Mechanisms of Dysregulated Innate Immune Responses to Lethal Infections

对致命感染的先天免疫反应失调的机制

• 批准号: 10404732
• 负责人: Haichao Wang
• 金额: $ 41.88万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404732
• 关键词: ACE2; Address; Affect; Animal Model; Antibodies; Bacteremia; Biological Markers; Blood Coagulation Disorders; Cells; Clinical; Clinical Management; Communicable Diseases; Complex; Data; Development; Endotoxemia; Funding; Future; Grant; HMGB1 Protein; Human; Immune; Immunoassay; Immunosuppression; Infection; Inflammasome; Innate Immune Response; Interferon Type II; Light; Mediator of activation protein; Metabolism; Monoclonal Antibodies; National Center for Complementary and Integrative Health; National Institute of General Medical Sciences; Pathogenesis; Phospholipase; Proteins; Regulation; Research; SARS-CoV-2 spike protein; Scheme; Science; Seminal; Sepsis; Septic Toxemia; Serum amyloid A protein; TNF gene; Time; Toxin; Treatment Efficacy; Viral; cytokine; dermcidin; extracellular; flexibility; high risk; improved; macrophage; microbial; novel; novel therapeutic intervention; receptor binding; secretory protein; systemic inflammatory response; treatment strategy

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.

项目概要 仅在美国，微生物感染每年就会造成数十万受害者，但其复杂性 我们对 HMGB1 作为致命性晚期介质的开创性发现仍知之甚少。 内毒素血症（Science，1999，被引用 >4,000 次）推动了对内毒素血症其他晚期介质的不断研究 凭借 NIGMS 的长期 R01 拨款支持（R01GM063075 15 年）和 NCCIH（R01AT005076 超过 10 年），我们发现了脓毒症的另一种晚期介质 Sequestosome-1 (SQSTM1)（Nat Microbiol，2020）同时，我们最近生成了令人兴奋的初步数据： 微生物毒素（例如 SARS-CoV-2 刺突蛋白 ACE2 受体结合基序，RBM）和多种宿主 分泌蛋白 [例如血清淀粉样蛋白 A (SAA)、组织蛋白酶原-L (pCTS-L) 和 dermcidin (DCD)] 不同 影响先天免疫细胞释放 HMGB1 和 SQSTM1 符合 MIRA 的鼓舞人心的精神。 资助计划，我们希望解决经常被认为是“高风险”或“雄心勃勃”的更大问题 提出一个大胆的假设，即微生物毒素和宿主蛋白诱导 HMGB1 和 SQSTM1 的释放 引发失调的焦亡、免疫抑制和凝血病这一假设是建立在我们的基础上的。 最近发现细胞外 HMGB1 会导致巨噬细胞焦亡和免疫抑制 高水平被动释放（Sci Transl Med，2020）因此，我们寻求解决三个关键问题。 与该假设相关的挑战第一个涉及 pCTS- 动态变化的表征。 L、HMGB1 和 SQSTM1 与临床脓毒症中的其他生物标志物平行使用半定量 第二个涉及了解免疫测定或高通量细胞因子抗体阵列。 微生物毒素（例如 LPS 和 RBM）和宿主分泌蛋白（例如 SAA、pCTS-L 和 DCD）通过检查它们对 HMGB1 和 SQSTM1 表达的影响来不同地影响 HMGB1 和 SQSTM1 的释放 巨噬细胞半通道和分泌性磷脂酶 A2s (sPLA2s)、炎症小体的激活和 在第三个项目中，我们建议评估治疗效果和免疫代谢。 DCD 以及针对 HMGB1、pCTS-L 和的单克隆抗体混合物的保护机制 SQSTM1 在致死性内毒素血症、菌血症、病毒毒血症和脓毒症动物模型中的作用。 几种晚效介质的调节机制和新型鸡尾酒的开发 治疗需要长期的承诺和相关的灵活性来探索不同的研究方向。 如果成功，它将显着提高我们对潜在复杂机制的理解 对致命感染的先天免疫反应失调，并揭示了新型药物的未来发展 人类脓毒症和其他传染病临床管理的治疗策略。