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Principal Investigator: Melody Y Zeng
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2023
Award: $678,002
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Atrophic Arthritis><Autoimmune Diseases><Autoregulation><Bacteria><Biological Markers><Blood Clotting><Blood Neutrophil><Blood Platelets><Blood Polymorphonuclear Neutrophil><Blood coagulation><Blood flow><Blood megakaryocyte><Body Tissues><Bone Marrow><Bone Marrow Blood-Deriving Cell><Bone Marrow Blood-Forming Cell><Bone Marrow Cells><Bone Marrow Reticuloendothelial System><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19 S protein><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID-19 virus infection><COVID19 S protein><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><Cancer Patient><Cell Communication and Signaling><Cell Signaling><Clotting><CoV-2><CoV2><Coagulation><Coagulation Process><Cricetinae><Data><Diet><Disease><Disorder><Fermentation><Fiber><GI microbiome><GI microbiota><Gastrointestinal microbiota><Germ-Free><Goals><Grippe><H1N1><H1N1 Virus><HDAC><HDAC Proteins><Hamsters><Hamsters Mammals><Heterogeneity><Histone Deacetylase><Homeostasis><Human><Impairment><Infection><Influenza><Influenza A Virus, H1N1 Subtype><Intracellular Communication and Signaling><Knowledge><Life><Ligands><Link><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Lung><Lung Respiratory System><Lupus Erythematosus Disseminatus><MERS><MERS coronavirus disease><MERS-CoV disease><Marrow Neutrophil><Marrow platelet><Mediating><Megakaryocytes><Megakaryocytopoieses><Megakaryopoiesis><Megalokaryocyte><Mice><Mice Mammals><Microscopic><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome coronavirus disease><Miscellaneous Antibiotic><Modern Man><Morbidity><Morbidity - disease rate><Murine><Mus><Neutrophilic Granulocyte><Neutrophilic Leukocyte><O element><O2 element><Oxygen><Pathway interactions><Patients><Pectins><Physiological Homeostasis><Platelets><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Predicting Risk><Predisposition><Probiotics><Receptor Protein><Regulation><Reporting><Rheumatoid 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