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m6A methylation of IRGM transcripts in epithelial-Cryptosporidium interactions

Award Number: R21AI177188
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: 02/14/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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m6A methylation of IRGM transcripts in epithelial-Cryptosporidium interactions - Summary Cryptosporidium, an apicomplexan parasite that infects the gastrointestinal epithelium in humans, remains an important opportunistic pathogen in AIDS patients who do not have access to HAART treatment. This parasite is also a leading cause of infectious diarrhea and diarrheal-related death in children worldwide. The N6- methyladenosine (m6 a reversible RNA post-transcriptional modification. Emerging A) RNA methylation is evidence from our lab and others has defined m6A RNA methylation as a crucial regulator in host antimicrobial response. The overall objective of this R21 proposal is to advance our understanding of the molecular mechanisms by which intestinal epithelial cells control the dynamic of m6A RNA modifications of mRNA transcripts to orchestrate IFN-γ-mediated epithelial anti-Cryptosporidium defense. We have recently demonstrated significant alterations in the topology of host m6A mRNA methylome in murine intestinal epithelial cells following Cryptosporidium infection. Although the RNA levels of several IFN-induced immunity- related GTPase family M (IRGM) genes are upregulated, a decreased in their m6A RNA methylation level and translation was identified in infected cells. In contrast, IFN-γ stimulation upregulates the RNA levels of IRGM genes with an increased m6A RNA methylation and importantly, m6A methylation of IRGM RNAs is associated with an increased translation. Given the fact that the IRGM proteins are critical effectors in IFN-γ-mediated cell- autonomous immunity in both mice and humans, we hypothesize that m6A methylation of IRGM mRNA transcripts promotes IFN-γ-mediated epithelial cell antimicrobial defense and to counteract IFN-γ-mediated host defense, Cryptosporidium has developed strategies to suppress m6A methylation of IRGM mRNA transcripts. We will use in vitro, ex vivo, and in vivo infection models and complementary biochemical, molecular, and morphologic approaches to elucidate the molecular mechanisms by which m6A methylation of IRGM mRNA transcripts promotes IFN-γ-mediated intestinal epithelial cell anti-Cryptosporidium defense (Aim 1) and determine how Cryptosporidium suppresses m6A methylation of IRGM mRNA transcripts, resulting in attenuation of IFN-γ-mediated epithelial anti-parasitic defence (Aim 2). Detailed mechanistic studies of the role m6A RNA methylation of IRGM transcripts in host-Cryptosporidium interactions could not only reveal new insights into the molecular immunology and immunopathology of intestinal Cryptosporidium infection but also establish a foundation on which to build long-term, mechanistic studies to define its pathogenesis and therapeutic interventaion.


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: 2026 ( Subtotal = $0 )
2026	2025	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	2	10/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $191,575 )
2025	2025	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	2	12/20/2024	NON-COMPETING CONTINUATION	$191,575
														Subtotal = $191,575

Issue Date FY: 2024 ( Subtotal = $237,000 )
2024	2024	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	002	1	9/12/2024	NEW	$23,700
2024	2024	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	1	2/14/2024	NEW	$213,300
2024	2024	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	001	1	7/11/2024	NEW	$0
														Subtotal = $237,000

Grand Total All Awards = $428,575

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m6A methylation of IRGM transcripts in epithelial-Cryptosporidium interactions

Award Number: R21AI177188

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: 02/14/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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