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

• 批准号: 10315781
• 负责人: Maile Kananiokala Hollinger
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 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/10315781
• 关键词: Inhibition; Th2; responses; secreted; components

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.

项目总结/文摘