Oxidative killing of Pneumococcus

氧化杀死肺炎球菌

• 批准号: 10116271
• 负责人: Balazs Rada
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116271
• 关键词: Affect; Air; Animal Model; Anions; Anti-Bacterial Agents; Attention; Attenuated; Autolysis; Automobile Driving; Bacteria; Biology; Cells; Child; Data; Economic Burden; Elderly; Encapsulated; Epithelial Cells; Foundations; Future; Goals; HIV; Human; Hydrogen Peroxide; Immune; Immune response; Impairment; In Vitro; Infection; Innate Immune Response; Innate Immune System; Intervention; Knowledge; Liquid substance; Lung; Lung infections; Mediating; Meningitis; Mission; Modeling; Mus; NADPH Oxidase; Outcome; Oxidases; Oxides; Pathogenesis; Patients; Pneumococcal Infections; Pneumonia; Production; Proteins; Public Health; Publishing; Research; Respiration; Role; Septicemia; Source; Streptococcus pneumoniae; System; Testing; Therapeutic; Thiocyanates; Time; Tissues; United States National Institutes of Health; Work; airway epithelium; airway surface liquid; anti-influenza; antimicrobial; apical membrane; base; bronchial epithelium; cell killing; co-infection; community acquired pneumonia; design; extracellular; fighting; human disease; hypothiocyanite; improved; in vitro testing; in vivo; influenza infection; influenza pneumonia; innate immune mechanisms; innovation; lung injury; microbicide; mortality; mouse model; novel; novel therapeutics; oxidation; respiratory; respiratory pathogen; weapons

Streptococcus pneumoniae (Spn) is the main cause of community acquired pneumonia and meningitis in children and the elderly, and of septicemia in HIV patients. Boosting the function of host immune responses could offer novel intervention strategies against Spn. There is a critical gap in our knowledge to identify new, broad range, anti-Spn mechanisms of the respiratory innate immune system. Bronchial epithelial cells (BEC) are the primary responders to Spn infection. BECs orchestrate an oxidative extracellular antimicrobial system present in the airway surface liquid consisting of the protein lactoperoxidase (LPO), the thiocyanate anion (SCN-) and hydrogen peroxide (H2O2). LPO oxidizes SCN- using H2O2 into microbicidal hypothiocyanite (OSCN-). Dual oxidase 1 (Duox1), an NADPH oxidase protein highly expressed in the apical membrane of BECs, is the H2O2 source for the antimicrobial action of LPO. Our preliminary result show that the Duox1/LPO-based system efficiently kills several strains of Spn in different experimental systems. Our long-term goal is to determine whether the Duox1/LPO/SCN- antibacterial system could be manipulated in Spn infection for therapeutic purposes in humans. The objective of this proposal is to establish the anti-Spn role of the Duox1/LPO-based oxidative mechanism. Based on preliminary data our central hypothesis is that the Duox1/H2O2/LPO/SCN- system kills Spn bacteria in a strain-independent manner, attenuates infection and associated tissue damage in a mouse model of Spn lung infection. To test this hypothesis, our specific aims are to determine the mechanism of Spn killing by Duox1/LPO in vitro, to establish the in vivo role of Duox1 in Spn killing, and to explore whether therapeutic manipulation of the Duox1/LPO-based system attenuates Spn pneumonia in an animal model. The rationale for the proposed research is that we need to characterize how powerful the Duox1/LPO-based system is in fighting Spn to explore its therapeutical potential in humans in the future. It is anticipated that our aims will yield the following expected outcomes: 1) identification of the antibacterial mechanism of the Duox1/LPO-based system against Spn, 2) establishing the in vivo relevance of Duox1 in Spn infection; and 3) providing essential results on the therapeutic potential of the Duox1/LPO-based mechanism to attenuate Spn lung infection. Our innovative work shows that a unique antimicrobial system is powerful in killing Spn and explores a novel, nontraditional immune mechanism for its potential to be used against a major lung pathogen. In summary, our proposal will have a positive impact in the fields of airway epithelial and Spn biology, and general antibacterial innate immune responses by identifying Duox1 and LPO, as a novel, crucial, innate immune weapons of the respiratory innate immune system against Spn.

肺炎链球菌（Spn）是社区获得性肺炎的主要病因