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Detection of intestinal pathogens through host surveillance of bacterial toxins

Award Number: F30DK127690
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Detection of intestinal pathogens through host surveillance of bacterial toxins - PROJECT SUMMARY/ABSTRACT Although commensal and pathogenic bacteria can be recognized by host pattern recognition receptors, intestinal epithelial cells target protective inflammatory responses towards pathogenic organisms through mechanisms that are incompletely understood. Additional mechanisms of pathogen sensing must exist that allow intestinal cells to target inflammatory defenses towards bona fide pathogens during an infection, and not harmless commensal bacteria. Pathogenic bacteria can express virulence determinants. Phenazine toxins are a family of redox active virulence determinants that are produced by a variety of human pathogens, including P. aeruginosa. P. aeruginosa can colonize the intestines of immunocompromised patients and cause fulminant septicemia and subsequent death. The mechanism by which intestinal epithelial cells detect P. aeruginosa, and whether this involves the surveillance of phenazine toxins, is not known. Nuclear hormone receptors (NHR) are transcription factors that program adaptive host responses following recognition of specific exogenous or endogenous ligands. In particular, HNF4⍺ is an NHR expressed in the intestine. In the model organism C. elegans, the HNF4⍺ homolog NHR-86 is required for the transcriptional activation of innate immune effector genes that protect against P. aeruginosa infection. The central hypothesis of this proposal is that intestinal epithelial cells detect infection through the surveillance of pathogen-derived phenazine toxins by NHR-86/ HNF4⍺, which directly activates protective anti-pathogen defenses in the intestinal epithelium. The following key preliminary findings support this central hypothesis: i) P. aeruginosa mutants that cannot make phenazine toxins do not activate C. elegans innate immune defenses; ii) synthetic phenazine toxins can activate immune genes; and iii) induction of immune genes by phenazine toxins is dependent on the expression of NHR-86/ HNF4⍺. In this proposal, Aim 1 will characterize the C. elegans immune response towards bacterial phenazine toxins, and Aim 2 will define the role of intestinal NHR-86/HNF4⍺ in detecting P. aeruginosa infection in C. elegans. The research proposed here will define a new concept of immune activation in intestinal epithelial cells and will also attribute a novel role for NHRs in pathogen sensing in the intestine. Insights from these findings may identify unexplored approaches for the development of anti-inflammatory and anti-infective therapies.


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 = $24,687 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/14/2025	NON-COMPETING CONTINUATION	$24,593
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	5/29/2025	NON-COMPETING CONTINUATION	$94
														Subtotal = $24,687

Issue Date FY: 2024 ( Subtotal = $50,487 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	4/29/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/12/2024	NON-COMPETING CONTINUATION	$49,207
														Subtotal = $50,487

Issue Date FY: 2023 ( Subtotal = $32,688 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	2/17/2023	NON-COMPETING CONTINUATION	$942
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/31/2023	NON-COMPETING CONTINUATION	$31,746
														Subtotal = $32,688

Issue Date FY: 2022 ( Subtotal = $31,746 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/10/2022	NON-COMPETING CONTINUATION	$717
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/13/2021	NON-COMPETING CONTINUATION	$31,030
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	7/8/2022	NON-COMPETING CONTINUATION	-$1
														Subtotal = $31,746

Issue Date FY: 2021 ( Subtotal = $31,030 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	12/8/2020	NEW	$0
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	2/8/2021	NEW	$516
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/8/2020	NEW	$30,514
														Subtotal = $31,030

Grand Total All Awards = $170,638

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Detection of intestinal pathogens through host surveillance of bacterial toxins

Award Number: F30DK127690

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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