A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation

Tuan M. Tran, Rajan Guha, Silvia Portugal, Jeff Skinner, Aissata Ongoiba, Jyoti Bhardwaj, Marcus Jones, Jacqueline Moebius, Pratap Venepally, Safiatou Doumbo, Elizabeth A. DeRiso, Shanping Li, Kamalakannan Vijayan, Sarah L. Anzick, Geoffrey T. Hart, Elise M. O’Connell, Ogobara K. Doumbo, Alexis Kaushansky, Galit Alter, Phillip L. FelgnerHernan Lorenzi, