Thursday, April 3, 2025
4/3/2025
Mechanisms of Dysregulated Innate Immune Responses to Lethal Infections - 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).