Mechanisms of Haemophilus influenzae pathogenesis in the lung

流感嗜血杆菌肺部发病机制

基本信息

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
项目类别：
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

项目摘要

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）：流感嗜血杆菌的细菌居住在人类鼻咽和结膜中，并可以传播以引起肺炎，耳炎培养基或脑膜炎。目前针对B型菌株胶囊的疫苗对缺乏胶囊的临床相关菌株无效，该菌株称为不可能的流感H. thizae（NTHI）。流感病毒（IAV）感染后，NTHI与继发性肺炎有关，这是IAV感染死亡率的主要原因。 NTHI的脂肪糖（LOS）在菌血症和中耳炎模型中有助于毒力，但其在肺中的功能尚不清楚。我们已经在肺中确定了与逃避补体（C）途径有关的几种LOS结构基因的作用，该基因以吞噬细胞破坏了NTHI。我们还发现，在肺中NTHI生存至关重要的代谢途径，中性粒细胞的耗竭减轻了NTHI对这些途径的需求。了解肺中的NTHI发病机理受到限制，部分原因是正常小鼠迅速清除细菌，并且不会单独使用NTHI形成持续性肺炎。但是，我们的初步数据表明，在感染IAV的小鼠中NTHI的广泛繁殖和快速致死性。因此，IAV/NTHI共感染模型提供了一个机会，可以检查肺部疾病中临床相关的NTHI菌株先前未表征的致病机制。我们假设在呼吸道内进行nTHI的免疫逃避和生理适应，使该细菌可以利用IAV共同感染的易感性疾病中的宿主防御能力，从而增强了疾病。我们建议将IAV共感染用作模型系统，以表征细菌在肺中利用宿主脆弱性的分子基础。对角色进行首次全面检查在促进肺部疾病中，流感疫苗的多种定殖因子在我们将：全面比较IAV感染中NTHI生长和生存所需的细菌适应和免疫逃避因子与单独使用NTHI所需的感染所需的细菌适应性和免疫逃避因子；表征了与IAV共感染不同涉及的NTHI LOS结构和抗氧化剂防御的作用；并确定在改变宿主反应和IAV共同感染中NTHI发病机理的机制。相关性：拟议的工作将深入了解免疫逃避和生理适应性的细菌基因在体外建模的抗细菌防御所需的生物适应性，以及这些基因如何促进正常人对病毒感染小鼠的肺中细菌生存和殖民化的作用。该结果将为您对流感烟草和潜在的其他呼吸道病原体所使用的策略提供独特的见解，以抵抗肺部的防御能力，并利用潜在疾病患者的疾病。此外，了解该细菌与正常和病毒感染宿主中环境的分子成分的相互作用对于选择适当的靶标而是针对预防或治疗策略的适当靶标，这些策略是专门针对病毒共同感染和潜在的其他条件对抗细菌肺部感染的细菌的专门设计的。