Autophagy proteins in the immune response to Mycobacterium tuberculosis infection

自噬蛋白在结核分枝杆菌感染免疫反应中的作用

基本信息

批准号：
10509384
负责人：
Christina Leigh Stallings
金额：
$ 47.3万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-07 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10509384
关键词：
Affect Alveolar Macrophages Antigen Presentation Antigen-Presenting Cells Apoptosis Apoptotic Autophagocytosis Biological Assay Cell Survival Cells Cessation of life Data Defect Dendritic Cells Disease Outcome Dissection Host Defense Human ITGAX gene Immune Immune response Immunotherapy In Vitro Infection Infection Control Infectious Agent Infiltration Inflammation Inflammatory Interferon Type II Lead Lung Macrophage Monitor Mouse Strains Mus Mycobacterium tuberculosis Myeloid Cells Natural Immunity Pathogenesis Pathology Pathway interactions Persons Phagocytosis Phenotype Play Population Predisposition Production Proteins Reporting Role S100A8 gene Signal Transduction T-Lymphocyte Testing Tuberculosis adaptive immune response adaptive immunity chemokine cytokine effective therapy effector T cell expectation experimental study in vitro Assay in vivo insight interest monocyte neutrophil recruit response trafficking transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT Mycobacterium tuberculosis (Mtb) infection kills more people a year than any other single infectious agent. Both the disease outcome and the pathology of TB are driven by the immune response mounted in the host, which is dictated by interactions between cells involved in innate and adaptive immunity. Because of the pivotal role of the immune response in TB, there is a growing interest in developing immunotherapies that harness the immune response to control the infection. In particular, there is interest in stimulating autophagy to control Mtb infection. The role of autophagy in controlling Mtb infection was based on the observation that Atg5fl/fl-LysM-cre mice lacking Atg5 in monocyte-derived cells and neutrophils (polymorphonuclear cells, PMN) succumb to Mtb within 30 days, an extremely severe phenotype similar to mice lacking IFN-γ signaling. Atg5 is an essential autophagy protein and the dogma in the field was that Atg5 was required in macrophages to target Mtb for lysosomal degradation through macroautophagy. Contrary to expectation, we have demonstrated that Atg5 is required in myeloid cells to control Mtb infection due to an autophagy-independent function that regulates PMN-dominated inflammation. In addition, using mice that conditionally delete Atg5 only in PMN (Atg5fl/fl- MRP8-cre), we have shown that loss of Atg5 in PMNs can result in susceptibility to Mtb infection, revealing a PMN intrinsic role for Atg5 during Mtb infection. Therefore, it will be important to better understand the roles for autophagy proteins in host defense to understand the scope of effects that may occur while intervening with autophagic flux with host-directed therapies. Our dissection of Mtb pathogenesis in Atg5fl/fl-LysM-cre mice has revealed multiple stages where Atg5 functions in myeloid cells during infection. During Mtb infection, an early- infected Atg5-/- cell overproduces cytokines and chemokines that bring PMN into the lungs of Atg5fl/fl-LysM-cre mice in higher numbers than in control mice. The responding Atg5-/- PMN amplify the pro-inflammatory signals and a subset of Atg5-/- PMN are not cleared from the lung, which we predict occurs due to a defect in PMN apoptosis and/or efferocytosis of the apoptotic PMN. Efferocytosis of apoptotic Mtb-infected PMN is important for efficient antigen presentation. Indeed, the defect in clearing Atg5-/- PMN correlates with delayed trafficking of T cells to the lungs. Based on these preliminary data, I hypothesize that Atg5 plays roles in multiple myeloid cells during Mtb infection, including an autophagy-independent function in PMN, and together these functions of Atg5 lead to control of Mtb pathogenesis. To test this hypothesis, I will determine the mechanistic basis for how loss of Atg5 in myeloid cells leads to PMN accumulation and precludes a protective adaptive immune response to Mtb by pursuing the following aims: 1) Dissect the roles for Atg5 in regulating production of pro- inflammatory signals during infection, 2) Define the roles for Atg5 in regulating PMN accumulation and clearance during Mtb infection, 3) Determine how loss of Atg5 in myeloid cells affects adaptive immune responses to Mtb.

