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Effect of Microbial Metabolites on Growth of Cryptosporidium

Award Number: R01AI145496
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: 12/13/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Effect of Microbial Metabolites on Growth of Cryptosporidium - Summary Cryptosporidiosis is a common cause of severe, chronic diarrheal disease in immunocompromised patients such as those with HIV/AIDS. The only FDA approved drug for treatment of cryptosporidiosis, nitazoxanide, has limited effectiveness in immunocompromised patients. Despite the advent of HAART therapy, cryptosporidiosis still presents a major problem among patient populations where HIV diagnosis or anti-viral treatments are inadequate. As an enteric pathogen, Cryptosporidium interacts with the complex microbial community that constitutes the microbiome. Perturbations to the microbiota, such as through antibiotic treatment, are associated with increased susceptibility to infection in adult animals. Additionally, neonatal animals, which harbor an immature microbiota, are much more susceptible to Cryptosporidium infection than adults. One method by which the microbiota may influence susceptibility to Cryptosporidium infection is through the production of inhibitory small molecule metabolites. For example, high fecal indole levels were associated with lower susceptibility in a human challenge study of Cryptosporidium. Collectively, these findings raise the intriguing hypothesis that metabolites produced by the microbiota influence susceptibility to infection with Cryptosporidium. In preliminary studies, we have screened a library of bacterial metabolites that are abundant components of the normal adult microbiota for their ability to inhibit growth of C. parvum in vitro. We identified several classes of metabolites that are potent inhibitors of parasite growth at levels that are not toxic to host cells. The proposed studies will explore the mechanism(s) of inhibition by these microbial metabolites by determining which stage(s) of the parasite life cycle they target and whether they are static or cidal. We will also explore host cell signaling pathways that activate host defenses, as the potential mechanism by which these metabolites act. Finally, by employing animal models for cryptosporidiosis, we will test whether inhibitory metabolites can be used to treat infection in vivo. If successful, these studies may establish a new paradigm for treating persistent cryptosporidiosis in immunocompromised patients.


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 = $0 )
2025	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	4	4/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $670,711 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	4	11/10/2022	NON-COMPETING CONTINUATION	$670,711
														Subtotal = $670,711

Issue Date FY: 2022 ( Subtotal = $670,711 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	3	11/16/2021	NON-COMPETING CONTINUATION	$670,711
														Subtotal = $670,711

Issue Date FY: 2021 ( Subtotal = $670,711 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	2	11/16/2020	NON-COMPETING CONTINUATION	$670,711
														Subtotal = $670,711

Issue Date FY: 2020 ( Subtotal = $683,892 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	12/12/2019	NEW	$683,892
														Subtotal = $683,892

Grand Total All Awards = $2,696,025

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Effect of Microbial Metabolites on Growth of Cryptosporidium

Award Number: R01AI145496

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: 12/13/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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