Central role of Caspase-8 in control of host tolerance and resistance mechanisms in pulmonary macrophage populations during severe respiratory infections

Caspase-8 在严重呼吸道感染期间肺巨噬细胞群宿主耐受和抵抗机制中的核心作用

• 批准号: 10668787
• 负责人: Amanda M Jamieson
• 金额: $ 79.75万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668787
• 关键词: 5 year old; Alveolar Macrophages; Apoptosis; Bacterial Infections; Bacterial Pneumonia; Biochemical; Biological Assay; CASP8 gene; Caspase; Categories; Cause of Death; Cell Death; Cell Death Induction; Cell Line; Cell Membrane Permeability; Cells; Cessation of life; Child; Complex; Complication; Data; Disease; Equilibrium; Flow Cytometry; Foundations; Future; Genetic Models; Hospitalization; Host resistance; Human; Imaging Techniques; Immune; Immune response; In Vitro; Infection; Inflammasome; Influenza A virus; Lung; Lung infections; Macrophage; Membrane; Modeling; Morbidity - disease rate; Mus; Mutation; Myeloid Cells; Pathway interactions; Patients; Persons; Play; Pneumonia; Population; Process; Research; Resistance; Respiratory Tract Infections; Role; Streptococcus pneumoniae; System; Testing; Viral; Virus Diseases; antimicrobial; cell type; co-infection; global health; improved; in vitro Model; in vivo; in vivo Model; influenza epidemic; influenza infection; inhibitor; mortality; mouse model; novel; pandemic virus; pathogen; pathogenic bacteria; pharmacologic; productivity loss; resistance mechanism; response; seasonal influenza; secondary infection; timeline; tissue-repair responses; transcriptomics

PROJECT SUMMARY Pneumonia is an important global health problem 1. Influenza A virus (IAV) leads to an estimated 500,000 deaths annually, and these numbers can be even higher during IAV pandemic years 2. A complication following infection with IAV is bacterial pneumonia, and this can lead to a more severe disease 3- 21. To survive a given infection hosts must be able to not only clear the pathogen, but also tolerate to the effects of the pathogen or the host response. The latter processes are referred to as disease tolerance. Normally, a balance between these two processes is reached, and the infection resolves 2223. My research lab has been at the forefront of exploring the concept of host disease tolerance in deadly complex respiratory infections 242322 • 25 • 26. We have shown that during pulmonary IAV/bacterial coinfection this balance between resistance and tolerance is disrupted causing increased lethality 22,24. Regulated cell death (RCD) plays important roles in both resistance and tolerance to infection. Cell death can be broadly categorized as membrane permeable (e.g. necroptosis and pyroptosis) or membrane impermeable (e.g. apoptosis). During infection several different types of cell death can be induced each inducing a unique response. Macrophages are responsible for both resistance mechanisms such as coordination of the immune response, and they contribute to tolerance in the form of the tissue repair responses after damage. This proposal aims to bridge gaps in our current understanding of complex respiratory infections by investigating the role of Caspase-8. a key regulator of RCD. in relevant in vitro and in vivo models of IAV/bacterial coinfection. We will focus on understanding how Caspase-8 pathways in lung macrophages during IAV/bacterial coinfection contributes to resistance and tolerance. Our preliminary data has demonstrated that Caspase-8 deficiency in macrophages leads to increased host resistance at the expense of host tolerance in the early stages of coinfection. This is most likely due to increased necroptosis and anti-microbial responses. We hypothesize that during severe lung infections such as those that occur with bacterial infection following IAV infection macrophage cell death controlled by Caspase-8 plays an important role in regulating the balance between resistance and tolerance. In this study we will determine the role that Caspase-8 in macrophages plays throughout the course of infection. We will use relevant in vitro models using human primary macrophages, as well as in vivo models. These studies will lay the foundation for future studies on understanding the impact of RCD in macrophages during complex pulmonary infections, which may ultimately lead to improved treatment options for patients with complex and severe lung infections.

项目摘要 肺炎是一个重要的全球健康问题1。流感病毒（IAV）在IAV大流行期间每年估计每年50万例死亡。 IAV IAV IAV IAV IAV IAV IAV IAV IAV IAV To A More Severe Disease 3-21. To Survive a GiveN Hosts Must to Not ONLS THE PATHOGEN Gen or The Host Response. The Latter Processes is ARE Referred to as Disease Tolerance. Normally. ,达到了两个过程之间的平衡，感染解决了2223。致命的复杂呼吸道感染中的OST疾病耐受性242322•25•26•26。我们已经表明，在肺IV /细菌共同感染过程中，这种耐药性和耐受性之间的这种耐药性2222 ，24。 常规细胞死亡（RCD）。损坏后的组织修复反应的旨在弥合我们当前对caspase-8的复杂呼吸感染的理解。 IAV/细菌共感染期间的肺巨噬细胞的途径有助于我们的耐药性和耐受性。大灵托斯施特替诺斯施加剂和抗微生物反应。 。 在这项研究中，我们将确定人类的主要巨噬细胞以及体内模型。