The vital role of T404 phosphorylation of STAT2 in post-viral bacterial pneumonia

STAT2 T404 磷酸化在病毒后细菌性肺炎中的重要作用

基本信息

批准号：
10683783
负责人：
YUXIN WANG
金额：
$ 40.25万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10683783
关键词：
Acute Acute Lung Injury Acute Respiratory Distress Syndrome Agreement Alveolar Macrophages Anti-Bacterial Agents Antibacterial Response Antiviral Response Automobile Driving Bacteria Bacterial Infections Bacterial Pneumonia Binding Biological Assay Bone Marrow Cause of Death Cells Complex Complication Data Digestion Dinucleoside Phosphates Equilibrium Event Future Gene Activation Gene Expression Human Hyperactivity Immune response Impairment In Vitro Infection Inflammation Inflammatory Inflammatory Response Influenza Influenza A virus Innate Immune Response Interferon Type I Interferons Interleukin-17 Interleukin-6 Intracellular translocation Kinetics Knock-in Mouse Ligands Light Lung Mediating Modeling Mus NF-kappa B Outcome Pathogenesis Patients Periodicity Phenotype Phosphorylation Pneumonia Process Production Pseudomonas aeruginosa pneumonia Regulation Reporting Role Sepsis Severities Siblings Signal Transduction Stat2 protein Stimulator of Interferon Genes TNF gene Therapeutic Threonine Viral Viral Respiratory Tract Infection Virus Virus Diseases Wild Type Mouse Work base chemokine cytokine fighting gene function gene translocation in vivo in vivo Model insight lung injury macrophage microbial mimetics mortality novel novel therapeutic intervention p65 pandemic disease pathogenic bacteria pneumonia treatment recruit response therapeutic target

项目摘要

PROJECT SUMMARY Virus-associated bacterial pneumonia is a leading cause of death in pandemics. Since we use different strategies to fight viruses and bacteria, host innate immune responses are confused and impaired when both types of infection occur simultaneously, resulting in higher mortality in post-viral bacterial pneumonia. Determining the key events in the initial viral infection that disturb the subsequent antibacterial responses will guide therapies in treating post-viral bacterial pneumonia. STAT2, as a critical component of IFN-I signaling, is essential for the antiviral response, but elicits detrimental effects in antibacterial response though yet-unknown mechanisms. We discovered a novel T404 phosphorylation of STAT2, stimulated by virus infections, enabling an efficient antiviral response in infected cells. This proposal sheds new light on the role of STAT2 T404 phosphorylation in the pathogenesis of post-viral bacterial pneumonia from three perspectives: (1) the action of IFN: In response to viral infection, IFN-I is produced to limit viral dissemination, but with enigmatic functions in the subsequent bacterial infection, due to suppressing chemokine production, IL-17-dependent immune responses, and recruitment of macrophages. Considering the positive regulation of T404 phosphorylation in IFN-I signaling, STAT2 will compromise the integrity of lung barriers in post-viral bacterial pneumonia; (2) the regulation of inflammation: We reported that the presence of STAT2 augments the production of IL-6 and other NF-kB-dependent inflammatory cytokines in response to LPS. This subset of cytokines drives inflammation-associated lung injury. In agreement with this finding, our preliminary data show that STAT2 T404 phosphorylation-deficient mice are protected from a challenge with LPS, compared with wild-type siblings. (3) STING-mediated antibacterial functions of macrophages: By detecting bacterial-derived cyclic dinucleotides, STING mediates the antibacterial functions of macrophages, including cytokine production, and bacterial digestion. We found that T404 phosphorylation mediates pervasive functions of STAT2 in STING activation, including reshaping STING- mediated gene expression to a pro-inflammatory profile, and inhibiting subsequent outcomes, including bacterial clearance. In summary, we propose that T404 phosphorylation of STAT2 is a key event, induced by virus infection, that enhances IFN-I-dependent signaling, exaggerates inflammatory-associated acute lung injury, and compromises antibacterial functions of macrophages in secondary bacterial pneumonia. This proposal will carry our understanding from structural and mechanistic analyses forward to phenotypic changes in vitro and in vivo. We will also determine the kinetics of T404 phosphorylation of STAT2 in mice with post- influenza P. aeruginosa pneumonia, and validate the findings in macrophages from patients with ARDS- associated pneumonia. Successful completion of this proposal will provide a unique insight into these regulatory processes and guide future therapies, especially modulating T404 phosphorylation and STING function, in treating post-viral bacterial pneumonia.

项目概要病毒相关细菌性肺炎是大流行病中死亡的主要原因。由于我们使用不同的策略为了对抗病毒和细菌，当两种类型的病毒和细菌都存在时，宿主的先天免疫反应就会被混淆和受损。感染同时发生，导致病毒后细菌性肺炎死亡率较高。确定最初病毒感染中干扰随后抗菌反应的关键事件将指导治疗治疗病毒后细菌性肺炎。 STAT2 作为 IFN-I 信号传导的关键组成部分，对于抗病毒反应，但通过尚不清楚的机制引起抗菌反应的有害影响。我们发现了 STAT2 的新型 T404 磷酸化，在病毒感染的刺激下，能够实现有效的抗病毒受感染细胞的反应。该提议为 STAT2 T404 磷酸化在从三个角度探讨病毒后细菌性肺炎的发病机制：（1）IFN的作用：响应病毒感染时，会产生 IFN-I 以限制病毒传播，但在随后的细菌感染中具有神秘的功能感染，由于抑制趋化因子的产生、IL-17依赖性免疫反应以及招募巨噬细胞。考虑到T404磷酸化在IFN-I信号传导中的正向调节，STAT2将损害病毒后细菌性肺炎中肺屏障的完整性； (2)炎症的调节：我们报道 STAT2 的存在增强了 IL-6 和其他 NF-kB 依赖性物质的产生炎症细胞因子对 LPS 的反应。这部分细胞因子会导致炎症相关的肺损伤。与这一发现一致的是，我们的初步数据表明 STAT2 T404 磷酸化缺陷的小鼠与野生型兄弟姐妹相比，它们免受 LPS 的攻击。 (3) STING介导的抗菌作用巨噬细胞的功能：通过检测细菌来源的环状二核苷酸，STING 介导抗菌作用巨噬细胞的功能，包括细胞因子的产生和细菌的消化。我们发现T404 磷酸化介导 STAT2 在 STING 激活中的普遍功能，包括重塑 STING- 介导基因表达促炎症，并抑制后续结果，包括细菌清除。总之，我们认为 STAT2 的 T404 磷酸化是由病毒诱导的关键事件感染，增强 IFN-I 依赖性信号传导，加剧炎症相关的急性肺损伤，并损害继发性细菌性肺炎中巨噬细胞的抗菌功能。这该提案将把我们的理解从结构和机制分析推进到表型变化体外和体内。我们还将确定小鼠体内 STAT2 T404 磷酸化的动力学。流感铜绿假单胞菌肺炎，并验证 ARDS 患者巨噬细胞中的发现相关肺炎。该提案的成功完成将为这些监管提供独特的见解过程并指导未来的治疗，特别是调节 T404 磷酸化和 STING 功能，治疗病毒后细菌性肺炎。