Oxidative Burst in Influenza and MRSA Co-infection

项目总结 甲氧西林耐药金黄色葡萄球菌(MRSA)感染合并流感成为主要死亡原因 在最近的流感大流行和流行病期间。细菌控制缺陷和肺的夸大 炎症被认为是患者和动物高死亡率的原因。然而，到目前为止，一个 对混合感染的病理生理学认识不全面，阻碍了有效感染的发展。 治疗。 NADPH氧化酶2(NOX2)是一种主要由吞噬细胞表达的酶复合体。新一代人 肺部金黄色葡萄球菌需要通过NOX2产生活性氧种(ROS)，这一过程称为氧化爆发。 通行证。在最初的资助期间，Pi的实验室的工作已经确定细胞内ROS 在流感感染的恢复期吞噬细胞减少，从而导致对S。 金星。然而，尽管每个细胞的细胞内ROS减少，但有过多的炎症细胞 在混合感染期间释放氧化剂。这一事件最终会导致致命的氧化性肺损伤。 此外，Pi实验室的初步研究表明，I型干扰素(IFN-I)信号转导有助于单核细胞 而干扰素-γ信号则促进肺部炎症和 流感和金黄色葡萄球菌混合感染后致命的肺损伤。因此，假设流感- 诱导的干扰素反应破坏了氧化猝发相关的抗菌免疫和 炎症，不仅导致金黄色葡萄球菌继发感染，而且导致致命性肺损伤 之后。 检验这一假设的方法包括：1)确定流感诱导的干扰素-I是否会损害 通过促进单核细胞募集而产生抗菌免疫。具体地说，细胞和信号机制 对于干扰素-I抑制的细菌杀灭将在小鼠混合感染模型中进行检测；2)阐明干扰素-γ是如何 在流感和金黄色葡萄球菌混合感染期间，促进炎性细胞因子风暴和致命的肺损伤。 具体地说，干扰素-γ驱动的破坏性炎症级联对致命性肺损伤的贡献将是 在临床相关的合并感染小鼠模型中确定；以及3)改进联合治疗策略， 针对细胞内细菌和肺部炎症。据派的实验室报告， 抗生素和NOX2抑制剂联合治疗显著提高动物对流感的存活率 和耐甲氧西林金黄色葡萄球菌混合感染。具体目标3是优化这种联合治疗方法，基于 目标1和目标2中提出的研究结果。该项目的最终目标是建立治疗 在流感和耐甲氧西林金黄色葡萄球菌期间恢复抗菌素防御同时限制炎症性肺损害的策略 混合感染。

PROJECT SUMMARY Methicillin-resistant S. aureus (MRSA) infection complicated by influenza emerges as a leading cause of death during recent influenza pandemics and epidemics. Defective bacterial control and exaggerated lung inflammation are believed to be responsible for high mortality in patients and animals. However, a hitherto incomplete understanding of coinfection pathophysiology has hampered the development of effective treatments. NADPH oxidase 2 (NOX2) is an enzyme complex predominantly expressed by phagocytes. The generation of reactive oxygen species (ROS) through NOX2, a process called oxidative burst, is required for lung S. aureus clearance. During the initial funding period, the work from PI's laboratory has established that intracellular ROS in phagocytes decrease at the recovery stage of influenza infection, thereby leading to defective killing of S. aureus. However, although intracellular ROS are reduced per cell, there are excessive inflammatory cells that release oxidants during coinfection. This event eventually culminates in lethal oxidative lung damage. Furthermore, preliminary studies in PI's laboratory reveal that type I IFN (IFN-I) signaling facilitates monocyte recruitment as it inhibits lung bacterial clearance, whereas IFN-γ signaling promotes lung inflammation and lethal lung damage after influenza and S. aureus coinfection. Therefore, it is hypothesized that influenza- induced IFN responses disrupt the balance between oxidative burst-associated antibacterial immunity and inflammation, and results in not only susceptibility to secondary S. aureus infection but also lethal lung injury thereafter. The approaches to test the hypothesis include: 1) to determine whether influenza-induced IFN-I impairs antibacterial immunity by promoting monocyte recruitment. Specifically, the cellular and signaling mechanisms for IFN-I-suppressed bacterial killing will be examined in mouse coinfection models; 2) to elucidate how IFN-γ promotes an inflammatory cytokine storm and lethal lung injury during influenza and S. aureus coinfection. Specifically, the contribution of the IFN-γ-driven destructive inflammation cascade to lethal lung damage will be determined in a clinical-relevant coinfection mouse model; and 3) refine combination treatment strategies that target both intracellular bacteria and lung inflammation. It has been reported by PI's laboratory that combination treatment with antibiotic and NOX2 inhibitor significantly improves animal survival from influenza and MRSA coinfection. Specific aim 3 is to optimize this combination therapeutic approach based on the findings from studies proposed in aim 1 &2. The ultimate goal of this project is to establish the treatment strategy to restore antimicrobial defense while limiting inflammatory lung damage during influenza and MRSA coinfection.