Mechanisms of Haemophilus influenzae pathogenesis in the lung

流感嗜血杆菌肺部发病机制

• 批准号: 8416316
• 负责人: Brian Akerley
• 金额: $ 38.34万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416316
• 关键词: Affect; Anti-Bacterial Agents; Antigens; Antioxidants; Attenuated; Bacteremia; Bacteria; Bacterial Genes; Bacterial Pneumonia; Biological Models; Blood Circulation; Categories; Clinical; Complement; Complement Factor H; Data; Defect; Development; Disease; Environment; Genes; Genome; Growth; Haemophilus influenza virulence; Haemophilus influenzae; Host Defense; Human; Immune; Immune response; Incidence; Individual; Infection; Influenza A virus; Invaded; Investigation; Lactamase; Lung; Lung diseases; Measures; Meningitis; Metabolic Pathway; Modeling; Molecular; Monobactams; Mus; Nasopharynx; Nontypable Haemophilus influenza; Nose; Nutrient; Otitis Media; Oxidative Stress; Pathogenesis; Pathway interactions; Phagocytes; Physiological; Physiological Adaptation; Pneumonia; Prevalence; Resistance; Respiratory System; Respiratory tract structure; Role; Serotyping; Site; Structural Genes; Structure; Symptoms; System; Techniques; Therapeutic; Vaccines; Viral; Virulence; Virulence Factors; Virus Diseases; Work; antimicrobial; base; capsule; clinically relevant; combat; conjunctiva; design; fitness; in vitro Model; influenzavirus; insight; lipooligosaccharide; microbial host; middle ear; mortality; mutant; neutrophil; pathogen; respiratory; secondary infection

DESCRIPTION (provided by applicant): The bacterium Haemophilus influenzae inhabits the human nasopharynx and conjunctiva, and can disseminate to cause pneumonia, otitis media, or meningitis. The current vaccine against the capsule of type b strains is not effective against clinically relevant strains that lack the capsule, termed nontypeable H. influenzae (NTHi). After infection by influenza A virus (IAV), NTHi is associated with secondary pneumonia, a major cause of mortality in IAV infections. The lipooligosaccharide (LOS) of NTHi contributes to virulence in models of bacteremia and otitis media yet its function in the lung is not well understood. We have identified roles in the lung for several LOS structural genes involved in evasion of the complement (C) pathway, which targets NTHi for destruction by phagocytes. We have also found metabolic pathways critical for NTHi survival in the lung and depletion of neutrophils alleviates NTHi's requirement for these pathways. Understanding NTHi pathogenesis in the lung has been limited, in part because normal mice rapidly clear the bacterium and do not develop persistent pneumonia with NTHi alone. However, our preliminary data demonstrate extensive multiplication and rapid lethality of NTHi in mice infected with IAV. Therefore, the IAV/NTHi co-infection model provides an opportunity to examine previously uncharacterized pathogenic mechanisms of clinically relevant NTHi strains in the context of pulmonary disease. We hypothesize that immune evasion and physiological adaptations by NTHi within the respiratory tract allow this bacterium to exploit weakened host defenses in predisposing conditions such as IAV co-infection, thereby potentiating disease. We propose to use IAV co-infection as a model system to characterize the molecular basis by which bacteria exploit host vulnerability in the lung. To perform the first comprehensive examination of the roles of the diverse colonization factors of H. influenzae in promoting pulmonary disease we will: Comprehensively compare bacterial adaptations and immune evasion factors required for growth and survival of NTHi in IAV co- infection versus those required in infection with NTHi alone; Characterize roles in immune evasion of NTHi LOS structures and antioxidant defenses that are differentially involved in IAV co-infection; and Determine mechanisms of NTHi pathogenesis in the context of altered host response and in IAV co-infection. Relevance: The proposed work will generate insight into the roles of bacterial genes of immune evasion and physiological adaptation required to survive anti-bacterial defenses modeled in vitro, and how these genes contribute to bacterial survival and colonization in lungs of both normal versus virally infected mice. The results will provide unique insight into strategies used by H. influenza and potentially other respiratory pathogens to resist defenses in the lung and exploit conditions in individuals with underlying disease. Moreover, understanding this bacterium's interactions with molecular components of its environment in normal and virally infected hosts will be valuable for the selection of appropriate targets for preventative or therapeutic strategies specifically designed to combat bacteria in viral co-infections and potentially other conditions that predispose individuals to bacterial lung infection.

描述（由申请人提供）：流感嗜血杆菌居住在人的鼻咽和结膜中，并可传播引起肺炎，中耳炎或脑膜炎。目前针对b型流感嗜血杆菌胶囊的疫苗对缺乏胶囊的临床相关菌株无效，称为不可分型流感嗜血杆菌（NTHi）。甲型流感病毒（IAV）感染后，NTHi与继发性肺炎有关，继发性肺炎是IAV感染死亡的主要原因。NTHi的低脂寡糖（LOS）有助于菌血症和中耳炎模型的毒力，但其在肺中的功能尚不清楚。我们已经确定了几个LOS结构基因在肺中的作用，这些基因参与逃避补体(C)途径，其目标是NTHi被吞噬细胞破坏。我们还发现代谢途径对NTHi在肺中的存活至关重要，中性粒细胞的消耗减轻了NTHi对这些途径的需求。对NTHi在肺中的发病机制的了解有限，部分原因是正常小鼠迅速清除细菌，不会仅因NTHi而发展为持续性肺炎。然而，我们的初步数据显示NTHi在感染IAV的小鼠中广泛增殖和快速致死。因此，IAV/NTHi联合感染模型提供了一个机会来检查肺部疾病背景下临床相关NTHi菌株以前未表征的致病机制。我们假设呼吸道内NTHi的免疫逃避和生理适应允许这种细菌在易感条件下（如IAV合并感染）利用宿主防御减弱，从而增强疾病。我们建议使用IAV合并感染作为模型系统来表征细菌利用宿主肺部脆弱性的分子基础。对角色进行第一次全面检查