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

Award Number: F31HL156659
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$31,426 )
2025	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Lung Diseases Research	000	2	10/23/2024	NON-COMPETING CONTINUATION	-$31,426
														Subtotal = -$31,426

Issue Date FY: 2023 ( Subtotal = $47,694 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Lung Diseases Research	000	2	1/16/2023	NON-COMPETING CONTINUATION	$46,752
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Lung Diseases Research	001	2	4/3/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $47,694

Issue Date FY: 2021 ( Subtotal = $46,036 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Lung Diseases Research	001	1	8/27/2021	NEW	$0
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Lung Diseases Research	000	1	8/27/2021	NEW	$46,036
														Subtotal = $46,036

Grand Total All Awards = $62,304

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

Award Number: F31HL156659

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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