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Molecular basis of intestinal cryptosporidiosis

Award Number: R01AI116323
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: 02/04/2015
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Molecular basis of intestinal cryptosporidiosis - Summary Cryptosporidium remains a significant AIDS-related opportunistic infection among people with late HIV diagnosis or without access to HAART. This parasite infects the gastrointestinal epithelium in humans; infection is also a common cause of diarrhea in young children in developing countries. There is currently no fully effective therapy available for the infection. Cryptosporidium has been referred as a “minimally invasive” mucosal pathogen, and epithelial antimicrobial defense is key to mucosal innate anti-Cryptosporidium immunity. Whereas it is well appreciated that Type II interferon-gamma (IFN-γ) is required for preventing development of intestinal cryptosporidiosis, recent advances have revealed a significant Type I IFN response (e.g., induction of IFN-alpha and IFN-beta) in host epithelium following C. parvum infection. The molecular mechanisms underlying Type I IFN response and its potential role in the pathogenesis of cryptosporidiosis are unclear. Cryptosporidium parvum virus 1 (CSpV1) is a member of the family Partitiviridae, genus Cryspovirus that infects C. parvum and other Cryptosporidium spp. Our recent studies demonstrate that host delivery of CSpV1-RNAs at the host-parasite interface can trigger a Type I IFN response in host cells. C. parvum infection attenuates intestinal epithelial cell response to IFN-γ stimulation (i.e., infected cells are less susceptible to activation by IFN-γ). Surprisingly, knockout Type I IFN signaling in intestinal epithelial cells or inhibition of CSpV1-RNA delivery can restore cellular response to IFN-γ stimulation and promotes resistance to C. parvum infection, suggesting a negative impact of Type I IFN signaling on epithelial anti-Cryptosporidium defense. Based on these observations, we hypothesize that cryptosporidial infection triggers Type I IFN response in the intestinal epithelium and attenuates IFN-γ-mediated epithelial antimicrobial defense through delivery of CSpV1- RNAs. 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 Cryptosporidium infection triggers Type I IFN gene transcription in the intestinal epithelium (Aim 1), determine how Cryptosporidium infection modulates the JAK/STAT signaling in infected intestinal epithelial cells (Aim 2), and define the impact of Cryptosporidium-induced JAK/STAT signaling dysregulation on epithelial anti-parasite defense (Aim 3). The proposal is conceptually innovative as it tests a novel mechanism for symbiotic CSpV1 in the pathogenesis of cryptosporidiosis and has the potential to inform future development of new therapeutic strategies.


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 = $419,146 )
2025	2025	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	10	2/13/2025	NON-COMPETING CONTINUATION	$419,146
														Subtotal = $419,146

Issue Date FY: 2024 ( Subtotal = $429,026 )
2024	2024	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	9	2/22/2024	NON-COMPETING CONTINUATION	$386,123
2024	2024	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	001	9	5/23/2024	NON-COMPETING CONTINUATION	$42,903
														Subtotal = $429,026

Issue Date FY: 2023 ( Subtotal = $429,026 )
2023	2023	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	8	3/15/2023	NON-COMPETING CONTINUATION	$429,026
														Subtotal = $429,026

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	RUSH UNIVERSITY MEDICAL CENTER	1620 W HARRISON ST	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	002	7	3/24/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2020	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	6	10/22/2021	COMPETING CONTINUATION	$292,989
2022	2020	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	001	6	10/22/2021	COMPETING CONTINUATION	-$292,989
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $443,276 )
2021	2021	RUSH UNIVERSITY MEDICAL CENTER	1620 W HARRISON ST	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	006	7	9/24/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$695,986
2021	2021	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PRKWY	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	001	7	2/24/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$443,276
2021	2020	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	004	6	3/5/2021	COMPETING CONTINUATION	$517,166
2021	2020	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	6	2/24/2021	COMPETING CONTINUATION	$0
2021	2020	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	005	6	9/24/2021	COMPETING CONTINUATION	-$695,986
2021	2019	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	003	5	3/5/2021	NON-COMPETING CONTINUATION	-$407,626
2021	2018	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	002	4	3/5/2021	NON-COMPETING CONTINUATION	-$109,540
														Subtotal = $443,276

Issue Date FY: 2020 ( Subtotal = $402,997 )
2020	2020	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	001	6	2/25/2020	COMPETING CONTINUATION	$402,997
2020	2019	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	5	2/25/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $402,997

Issue Date FY: 2019 ( Subtotal = $407,626 )
2019	2019	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	5	1/25/2019	NON-COMPETING CONTINUATION	$407,626
														Subtotal = $407,626

Issue Date FY: 2018 ( Subtotal = $407,626 )
2018	2018	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	4	12/18/2017	NON-COMPETING CONTINUATION	$407,626
														Subtotal = $407,626

Issue Date FY: 2017 ( Subtotal = $407,626 )
2017	2017	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	3	1/30/2017	NON-COMPETING CONTINUATION	$407,626
														Subtotal = $407,626

Issue Date FY: 2016 ( Subtotal = $407,626 )
2016	2016	CREIGHTON UNIVERSITY	2500 CALIFORNIA STREET	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	2	1/22/2016	NON-COMPETING CONTINUATION	$407,626
2016	2016	CREIGHTON UNIVERSITY	2500 CALIFORNIA STREET	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	001	2	5/4/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $407,626

Issue Date FY: 2015 ( Subtotal = $407,626 )
2015	2015	CREIGHTON UNIVERSITY	2500 CALIFORNIA STREET	OMAHA	NE	68178	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	1	2/4/2015	NEW	$407,626
														Subtotal = $407,626

Grand Total All Awards = $4,161,601

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Molecular basis of intestinal cryptosporidiosis

Award Number: R01AI116323

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: 02/04/2015

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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