Tissues; Viral Load result; Virus Diseases; Volatile Fatty Acids; Work; commensal bacteria; gut bacteria; gut microbiome; gut microbiota; influenza infection; interest; microbial; mortality; mouse model; neutrophil; novel; progenitor; receptor; response; risk prediction; severe COVID-19; single-cell RNA sequencing; therapeutic development; transcriptomics; transmission process

Abnormal and potentially life-threatening blood clotting is seen in other severe infections, such as SARS- CoV-2, MERS, and H1N1 influenza. Platelets are produced by megakaryocytes. Enhanced megakaryopoiesis is found in severe COVID-19. Increased megakaryopoiesis is commonly found in autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus (SLE). Hypercoagulation also accounts for a significant percentage of mortality and morbidity in cancer patients. However, the regulation of megakaryocyte differentiation and function, however, remains poorly understood. The gut microbiome shapes tissue homeostasis beyond the gut through release of metabolites or microbial ligands. The link between the gut microbiome and megakaryocyte function is poorly understood. Our preliminary data demonstrate that fiber-fermenting gut bacteria that generate short-chain fatty acids (SCFAs) downregulate the ACE2 receptor, the entry receptor for SARS-CoV-2 infection and transmission; SCFA treatment led to reduced viral burdens in both mice and hamsters following infection with SARS-CoV-2 or a pseudovirus expressing the spike protein of SARS-CoV-2. In addition, our work uncovered a potentially novel function of SCFAs in limiting the coagulation response via the Sh2b3-Mpl axis to modulate megakaryopoiesis and platelet turnover. This proposal aims to define the role of the gut microbiome in the regulation of megakaryocyte maturation and function at steady state and in viral infection. This goal will be accomplished with the following 3 Specific Aims: 1. Define the role of the gut bacteria in steady-state maturation and function of megakaryocytes; 2. Interrogate the role of the gut microbiome in megakaryocyte maturation and function in viral infection; 3. Define the role of SCFAs in megakaryocyte maturation and function in homeostasis and viral infection. We will decipher the SCFA-Sh2b3-Mpl axis in the regulation of megakaryopoiesis and platelet turnover at steady state in viral infection, and explore the benefit of using SCFA-producing gut bacteria or pectin fiber to control megakaryocyte response in viral infection. This work will uncover a link between the gut microbiome and megakaryocyte response at steady state and in viral infection. Our findings will potentially identify specific gut commensal bacteria or metabolites that, either directly or indirectly, modulate the maturation of megakaryocytes and function; this knowledge can be leveraged in the development of therapeutics to treat uncontrolled megakaryopoiesis in various disease settings. These bacteria and metabolites of interest, including SCFAs as our data supported, could be additionally used as biomarkers to predict the risk of excessive megakaryopoiesis.

在其他严重的感染中，如SARS，也会出现异常的和可能危及生命的凝血。 CoV-2、MERS和H1N1流感。血小板由巨核细胞产生。增强 在严重的COVID-19中发现了巨核细胞生成。增加的巨核细胞生成常见于 自身免疫性疾病，包括类风湿性关节炎、系统性红斑狼疮（SLE）。 高凝状态也占癌症患者死亡率和发病率的显著百分比。 然而，巨核细胞分化和功能的调节仍然很差 明白肠道微生物组通过释放微生物来塑造肠道以外的组织稳态。 代谢物或微生物配体。肠道微生物组和巨核细胞功能之间的联系是 不太了解。我们的初步数据表明，纤维发酵肠道细菌，产生 短链脂肪酸（SCFAs）下调ACE 2受体，SARS-CoV-2的进入受体 感染和传播; SCFA治疗导致小鼠和仓鼠的病毒负荷降低 在用SARS-CoV-2或表达SARS-CoV-2刺突蛋白的假病毒感染后。在 此外，我们的工作揭示了SCFAs在限制凝血反应方面的潜在新功能 通过Sh 2b 3-Mpl轴调节巨核细胞生成和血小板周转。该提案旨在定义 肠道微生物组在稳态巨核细胞成熟和功能调节中的作用 和病毒感染。这一目标将通过以下三个具体目标来实现：1。定义角色 肠道菌群的稳态成熟和巨核细胞的功能; 2.质疑…的作用 巨核细胞成熟中的肠道微生物组和病毒感染中的功能; 3.定义的作用 SCFAs在巨核细胞成熟中的作用以及在体内平衡和病毒感染中的作用。我们将破译 SCFA-Sh 2b 3-Mpl轴在巨核细胞生成和稳态血小板周转调节中的作用 病毒感染，并探索使用SCFA生产肠道细菌或果胶纤维来控制 巨核细胞在病毒感染中的反应。 这项工作将揭示肠道微生物组与稳态巨核细胞反应之间的联系 和病毒感染。我们的研究结果将有可能确定特定的肠道细菌或代谢物 直接或间接调节巨核细胞的成熟和功能;这种知识 可用于开发治疗各种不受控制的巨核细胞生成的疗法， 疾病设置。这些感兴趣的细菌和代谢物，包括我们的数据支持的SCFA， 还可以用作生物标志物来预测过度巨核细胞生成的风险。