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Principal Investigator: Haichao Wang
Organization: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
Fiscal Year: 2024
Award: $418,750
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
Microbial infections annually claim hundreds of thousands of victims in the U.S. alone, but its complex
pathogenesis is still poorly understood. Our seminal discovery of HMGB1 as a late mediator of lethal
endotoxemia (Science, 1999, Cited >4,000 times) has fueled continuous search for other late mediators of
lethal infections. With the long-standing R01 grant support from NIGMS (R01GM063075 for 15 years) and
NCCIH (R01AT005076 for > 10 years), we identified another late mediator of sepsis, Sequestosome-1
(SQSTM1) (Nat Microbiol, 2020). Meanwhile, we recently generated exciting preliminary data that
microbial toxins (e.g., the SARS-CoV-2 spike protein ACE2 receptor binding motif, RBM) and several host
secretory proteins [e.g., serum amyloid A (SAA), procathepsin-L (pCTS-L) and dermcidin (DCD)] divergently
affect the release of HMGB1 and SQSTM1 by innate immune cells. In line with the inspiring spirit of the MIRA
funding scheme, we wish to tackle bigger questions frequently considered as “higher-risk” or “ambitious” by
proposing a bold hypothesis that microbial toxins and host proteins induce the release of HMGB1 and SQSTM1
to trigger dysregulated pyroptosis, immunosuppression and coagulopathy. This hypothesis is built upon our
recent realization that extracellular HMGB1 causes macrophage pyroptosis and immunosuppression when
passively released in high levels (Sci Transl Med, 2020). Accordingly, we seek to address three key
challenges related to this hypothesis. The first involves the characterization of the dynamic changes of pCTS-
L, HMGB1 and SQSTM1 in parallel with other biomarkers in clinical sepsis using semi-quantitative
immunoassays or high-throughput Cytokine Antibody Arrays. The second involves understanding the
mechanisms by which microbial toxins (e.g., LPS and RBM) and host secretory proteins (e.g., SAA, pCTS-L and
DCD) divergently affect the release of HMGB1 and SQSTM1 by examining their effects on the expression of
macrophage hemichannels and secretory phospholipase A2s (sPLA2s), the activation of inflammasome and
pyroptosis, or immuno-metabolism. In the third project, we propose to evaluate the therapeutic efficacy and
protective mechanisms of DCD as well as cocktail of monoclonal antibodies against HMGB1, pCTS-L and
SQSTM1 in animal models of lethal endotoxemia, bacteremia, viral toxemia and sepsis. Elucidating the
mechanisms underlying the regulation of several late-acting mediators and development of novel cocktail
therapies requires a long-term commitment and associated flexibility to explore different research directions.
If successful, it will significantly improve our understanding of the intricate mechanisms underlying the
dysregulated innate immune responses to lethal infections, and shed light on the future development of novel
therapeutic strategies for the clinical management of human sepsis and other infectious diseases.
Terms: <(TNF)-α><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><Address><Affect><Amphoterin><Amphoterin Gene><Amyloid A Precursor><Amyloid A Protein-Related Serum Component><Amyloid Protein AA Precursor><Amyloid Protein SAA><Amyloid Serum Protein SAA><Amyloid-Related Serum Protein (SAA)><Animal Model><Animal Models and Related Studies><Antibodies><Bacteremia><Biological Markers><Blood Coagulation Disorders><COVID-19 S protein><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><Cachectin><Cell Body><Cells><Chromosomal Protein, Nonhistone, HMG1><Chromosomal Protein, Nonhistone, HMG1 Gene><Clinical><Clinical Management><Clinical Treatment Moab><Coagulation Disorder><Coagulopathy><Communicable Diseases><Complex><Data><Development><Endotoxemia><FM1 Gene Product><Funding><Future><Grant><HMG-1><HMG-1 Gene><HMG-1 Protein><HMG1><HMG1 Gene><HMG3><HMG3 Gene><HMGB1><HMGB1 Protein><HMGB1 gene><Heparin-Binding Protein p30><High Mobility Group Box Protein 1><High Mobility Group Protein 1><High Mobility Group Protein 1 Gene><High-Mobility Group (Nonhistone Chromosomal) Protein 1><High-Mobility Group (Nonhistone Chromosomal) Protein 1 Gene><High-Mobility Group Box 1><High-Mobility Group Box 1 Gene><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune><Immune Interferon><Immunes><Immunoassay><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammasome><Innate Immune Response><Interferon Gamma><Interferon Type II><Lecithinases><Macrophage><Macrophage-Derived TNF><Mediator><Modern Man><Monoclonal Antibodies><Monocyte-Derived TNF><Mφ><NCCAM><NCCIH><NIGMS><National Center for Complementary and Integrative Health><National Center for Complementary and Integrative Medicine><National Institute of General Medical Sciences><Nonhistone Chromosomal Protein HGM1><Nonhistone Chromosomal Protein HGM1 Gene><Pathogenesis><Phospholipase><Proteins><Regulation><Research><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SBP-1><SBP-1 Gene><Scheme><Science><Seminal><Sepsis><Septic Toxemia><Serum A Related Protein><Serum Amyloid A><Serum amyloid A protein><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Sulfoglucuronyl Carbohydrate Binding Protein><Sulfoglucuronyl Carbohydrate Binding Protein Gene><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Toxemia><Toxin><Treatment Efficacy><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Viral><angiotensin converting enzyme 2><angiotensin converting enzyme II><bacteraemia><bacterial sepsis><bio-markers><biologic marker><biomarker><bleeding disorder><blood infection><bloodstream infection><clotting disorder><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><cytokine><dermcidin><developmental><extracellular><flexibility><flexible><high risk><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><intervention efficacy><lFN-Gamma><mAbs><microbial><model of animal><monoclonal Abs><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><receptor binding><receptor bound><secretory protein><spike proteins on SARS-CoV-2><systemic inflammation><systemic inflammatory response><therapeutic efficacy><therapy efficacy><treatment strategy>