Oxidative Burst in Influenza and MRSA Co-infection

流感和 MRSA 混合感染中的氧化爆发

• 批准号: 8481046
• 负责人: Keer Sun
• 金额: $ 4.24万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-22 至 2013-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8481046
• 关键词: Alveolar Macrophages; Animal Model; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Therapy; Antibiotics; Bacteria; Cause of Death; Clinical; Communicable Diseases; Data; Development; Epidemic; Functional disorder; Generations; Genes; Goals; Human; Immune; Immunity; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Interferons; Interleukin-10; Laboratories; Linezolid; Lung; Lung Inflammation; Mediating; Modeling; Molecular; Morbidity - disease rate; Mucous Membrane; Multienzyme Complexes; Mus; NADPH Oxidase; Nitric Oxide; Outcome; Oxidants; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Peroxonitrite; Phagocytes; Play; Pneumococcal Infections; Pneumonia; Predisposition; Production; Reactive Oxygen Species; Regulation; Reporting; Resistance; Respiratory Burst; Role; Secondary to; Source; Staphylococcus aureus; Superoxides; Supportive care; Survival Rate; T-Lymphocyte; Testing; Therapeutic; Tissues; Treatment Efficacy; antimicrobial; bactericide; base; comparative efficacy; defined contribution; effective therapy; extracellular; flu; human NOS2A protein; improved; influenzavirus; inhibitor/antagonist; innovation; killings; lung injury; methicillin resistant Staphylococcus aureus; mortality; novel therapeutics; pandemic influenza; public health relevance; treatment strategy

DESCRIPTION (provided by applicant): Influenza-complicated methicillin-resistant S. aureus (MRSA) infection has emerged as a leading cause of death during recent influenza pandemics and epidemics. Both heightened bacterial burden and exaggerated lung inflammation are believed to be responsible for high mortality in patients and animal models. However, a hitherto incomplete understanding of co-infection pathophysiology has slowed the development of effective treatment strategies. NADPH oxidase 2 (NOX2) is an enzyme complex predominantly expressed by phagocytes. NOX2 produces superoxide which reacts with nitric oxide and results in the formation of highly toxic peroxynitrite. Therefore, both NOX2 and inducible nitric oxide synthase (iNOS) activities critically contribute to oxidative stress which has long been known to be involved in inflammatory lung damage. On the other hand, reactive oxygen species (ROS) generated by NOX2 activity has been shown to exacerbate influenza virus-induced tissue inflammation but to contribute to resistance to S. aureus lung infection~ whereas iNOS activity plays a detrimental role during influenza infection, it is dispensable for pulmonary S. aureus clearance. Preliminary studies in the PI's laboratory revealed that influenza infection reduces phagocyte ROS level but increases IFN-?/iNOS expression. Therefore, it is hypothesized that dysregulation of oxidative burst following influenza infection causes defective bacterial killing s well as excessive oxidative stress, and results in fatal influenza and MRSA co-infection. The approaches to test the hypothesis include: 1) determine the influence of influenza infection on NOX2 activity and its contribution to influenza-suppressed phagocytic MRSA killing. Particularly, the molecular mechanisms for influenza-suppressed NOX2-dependent MRSA clearance will be examined in selected gene- deficient mice~ 2) determine the contribution of oxidative stress to lung injury during lethal influenza and MRSA co-infection. Specifically, the synergistic or overlapping contribution of NOX2 versus IFN-?/iNOS activity to oxidative tissue damage will be examined in NOX2, IFN-?R and iNOS gene-deficient mice~ 3) refine combination treatment targeting both intracellular bacteria and oxidative stress. Supportive data demonstrated that combination treatment with antibiotic and NOX2 inhibitor significantly improved the survival rate of influenza and MRSA co-infected mice compared with antibiotic treatment alone. 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 activity but to control inflammatory lung damage during influenza and MRSA co-infection. The results achieved from these proposed studies will provide not only pivotal but also directly applicable information for the development of novel therapeutics to reduce the high mortality in patients.

描述(申请人提供)：在最近的流感大流行和流行病中，流感并发的耐甲氧西林金黄色葡萄球菌(MRSA)感染已成为主要的死亡原因。细菌负荷的增加和肺部炎症的夸大都被认为是患者和动物模型高死亡率的原因。然而，到目前为止，对合并感染病理生理学的不完全理解减缓了有效治疗策略的发展。NADPH氧化酶2(NOX2)是一种主要由吞噬细胞表达的酶复合体。NOX2产生超氧化物，与一氧化氮反应，形成剧毒的过氧亚硝酸盐。因此，NOX2和诱导型一氧化氮合酶(INOS)活性在氧化应激中起关键作用，氧化应激长期以来一直被认为与炎症性肺损伤有关。另一方面，由NOX2活性产生的活性氧物种(ROS)被证明可以加重流感病毒诱导的组织炎症，但有助于抵抗金黄色葡萄球菌的肺部感染。而iNOS活性在流感感染过程中起着有害的作用，对于肺部金黄色葡萄球菌的清除是必不可少的。PI实验室的初步研究表明，流感感染降低了吞噬细胞的ROS水平，但增加了干扰素-1/iNOS的表达。因此，我们推测流感病毒感染后的氧化猝发调节失调会导致缺陷细菌杀死S和过度的氧化应激，从而导致致死性流感和耐甲氧西林金黄色葡萄球菌的混合感染。验证这一假说的方法包括：1)确定流感感染对NOX2活性的影响及其对流感抑制的吞噬MRSA杀伤的贡献。特别是，流感抑制NOX2依赖的MRSA清除的分子机制将在选定的基因缺陷小鼠中进行研究~2)确定致命流感和MRSA混合感染期间氧化应激对肺损伤的贡献。具体来说，将在NOX2、干扰素-R和诱导型一氧化氮合酶基因缺陷小鼠中检验NOX2和干扰素-β/诱导型一氧化氮合酶活性对氧化组织损伤的协同或重叠贡献。支持性数据表明，与单独使用抗生素相比，抗生素和NOX2抑制剂联合治疗显著提高了流感和MRSA混合感染小鼠的存活率。具体目标3是根据目标1和2中建议的研究结果优化这种联合治疗方法。该项目的最终目标是建立治疗策略，以恢复抗菌活性，但控制流感和MRSA合并感染期间的炎性肺损伤。这些拟议研究的结果不仅将为开发新的治疗方法以降低患者的高死亡率提供关键信息，而且还将直接适用于此。