The role of PMNs and CD73 in host-resistance against S. pneumoniae / influenza A virus co-infection

PMNs和CD73在宿主抵抗肺炎链球菌/甲型流感病毒混合感染中的作用

• 批准号: 10652758
• 负责人: Elsa Bou Ghanem
• 金额: $ 22.96万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-24 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652758
• 关键词: Accounting; Adenosine; Adoptive Transfer; Age; Aging; Animal Model; Anti-Bacterial Agents; Antibacterial Response; Bacteria; Bacterial Infections; Bacterial Pneumonia; Cells; Cessation of life; Clinical; Disease; Drug Targeting; Economic Burden; Elderly; Environment; Enzymes; Epithelium; Etiology; Evolution; Goals; Healthcare; Host resistance; Human; Immune; Immune response; Impairment; Individual; Infection; Inflammation; Influenza; Influenza A virus; Knockout Mice; Lower respiratory tract structure; Lung; Lung diseases; Mediating; Microbial Biofilms; Modeling; Mus; Nasal cavity; Nasopharynx; Outcome; Pathway interactions; Pharmaceutical Preparations; Physiological; Play; Pneumococcal Infections; Pneumococcal Pneumonia; Predisposition; Production; Resistance; Resistance to infection; Respiratory Tract Infections; Risk; Role; Secondary to; Signal Transduction; Streptococcus pneumoniae; Testing; Time; Tissues; Virus Diseases; Vulnerable Populations; Work; age effect; aged; antimicrobial; cell injury; co-infection; combat; design; extracellular; human disease; human old age (65+); improved; influenza infection; innovation; lung injury; mouse model; neutrophil; novel; novel strategies; novel therapeutics; pandemic disease; pathogen; pharmacologic; receptor; recruit; response; synergism; time use

ABSTRACT Following influenza A virus (IAV) infection, the risk for subsequent pneumococcal pneumonia caused by Streptococcus pneumoniae is enhanced 100-fold. Host aging is associated with more severe outcomes, thus novel approaches that boost resistance to infections are needed. Our goal is to elucidate how IAV infection alters the responses of polymorphonuclear leukocytes (PMN) and the extracellular adenosine (EAD) pathway across host age, during pneumococcal pneumonia. Background: Following primary S. pneumoniae infection, PMNs, which are innate immune cells whose function declines with age, are required for controlling bacterial numbers. EAD, which is produced from breakdown of ATP leaking from injured cells by CD73, controls PMN responses during infection. We found that CD73 was crucial for host resistance and PMN pulmonary influx as well as anti-microbial function during primary pneumococcal pneumonia. Importantly, old mice had significant changes in expression of EAD enzymes and receptors and targeting this pathway reversed the age-driven susceptibility to primary pneumococcal infection. In humans, pneumococcal carriage in the nasopharynx is a prerequisite to invasive diseases. Further, IAV infection of the respiratory tract where it triggers epithelial damage and impairs host antibacterial responses is key for the lethal synergy of co-infection. However, animal models incorporating the evolution of S. pneumoniae from colonizer to pathogen during IAV co-infection while mimicking the severe disease seen in humans, are lacking. Therefore, we established an optimized model where mice are intra-nasally colonized with pneumococci followed by IAV infection of the nasopharynx and lungs. This model resulted in obvious signs of illness and lethality in half of the young mice and importantly, reproduced the susceptibility of aging, where significantly more old mice displayed severe clinical signs and succumbed to lethality compared to young controls. Using this model, we strikingly found that the role of CD73 was reversed, where CD73 became detrimental to resistance of young hosts to co-infection. This highlighted that IAV infection triggers profound changes in the interaction of the host with pneumococci. However, the effect of polymicrobial infections on host responses and the mechanisms behind that remain a gap in the field. Here we will use our improved model to test the Hypothesis that IAV infection alters CD73-mediated control of PMN responses to pneumococcal infection across host age using two specific Aims: 1) Test the effect of age and IAV infection on PMN responses during secondary pneumococcal pneumonia; 2) Test the role of CD73 in PMN responses and host resistance to S. pneumoniae/IAV co-infection. Significance/innovation/ relevance: Using this physiologically relevant model that mimics aspects of human disease to elucidate how PMN responses change in mono vs polymicrobial infections across host age and the role of CD73 in that, has the potential to uncover novel pathways that drive host susceptibly to infection. This work can lead to highly innovative approaches incorporating adenosine-based drugs to combat this serious lung disease.

抽象的 感染甲型流感病毒 (IAV) 后，继发肺炎球菌肺炎的风险 肺炎链球菌增强100倍。宿主衰老与更严重的结果相关，因此 需要增强抗感染能力的新方法。我们的目标是阐明 IAV 感染是如何发生的 改变多形核白细胞 (PMN) 和细胞外腺苷 (EAD) 途径的反应 在肺炎球菌肺炎期间，跨越宿主年龄。背景：原发性肺炎链球菌感染后， PMN 是一种先天免疫细胞，其功能随着年龄的增长而下降，是控制细菌所必需的 数字。 EAD 是由 CD73 分解受损细胞泄漏的 ATP 产生的，它控制 PMN 感染期间的反应。我们发现 CD73 对于宿主抵抗和 PMN 肺部流入至关重要 以及原发性肺炎球菌肺炎期间的抗菌功能。重要的是，老年小鼠有显着的 EAD 酶和受体表达的变化以及针对该途径的研究逆转了年龄驱动的 对原发性肺炎球菌感染的易感性。在人类中，鼻咽部的肺炎球菌携带是 侵袭性疾病的先决条件。此外，IAV 引起呼吸道上皮感染 损害和损害宿主抗菌反应是共同感染致命协同作用的关键。然而，动物 模型结合了 IAV 共感染期间肺炎链球菌从定植者到病原体的进化，同时 缺乏模仿人类严重疾病的方法。因此，我们建立了一个优化模型 小鼠鼻内定植肺炎球菌，随后 IAV 感染鼻咽部， 肺。该模型导致一半幼鼠出现明显的疾病和死亡迹象，重要的是， 再现了衰老的易感性，其中明显更多的老年小鼠表现出严重的临床症状，并且 与年轻对照相比，他们死于致命。使用这个模型，我们惊人地发现 CD73 的作用 情况被逆转，CD73 变得不利于年轻宿主对共感染的抵抗力。这突出显示了 IAV 感染引发宿主与肺炎球菌相互作用的深刻变化。然而， 多种微生物感染对宿主反应的影响及其背后的机制仍然是该领域的空白。 在这里，我们将使用改进的模型来测试 IAV 感染改变 CD73 介导的控制的假设 PMN 对不同年龄宿主的肺炎球菌感染的反应有两个具体目标：1) 测试年龄的影响 IAV 感染对继发性肺炎球菌肺炎期间 PMN 反应的影响； 2）测试CD73的作用 PMN 反应和宿主对肺炎链球菌/IAV 联合感染的抵抗力。意义/创新/相关性： 使用模拟人类疾病各个方面的生理相关模型来阐明中性粒细胞 (PMN) 单一微生物与多种微生物感染的反应随宿主年龄的不同而变化，以及 CD73 在其中的作用，具有 有可能发现导致宿主易受感染的新途径。这项工作可以带来高度 结合腺苷药物来对抗这种严重肺部疾病的创新方法。