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。甲型流感病毒（IAV）每年导致约500，000人死亡，在IAV大流行年份，这些数字甚至可能更高。感染IAV后的并发症是细菌性肺炎，这可能导致更严重的疾病3- 21。为了在给定的感染中存活，宿主必须不仅能够清除病原体，而且能够耐受病原体的影响或宿主的反应。后一个过程被称为疾病耐受性。正常情况下，这两个过程之间达到平衡，感染解决2223。我的研究实验室一直处于探索致命复杂呼吸道感染中宿主疾病耐受性概念的最前沿。我们已经表明，在肺部IAV/细菌共感染期间，抵抗力和耐受性之间的平衡被破坏，导致致死率增加22，24。 调节性细胞死亡（Regulated cell death，RCD）在抗感染和耐感染中起重要作用。细胞死亡可大致分类为膜可渗透性（例如坏死性凋亡和焦亡）或膜不可渗透性（例如凋亡）。在感染期间，可以诱导几种不同类型的细胞死亡，每种细胞死亡诱导独特的反应。巨噬细胞负责两种抗性机制，如免疫应答的协调，并且它们以损伤后的组织修复应答的形式促进耐受性。该提案旨在通过调查Caspase-8的作用来弥合我们目前对复杂呼吸道感染的理解中的差距。刚果民盟的一个关键监管机构。在IAV/细菌共感染的相关体外和体内模型中。我们将专注于了解在IAV/细菌共感染期间肺巨噬细胞中的Caspase-8通路如何有助于抵抗和耐受。我们的初步数据已经证明，巨噬细胞中的Caspase-8缺陷导致宿主抗性增加，而在合并感染的早期阶段，宿主耐受性降低。这很可能是由于坏死性细胞死亡和抗微生物反应增加所致。我们假设，在严重的肺部感染期间，例如IAV感染后发生的细菌感染期间，由Caspase-8控制的巨噬细胞死亡在调节抵抗力和耐受性之间的平衡方面发挥着重要作用。 在这项研究中，我们将确定Caspase-8在巨噬细胞在整个感染过程中发挥的作用。我们将使用使用人原代巨噬细胞的相关体外模型以及体内模型。这些研究将为未来了解RCD在复杂肺部感染期间对巨噬细胞的影响的研究奠定基础，这可能最终导致复杂和严重肺部感染患者的治疗选择得到改善。