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

Information

  • Research Project
  • 10256128
  • ApplicationId
    10256128
  • Core Project Number
    R21AI158260
  • Full Project Number
    1R21AI158260-01A1
  • Serial Number
    158260
  • FOA Number
    PA-20-195
  • Sub Project Id
  • Project Start Date
    2/22/2021 - 3 years ago
  • Project End Date
    1/31/2023 - a year ago
  • Program Officer Name
    LIU, BAOYING
  • Budget Start Date
    2/22/2021 - 3 years ago
  • Budget End Date
    1/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
    A1
  • Award Notice Date
    2/23/2021 - 3 years ago

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.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R21
  • Administering IC
    AI
  • Application Type
    1
  • Direct Cost Amount
    150000
  • Indirect Cost Amount
    20219
  • Total Cost
    170219
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
    SCHOOLS OF ARTS AND SCIENCES
  • Funding ICs
    NIAID:170219\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    HCAC
  • Study Section Name
    HIV Coinfections and HIV Associated Cancers Study Section
  • Organization Name
    TEXAS CHRISTIAN UNIVERSITY
  • Organization Department
    BIOLOGY
  • Organization DUNS
    043807882
  • Organization City
    FORT WORTH
  • Organization State
    TX
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    761290001
  • Organization District
    UNITED STATES