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5-Lipoxygenase Inhibition as a Therapy to Prevent Cryptococcus-related IRIS

Award Number: R21AI158260
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: 02/22/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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5-Lipoxygenase Inhibition as a Therapy to Prevent Cryptococcus-related IRIS - Cryptococcal meningoencephalitis (CM) is the most common disseminated fungal disease in AIDS patients and is responsible for 15% of AIDS-related deaths globally. A complication associated with the initiation of antiretroviral therapy (ART) in HIV positive patients with CM is the development of immune reconstitution inflammatory syndrome (IRIS) which can lead to severe neurological sequela, morbidity, and significant mortality. IRIS afflicts up to 30% of HIV positive patients with a prior diagnosis of cryptococcosis who begin ART. Current efforts to mitigate Cryptococcus-related IRIS (C-IRIS) include delaying initiation of ART until sterile immunity is achieved, and/or using corticosteroid and/or non-steroidal anti-inflammatory drugs (NSAIDs) as anti-inflammatory agents to prevent C-IRIS. Significant drawbacks to these efforts are that delaying ART therapy in HIV positive patients allows the virus to propagate unchecked and anti- inflammatory drugs can inhibit host immune responses and potentially reduce anti-cryptococcal drug activity. Thus, therapies that allow for ART initiation at the onset of diagnosis, do not inhibit the efficacy of antifungal drugs or protective anti-cryptococcal host responses, and prevent deleterious inflammatory responses will have a significant impact towards reducing morbidity associated with C-IRIS. Preliminary studies in our laboratory show that inhibition of 5- lipoxygenase (5-LO) activity results in a significant reduction in the neurological deterioration, morbidity and mortality associated with CM. Specifically, studies using an experimental mouse model of cryptococcosis show that 5-LO knockout (KO) mice, in contrast to wild-type (WT) mice, do not exhibit the classic neurological sequela or mortality associated with CM. Moreover, myeloid cell infiltration and the production of chemokines associated with the development of C- IRIS in humans (i.e., CCL2 and CCL3) were significantly reduced in brain tissues of 5-LO KO mice compared to WT mice. Taken together, these results lead us to hypothesize that inhibition of 5-LO signaling reduces the neurological inflammatory sequelae leading to the development of C-IRIS. To test our hypothesis, we propose to: 1) determine the impact of 5- LO blockade on the development of C-IRIS and 2) demonstrate the therapeutic impact of 5-LO inhibitors as an adjunct to antifungal therapy using a murine model of C-IRIS.


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 = -$11,137 )
2025	2022	TEXAS CHRISTIAN UNIVERSITY	3101 BELLAIRE DRIVE NORTH	FORT WORTH	TX	76129	TARRANT	USA	Allergy and Infectious Diseases Research	000	2	6/9/2025	NON-COMPETING CONTINUATION	-$11,137
														Subtotal = -$11,137

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	TEXAS CHRISTIAN UNIVERSITY	3101 BELLAIRE DRIVE NORTH	FORT WORTH	TX	76129	TARRANT	USA	Allergy and Infectious Diseases Research	000	2	1/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $145,825 )
2022	2022	TEXAS CHRISTIAN UNIVERSITY INC	2800 S UNIVERSITY DR	FORT WORTH	TX	76129	TARRANT	USA	Allergy and Infectious Diseases Research	000	2	1/19/2022	NON-COMPETING CONTINUATION	$145,825
														Subtotal = $145,825

Issue Date FY: 2021 ( Subtotal = $170,219 )
2021	2021	TEXAS CHRISTIAN UNIVERSITY INC	2800 S UNIVERSITY DR	FORT WORTH	TX	76129	TARRANT	USA	Allergy and Infectious Diseases Research	001	1	4/16/2021	NEW	$0
2021	2021	TEXAS CHRISTIAN UNIVERSITY INC	2800 S UNIVERSITY DR	FORT WORTH	TX	76129	TARRANT	USA	Allergy and Infectious Diseases Research	000	1	2/23/2021	NEW	$170,219
														Subtotal = $170,219

Grand Total All Awards = $304,907

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5-Lipoxygenase Inhibition as a Therapy to Prevent Cryptococcus-related IRIS

Award Number: R21AI158260

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: 02/22/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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