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Pathogen sensing by nuclear hormone receptors in C. elegans intestinal epithelial cells

Award Number: F30AI150127
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 09/30/2023

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Pathogen sensing by nuclear hormone receptors in C. elegans intestinal epithelial cells - PROJECT SUMMARY/ABSTRACT The mechanisms of pathogen sensing and immune effector induction in intestinal epithelial cells are not completely understood. Disruption in the mechanisms of pathogen sensing and immune homeostasis in intestinal epithelial cells can lead to dysbiosis and inflammation, as well as susceptibility to bacterial infection. Key insights into intestinal epithelial cell immunity and host-pathogen interactions have been made using the nematode C. elegans. Nematodes mount innate immune defenses against bacterial infection via conserved immune pathways, but the mechanisms of pathogen detection are unknown in this organism. In nematodes, the family of nuclear hormone receptors (NHRs) has dramatically expanded compared to other metazoans. NHRs are ligand-gated transcription factors that sense endogenous and exogenous signals to induce adaptive transcriptional responses. The C. elegans genome encodes 274 NHRs, of which 260 are homologs of human HNF4α. HNF4α is a key NHR involved in inflammatory bowel disease, though the mechanism through which HNF4α mediates inflammatory bowel disease in humans is unknown. The central hypothesis of this proposal is that C. elegans HNF4α homologs are an ancient family of pathogen sensors whose evolutionary expansion in C. elegans was driven by their function in detecting diverse pathogens. The following key findings support this hypothesis: (i) The nuclear hormone receptor, NHR-86/HNF4α, senses the cellular environment and activates C. elegans intestinal immune defenses; (ii) NHR-86/HNF4α is required for pathogen resistance and immune response towards the gram positive human pathogen E. faecalis; and (iii) A different C. elegans HNF4α homolog is required for pathogen defense and immune effector regulation against the gram negative pathogen P. aeruginosa. In this proposal, Aim 1 will define the role of C. elegans NHR-86/HNF4α in pathogen detection and immune effector induction during E. faecalis infection using a combination of transcriptomics, ChIP- sequencing, tissue-specific rescue and genetic epistasis. Aim 2 will characterize the function of a separate C. elegans HNF4α homolog in pathogen sensing during P. aeruginosa infection. The approach includes: transcriptomics, global NHR binding site identification, tissue specific rescue, and P. aeruginosa genetics. Collectively, these studies will characterize a fundamentally new paradigm of immune activation, which will solve a major conundrum of how pathogens are sensed in C. elegans. These findings will also establish NHRs as evolutionarily ancient pathogen sensors. Ultimately, the expectation is that detailed dissection of this mechanism will shed light on the role of HNF4α in mammalian pathogen sensing and inflammatory bowel disease.


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: 2024 ( Subtotal = -$5,954 )
2024	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	4	7/24/2024	NON-COMPETING CONTINUATION	-$5,954
														Subtotal = -$5,954

Issue Date FY: 2023 ( Subtotal = $38,442 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	001	4	2/17/2023	NON-COMPETING CONTINUATION	$628
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	4	12/20/2022	NON-COMPETING CONTINUATION	$37,814
														Subtotal = $38,442

Issue Date FY: 2022 ( Subtotal = $31,746 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	002	3	5/24/2022	NON-COMPETING CONTINUATION	-$1
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	3	1/14/2022	NON-COMPETING CONTINUATION	$31,030
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	001	3	5/3/2022	NON-COMPETING CONTINUATION	$717
														Subtotal = $31,746

Issue Date FY: 2021 ( Subtotal = $31,030 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	2	2/11/2021	NON-COMPETING CONTINUATION	$31,030
														Subtotal = $31,030

Issue Date FY: 2020 ( Subtotal = $30,514 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	1	1/8/2020	NEW	$30,010
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	002	1	2/21/2020	NEW	$0
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	001	1	2/21/2020	NEW	$504
														Subtotal = $30,514

Grand Total All Awards = $125,778

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Pathogen sensing by nuclear hormone receptors in C. elegans intestinal epithelial cells

Award Number: F30AI150127

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 09/30/2023

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