Browsing by Author "Hart, Geoffrey T."

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    Adaptive NK cells in people exposed to Plasmodium falciparum correlate with protection from malaria
    (Rockefeller University Press, 2019-04-12) Hart, Geoffrey T.; Tran, Tuan M.; Theorell, Jakob; Schlums, Heinrich; Arora, Gunjan; Rajagopalan, Sumati; Sangala, A. D. Jules; Welsh, Kerry J.; Traore, Boubacar; Pierce, Susan K.; Crompton, Peter D.; Bryceson, Yenan T.; Long, Eric O.; Medicine, School of Medicine
    How antibodies naturally acquired during Plasmodium falciparum infection provide clinical immunity to blood-stage malaria is unclear. We studied the function of natural killer (NK) cells in people living in a malaria-endemic region of Mali. Multi-parameter flow cytometry revealed a high proportion of adaptive NK cells, which are defined by the loss of transcription factor PLZF and Fc receptor γ-chain. Adaptive NK cells dominated antibody-dependent cellular cytotoxicity responses, and their frequency within total NK cells correlated with lower parasitemia and resistance to malaria. P. falciparum–infected RBCs induced NK cell degranulation after addition of plasma from malaria-resistant individuals. Malaria-susceptible subjects with the largest increase in PLZF-negative NK cells during the transmission season had improved odds of resistance during the subsequent season. Thus, antibody-dependent lysis of P. falciparum–infected RBCs by NK cells may be a mechanism of acquired immunity to malaria. Consideration of antibody-dependent NK cell responses to P. falciparum antigens is therefore warranted in the design of malaria vaccines.
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    A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation
    (Elsevier, 2019-10-15) Tran, Tuan M.; Guha, Rajan; Portugal, Silvia; Skinner, Jeff; Ongoiba, Aissata; Bhardwaj, Jyoti; Jones, Marcus; Moebius, Jacqueline; Venepally, Pratap; Doumbo, Safiatou; DeRiso, Elizabeth A.; Li, Shanping; Vijayan, Kamalakannan; Anzick, Sarah L.; Hart, Geoffrey T.; O’Connell, Elise M.; Doumbo, Ogobara K.; Kaushansky, Alexis; Alter, Galit; Felgner, Phillip L.; Lorenzi, Hernan; Kayentao, Kassoum; Traore, Boubacar; Kirkness, Ewen F.; Crompton, Peter D.; Medicine, School of Medicine
    Immunity that controls parasitemia and inflammation during Plasmodium falciparum (Pf) malaria can be acquired with repeated infections. A limited understanding of this complex immune response impedes the development of vaccines and adjunctive therapies. We conducted a prospective systems biology study of children who differed in their ability to control parasitemia and fever following Pf infection. By integrating whole-blood transcriptomics, flow-cytometric analysis, and plasma cytokine and antibody profiles, we demonstrate that a pre-infection signature of B cell enrichment; upregulation of T-helper type 1 (Th1) and Th2 cell-associated pathways, including interferon responses; and p53 activation associated with control of malarial fever and coordinated with Pf-specific IgG and Fc receptor activation to control parasitemia. Our hypothesis-generating approach identified host molecules that may contribute to differential clinical outcomes during Pf infection. As a proof of concept, we have shown that enhanced p53 expression in monocytes attenuated Plasmodium-induced inflammation and predicted protection from fever.