1606. Novel adjunctive therapies for cerebral malaria that target metabolism
Session: Poster Abstract Session: Global Health
Saturday, October 10, 2015
Room: Poster Hall
Posters
  • TUAN TRAN IDWeek 2015 Poster.pdf (2.0 MB)
  • Background: Cerebral malaria (CM) caused by Plasmodium falciparum has a case fatality rate of 15-25%, resulting in ~600,000 malaria deaths annually despite effective antimalarial chemotherapy. Currently, there are no adjunctive treatments for CM, emphasizing the need to identify novel targets for therapy. Using the mouse model of CM, experimental CM (ECM), we have demonstrated that targeting specific metabolic pathways important to the host immune response protects against the progression of ECM and improves survival. We recently showed that treatment with sirolimus, which inhibits the kinase mammalian target of rapamycin (mTOR), within 4 days of infection increased survival and decreased the accumulation of CD4+ and CD8+ T cells as well as parasitized erythrocytes in the infected brain despite an increase in systemic inflammatory responses. Transcriptomic analysis of infected brains revealed inhibition of cellular trafficking and cellular proliferation during sirolimus treatment. In the current study, we target glutamine metabolism, which plays a critical role in the activation and proliferation of T cells.

    Methods:

    We infected C57BL/6 mice with P. berghei ANKA, which causes ECM, and treated mice with an active site inhibitor of glutaminase or saline during late-stage ECM, at a time when animals exhibit profound neurological signs of infection. We determined differences between treatment and control groups in terms of survival, clinical scores, immunopathology in the brain, and metabolomics within the brain, liver and serum.

    Results:

    Treatment of infected mice with the glutaminase inhibitor, but not saline, rescued mice from ECM, restored blood-brain barrier integrity, decreased brain swelling, reduced the function of activated effector CD8+ T cells, and reversed infection-induced metabolomic changes specifically in the brain.

    Conclusion: These results provide evidence that targeting metabolic pathways critical to the host immune response may be a useful strategy for the development of highly selective adjunctive therapies for CM.

    Tuan M. Tran, MD, PhD1, Emile B. Gordon, BS1, Geoffrey T. Hart, PhD1, Michael Waisberg, MD, PhD1, Munir Akkaya, PhD1, Ann Kim, BS1, Sara E. Hamilton, PhD2, Mirna Pena, BS1, Takele Yazew, BS1, Chen-Feng Qi, MD, PhD1, Louis H. Miller, MD3, Jonathan D. Powell, MD, PhD4 and Susan K. Pierce, PhD1, (1)Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, (2)Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, (3)Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, (4)Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD

    Disclosures:

    T. M. Tran, None

    E. B. Gordon, None

    G. T. Hart, None

    M. Waisberg, None

    M. Akkaya, None

    A. Kim, None

    S. E. Hamilton, None

    M. Pena, None

    T. Yazew, None

    C. F. Qi, None

    L. H. Miller, None

    J. D. Powell, None

    S. K. Pierce, None

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