Inhibition of Th2 responses by secreted components of a common farm bacterium

常见农场细菌的分泌成分对 Th2 反应的抑制

基本信息

批准号：
10563116
负责人：
Maile Kananiokala Hollinger
金额：
$ 4.77万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10563116
关键词：
Acinetobacter Activities of Daily Living Acute Lung Injury Address Affect Allergic Allergic inflammation Amish Animal Husbandry Anti-Asthmatic Agents Anti-Inflammatory Agents Antigen-Presenting Cells Asthma Attenuated Bacillus Bacillus subtilis Bacteria Cells Child Computational Biology Country Cytometry Dangerousness Data Dendritic Cells Developed Countries Development Diagnosis Dust Endotoxins Eosinophilia Ethnic Population Event Exposure to Extrinsic asthma Farm Farming environment Fellowship GATA3 gene Gases Generations Genetic Models Goals Helper-Inducer T-Lymphocyte Hour House Dust Human Immune Immune response Immunity Immunology Inflammation Inflammatory Inflammatory Response Life Lung Mediating Microbe Modeling Mus Myeloid Cells Opportunistic Infections Pathogenesis Pathogenicity Pathway interactions Persons Phenotype Prevalence Probiotics Proliferating Pyroglyphidae Refractory Regulatory T-Lymphocyte Research Personnel Risk Role School-Age Population Shortness of Breath Signal Transduction Sorting Staphylococcus aureus infection Stimulus T-Lymphocyte Techniques Testing Therapeutic Wheezing Work airway goblet cell hyperplasia arm asthmatic cell type chronic inflammatory disease enteric infection experience immune activation insight lung injury microbial microbial products migration mouse model neonatal immune system next generation sequencing novel polarized cell prevent response side effect skills

项目摘要

PROJECT SUMMARY/ABSTRACT Asthma is a chronic inflammatory disease affecting an estimated 339 million people worldwide and is characterized by wheezing, shortness of breath, and inefficient gas exchange 2. The prevalence of asthma has increased dramatically in industrialized nations over the past half-century; however, microbial exposures within these nations appear to be protective against asthma development. Multiple studies have found that children exposed to a farm environment early in life have a reduced prevalence of asthma at school age as compared to their non-farming counterparts 3-6. This “farm effect” has been validated across decades, countries, and ethnic groups 7-10; however, the means by which microbial exposure leads to an anti-asthmatic phenotype remain unclear. Current studies from both mice and humans suggest that Amish house dust 9, 11 as well as microbial products in farm dust can protect from development of asthma. Endotoxin 10, 12-16 and the farm shed associated-bacterium Acinetobacter lwoffii 17 can render the neonatal immune system refractory to allergic stimuli. However, the therapeutic capacity of these agents is limited by potential off-target inflammatory consequences such as acute lung injury for endotoxin and opportunistic infection for A. lwoffii. Therefore, there is a need to isolate farm-associated microbial products that inhibit allergic inflammation while not inducing other, deleterious inflammatory events. Our collaborator has that found that exopolysaccharide (EPS) from the common hay bacillus B. subtilis can limit inflammation in several mouse models including enteric infection 18, 19 and systemic Staphylococcus aureus infection 20. I now present data that treatment of house dust mite (HDM)- sensitized mice with EPS prevents allergic sequelae such as airway goblet cell hyperplasia, lung eosinophilia, and lung Th2 accumulation. EPS also inhibited generation of GATA3-expressing Tregs, which have been recently implicated in exacerbating allergic inflammation 21, 22. Notably, EPS alone does not cause inflammation or lung injury in the absence of an inflammatory signal such as HDM, making is a much safer alternative for suppression of allergic inflammation. I have also found that EPS changes DC lung composition as early as 24 hours after co-exposure with HDM. These data clearly demonstrate an effect of EPS on innate immune cells, yet the mechanisms by which EPS acts to suppress allergic inflammation are unknown. The overall hypothesis of this project is that EPS inhibits allergic inflammation by interfering with innate cell activation and the generation of pathogenic pro-type 2 adaptive cells. To address my hypothesis, I propose to 1) determine how EPS impacts the lung innate cell repertoire and 2) determine the role of EPS in suppressing pro-allergenic T cells. Understanding how microbial products such as EPS inhibit the generation of inflammation will provide valuable insight into the pathogenesis of type 2 responses. Furthermore, the work in this proposal will uncover alternative targets for preventing or treating allergic asthma, and thus has potential therapeutic impact.

项目摘要/摘要哮喘是一种慢性炎症性疾病，影响全球估计有3.39亿人，是以喘息，呼吸急促和效率低下的气体交换为特征。哮喘的患病率在过去的半个世纪中，工业化国家的大幅增长；但是，微生物暴露在内这些国家似乎受到保护免受哮喘发展的影响。多项研究发现孩子与之相比与他们的非农场3-6同行。在数十年，国家和种族7-10；然而，微生物暴露导致抗哮喘表型的手段保持不清楚。目前来自小鼠和人类的研究表明，阿米什人的尘埃9、11以及农场灰尘中的微生物产品可以防止哮喘发育。内毒素10、12-16和农场棚相关的 - 细菌杆菌lwoffii 17可以使新生儿免疫系统对过敏性难治刺激。但是，这些药物的治疗能力受到潜在脱靶炎症的限制诸如内毒素急性肺损伤和lwoffii的机会性感染等后果。因此，那里是需要分离抑制过敏注射而未诱导的与农场相关的微生物产物其他，删除的炎症事件。我们的合作者发现，来自常见的干草芽孢杆菌梭菌可以限制在包括肠感染在内的几种小鼠模型中的注射18，19 和全身性金黄色葡萄球菌感染20。具有EPS的敏感小鼠可防止过敏后遗症，例如气道杯状细胞增生，肺嗜酸性粒细胞增生，和肺Th2积累。 EP还抑制了表达GATA3的Treg的产生，最近在加剧过敏注射21、22中实施了在没有HDM等炎症信号的情况下，肺部受伤是一种更安全的选择。抑制过敏注射。我还发现EPS早在24 与HDM共同暴露后数小时。这些数据清楚地证明了EPS对先天免疫细胞的影响，然而，EPS抑制过敏注射的机制尚不清楚。总体该项目的假设是，EPS通过干扰先天细胞激活和致病性pro型2自适应细胞的产生。为了解决我的假设，我建议1）确定 EPS如何影响肺与生俱来的细胞库，2）确定EP在抑制prolermencenic中的作用 T细胞。了解微生物产品（例如EPS）如何抑制炎症的产生将提供对2型反应的发病机理的有价值的见解。此外，该提案中的工作将揭开预防或治疗过敏性哮喘的替代靶标，因此具有潜在的治疗影响。