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Regulation of C. difficile colitis by host genetic and immune factors

Award Number: R01AI158451
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/17/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Regulation of C. difficile colitis by host genetic and immune factors - Project Summary: Clostridium difficile is the leading nosocomial infection in the U.S. Host factors are a key predictor of disease outcomes after C. difficile infection (CDI). We have discovered a key role for leptin receptor (LEPR) pathway and the pro-inflammatory cytokine Macrophage Inhibitory Factor (MIF) in CDI pathogenesis. Our data reveal that a common single nucleotide polymorphism (SNP) in the gene for LEPR (Q223R; present in up to 50% of humans) is associated with exaggerated MIF production after CDI in humans. CDI in mice homozygous for the mutant SNP (RR) resulted in higher MIF production, more colonic neutrophilia and tissue damage, without effects on pathogen. We reported that neutralizing MIF using antibody resulted in reduced tissue injury and improved survival in mice, without effects on C. difficile pathogen. Finally, blocking a key receptor for MIF, CXC chemokine receptor 2 (CXCR2) also reduced CDI-induced neutrophil accrual in tissue. This proposal is based on these published results and new preliminary data which indicate that LEPR Q to R change augments Bcl-2 like protein 11 (Bim) expression which controls MIF release by modulating pathways of autophagy/mitophagy/apoptosis. The overall hypothesis of our studies is that: LEPR Q to R substitution exaggerates CDI-induced, Bim-dependent MIF release that augments CXCR2-dependent tissue neutrophil accrual and worsens disease severity. To test this hypothesis, we propose three specific aims. Aim 1 will define the key pathogen-associated drivers of MIF and the main cellular sources of MIF production in CDI. We will use WT and toxin-deficient C. difficile strains to determine the role of toxins and non-toxin factors in driving MIF expression. Cellular sources of MIF will be defined after CDI in WT mice by intracellular staining and immunohistochemistry and their role in CDI will be tested by using selective MIF deletion in intestinal epithelial cells and in hematopoietic cells. Aim 2 will examine the mechanism of CDI-induced MIF release. We will determine the role of LEPR Q to R substitution in regulating Bim expression and subsequent autophagy, mitophagy and apoptosis pathways. Studies will use Bim-reporter and Bim-deficient mice, and Bim+/+ and Bim-/- human intestinal organoids generated from induced pluripotent stem cells in both QQ and RR background. Aim 3 will investigate the role of MIF-CXCR2 axis in CDI-induced tissue neutrophilia in QQ and RR mice. We will compare the effect of MIF on neutrophil trafficking and on their lifespan. We will utilize neutrophils derived from WT and CXCR2-/- mice in in vitro (migration assays) and in vivo (after depletion of endogenous neutrophils and reconstitution with labeled neutrophils prior to infection) experiments. We expect these studies to provide a greater understanding of the role of host genetics in regulating MIF during CDI pathogenesis. Our studies have the potential to identify new host-based targets that can be used in the design of novel CDI 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 = $405,000 )
2025	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Allergy and Infectious Diseases Research	000	5	7/17/2025	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2024 ( Subtotal = $405,000 )
2024	2024	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Allergy and Infectious Diseases Research	000	4	8/13/2024	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2023 ( Subtotal = $407,758 )
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Allergy and Infectious Diseases Research	000	3	8/2/2023	NON-COMPETING CONTINUATION	$407,758
														Subtotal = $407,758

Issue Date FY: 2022 ( Subtotal = $411,085 )
2022	2022	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Allergy and Infectious Diseases Research	000	2	8/12/2022	NON-COMPETING CONTINUATION	$411,085
														Subtotal = $411,085

Issue Date FY: 2021 ( Subtotal = $411,085 )
2021	2021	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Allergy and Infectious Diseases Research	000	1	9/17/2021	NEW	$411,085
														Subtotal = $411,085

Grand Total All Awards = $2,039,928

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Regulation of C. difficile colitis by host genetic and immune factors

Award Number: R01AI158451

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/17/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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