Mechanisms of Haemophilus influenzae pathogenesis in the lung

流感嗜血杆菌肺部发病机制

• 批准号: 8297393
• 负责人: Brian Akerley
• 金额: $ 23.79万
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297393
• 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. PUBLIC HEALTH RELEVANCE: Haemophilus influenzae is a bacterial pathogen that persistently infects the human nasal passages and causes disease by invading and multiplying in the bloodstream, lungs, or middle ear. The proposed studies will comprehensively investigate adaptations this pathogen uses to evade host immune responses in the both the normal lung and in the context of co-infection with Influenza virus, an infection which predisposes individuals to lethal secondary bacterial pneumonia. These studies will provide information needed to devise more effective preventative and therapeutic measures against infections by H. influenzae and other bacteria that use similar pathogenic strategies in the respiratory tract.

描述（由申请方提供）：流感嗜血杆菌寄生于人鼻咽和结膜，可传播引起肺炎、中耳炎或脑膜炎。目前针对B型毒株荚膜的疫苗对缺乏荚膜的临床相关毒株（称为不可分型H）无效。流感病毒（NTHi）。在被甲型流感病毒（IAV）感染后，NTHi与继发性肺炎相关，继发性肺炎是IAV感染中死亡的主要原因。NTHi的脂寡糖（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。我们已经鉴定了参与补体（C）途径逃避的几种LOS结构基因在肺中的作用，所述补体（C）途径靶向NTHi以被吞噬细胞破坏。我们还发现了对NTHi在肺中存活至关重要的代谢途径，并且中性粒细胞的消耗减少了NTHi对这些途径的需求。对NTHi在肺中的发病机制的理解是有限的，部分原因是正常小鼠快速清除细菌，并且单独使用NTHi不会发展为持续性肺炎。然而，我们的初步数据表明，在感染IAV的小鼠中NTHi的广泛增殖和快速致死性。因此，IAV/NTHi共感染模型提供了一个机会，以检查以前未表征的致病机制的临床相关的NTHi菌株在肺部疾病的情况下。我们推测，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）利用减弱的宿主防御，从而增强疾病。我们建议使用IAV合并感染作为一个模型系统来表征细菌利用宿主在肺部的脆弱性的分子基础。进行第一次全面的角色考核 H.全面比较IAV合并感染中NTHi生长和存活所需的细菌适应和免疫逃避因素与单独感染NTHi所需的因素;表征在IAV合并感染中不同参与的NTHi LOS结构和抗氧化防御的免疫逃避作用;并确定在宿主反应改变和IAV共感染的背景下NTHi发病机制。相关性：拟议的工作将深入了解细菌基因的免疫逃避和生理适应的作用，这些基因是在体外模拟的抗细菌防御中生存所需的，以及这些基因如何有助于细菌在正常小鼠和病毒感染小鼠的肺部存活和定植。研究结果将为H.流感和潜在的其他呼吸道病原体，以抵抗肺部的防御，并利用具有潜在疾病的个体的条件。此外，了解这种细菌与其在正常和病毒感染宿主中的环境的分子组分的相互作用对于选择适当的靶点用于专门设计用于对抗病毒合并感染中的细菌和潜在的使个体易患细菌性肺部感染的其他病症的预防或治疗策略将是有价值的。 公共卫生相关性：流感嗜血杆菌是一种细菌病原体，持续感染人的鼻腔，并通过侵入血液、肺或中耳并在其中繁殖而致病。拟议的研究将全面调查这种病原体用于逃避正常肺部和与流感病毒合并感染的情况下的宿主免疫反应的适应性， 致命的继发性细菌性肺炎这些研究将为设计更有效的预防和治疗措施提供所需的信息。流感和其他在呼吸道中使用类似致病策略的细菌。