项目摘要/摘要结核分枝杆菌（MTB）感染每年杀死的人数比任何其他单一感染剂都多。两个都疾病结果和结核病的病理是由宿主中安装的免疫反应驱动的，由与先天和适应性免疫史的细胞之间的相互作用决定。因为 TB的免疫反应，对发展免疫的免疫疗法越来越兴趣反应控制感染。特别是，有兴趣刺激自噬控制MTB感染。自噬在控制MTB感染中的作用是基于ATG5FL/FL-LYSM-CRE小鼠的观察结果在单核细胞衍生的细胞和中性粒细胞（多形核细胞，PMN）中缺乏ATG5 30天，一种非常严重的表型，类似于缺乏IFN-γ信号传导的小鼠。 ATG5是必不可少的自噬蛋白和该领域的教条是巨噬细胞中需要ATG5才能针对MTB 溶酶体通过大噬细胞降解。与期望相反，我们已经证明了ATG5是在髓样细胞中需要控制MTB感染，这是由于自动独立的功能而导致的 PMN为主导的炎症。另外，使用仅在PMN中有条件删除ATG5的小鼠（ATG5FL/FL- MRP8-CRE），我们已经表明，PMN中ATG5的损失可能会导致MTB感染的敏感性，从而揭示了A MTB感染期间ATG5的PMN固有作用。因此，重要的是要更好地了解宿主防御中的自噬蛋白，以了解介入时可能发生的效果范围自噬通量带有宿主定向疗法。我们在ATG5FL/FL-LYSM-CRE小鼠中对MTB发病机理的解剖揭示了多个阶段，其中ATG5在感染过程中在髓样细胞中起作用。在MTB感染期间，早期感染ATG5 - / - 细胞过多产生的细胞因子和趋化因子，将PMN引入ATG5FL/FL-LYSM-CRE的肺中小鼠的数量比对照小鼠更高。响应的ATG5 - / - PMN放大了促炎信号并且未从肺中清除ATG5 - / - PMN的子集，我们预测这是由于PMN中的缺陷而发生的凋亡PMN的细胞凋亡和/或胞吞作用。凋亡MTB感染的PMN的吞噬作用很重要用于有效的抗原表现。实际上，清除ATG5 - / - PMN的缺陷与延迟的贩运相关 T细胞到肺部。基于这些初步数据，我假设ATG5在多个髓样中扮演角色 MTB感染期间的细胞，包括PMN中无自噬功能，并将这些功能一起 ATG5导致控制MTB发病机理。为了检验这一假设，我将确定髓样细胞中ATG5的损失如何导致PMN积累并排除保护性适应性免疫通过追求以下目的对MTB的反应：1）剖析ATG5在监管生产中的作用感染期间的炎症信号，2）定义ATG5在调节PMN积累和清除率中的作用在MTB感染期间，3）确定髓样细胞中ATG5的损失如何影响对MTB的适应性免疫回报。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Autophagy prevents early proinflammatory responses and neutrophil recruitment during Mycobacterium tuberculosis infection without affecting pathogen burden in macrophages.

DOI：
10.1371/journal.pbio.3002159
发表时间：
2023-06
期刊：
PLoS biology
影响因子：
9.8
作者：
通讯作者：

Exploring the Role of Low-Density Neutrophils During Mycobacterium tuberculosis Infection.

DOI：
10.3389/fcimb.2022.901590
发表时间：
2022
期刊：
Frontiers in cellular and infection microbiology
影响因子：
5.7
作者：
通讯作者：

Myeloid autophagy genes protect mice against fatal TNF- and LPS-induced cytokine storm syndromes.

DOI：
10.1080/15548627.2022.2116675
发表时间：
2023-04
期刊：
AUTOPHAGY
影响因子：
13.3
作者：
Wang, Ya-Ting;Sansone, Amy;Smirnov, Asya;Stallings, Christina L.;Orvedahl, Anthony
通讯作者：
Orvedahl, Anthony

Editorial overview: Attrition warfare: host cell weapons against intracellular pathogens, and how the pathogens fight back.

编辑概述：消耗战：针对细胞内病原体的宿主细胞武器，以及病原体如何反击。