Megakaryocyte regulation by the gut microbiome

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.