Role reversal of MAVS in bacterial sepsis

MAVS 在细菌性脓毒症中的作用逆转

• 批准号: 9759979
• 负责人: Markus Bosmann
• 金额: $ 48.24万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759979
• 关键词: Address; Antibodies; Antiviral Agents; Bacteria; Bacterial Infections; Bacterial RNA; Blood Coagulation Disorders; Blood coagulation; CRISPR/Cas technology; Cells; Cessation of life; Clinical Trials; Coagulation Process; Complication; Consensus; Critical Care; Cytosol; Data; Development; Disease; Engineering; Equilibrium; Event; Extravasation; FDA approved; Failure; Family; Functional disorder; Future; Gene Deletion; Gene Expression; Genes; Histones; Human; Immune; Immune response; Immunosuppression; Infection; Injury; Interleukin-12; Interleukin-6; Knockout Mice; Life; Microbe; Mitochondria; Molecular; Molecular Target; Morbidity - disease rate; Mouse Protein; Mus; Organ; Outcome; Outer Mitochondrial Membrane; Pathway interactions; Pattern; Phagocytes; Pharmacologic Substance; Pharmacology; Phosphorylation; Proteome; RNA; RNA Helicase; Research; Resistance; Role; Sepsis; Shapes; Signal Pathway; Signal Transduction; Signaling Protein; TBK1 gene; TRAF2 gene; Testing; Therapeutic Intervention; Tissues; United States; Virus; Virus Diseases; base; cytokine; cytotoxic; effective therapy; experimental study; extracellular; fungus; immunopathology; injured; innovation; insight; interest; macrophage; microbial; monocyte; mortality; mouse model; neutrophil; novel; novel therapeutic intervention; pathogen; pathogenic microbe; polymerization; polymicrobial sepsis; programs; protein activation; protein degradation; sensor; septic; spatiotemporal; transcription factor; transcriptome; transcriptome sequencing; translational study

Sepsis is a frequent and life-threatening complication of microbial infections. It is estimated that more than 750,000 annual cases of sepsis occur in the United States and mortality rates remain around 20-50% despite recent advances of critical care support. In the current absence of FDA-approved pharmacologic compounds, there remains an urgent need for a complete characterization of the underlying cellular and molecular mechanisms of sepsis. The dysregulated host response is a prominent feature during the pathophysiology of bacterial sepsis, but the delicate balance of its integrating molecular pathways appear not entirely clear. Mitochondrial antiviral-signaling protein (MAVS) is an adaptor molecule in the outer mitochondrial membrane and is highly expressed in professional phagocytes. MAVS is activated by the cytoplasmic RNA helicases, RIG- I and MDA5, and confers protection against viral infections. Surprisingly, our preliminary findings suggest deletion of MAVS or RIG-I/MDA5 in mice confers immense resistance to mortality and modulates phagocyte transcriptomes, immunoproteasomes, extracellular traps, IL-6/IL-12 cytokines and blood coagulation during polymicrobial bacterial sepsis. Bacterial RNAs are a viability-associated pathogen patterns (`vita-PAMPs') sensed by the MAVS pathway in macrophages. Together, these findings suggest a detrimental role reversal of MAVS during bacterial sepsis as opposed to protective MAVS pathway functions during infections with viruses. To test our central hypothesis that MAVS signaling provides a lethal switch for obstructing favorable sepsis outcomes, we will pursue 3 specific aims: (1) We will study the gene expression, activation mechanisms, signaling events and functional roles of MAVS in professional phagocytes (macrophages, neutrophils) during polymicrobial bacterial sepsis. For these studies, mice with total or conditional gene deletion of MAVS, or the RIG-I/MDA5 sensors are available. MAVS-deficient human macrophages will be generated using CRISPR-Cas9. (2) We will determine how MAVS-induced transcription factors promote gene expression of immunoproteasome subunits, what the pleiotropic functions of the immunoproteasome are during bacterial sepsis, and how the immunoproteasome shapes the proteomes and transcriptomes of macrophages. These studies will include using triple-knockout mice for all three regulatory immunoproteasome subunits (PSMB8/9/10). (3) We will study how the MAVS pathway amplifies the harmful molecular sequelae of bacterial sepsis focusing on phagocyte extracellular traps (NETs/METs), IL-6/IL-12 cytokines, septic coagulopathy and immunosuppression; which all contribute to tissue injury, organ dysfunction and sepsis lethality. In particular, we will consider a novel role of the immunoproteasome in subcellular protein degradation for facilitating extracellular trap formation. In summary, elucidating the previously unsuspected involvement of the MAVS pathway during bacterial infection will provide novel and important information and may add critical insights for guiding future efforts to develop effective therapies for sepsis.

脓毒症是一种常见的危及生命的微生物感染并发症。据估计，超过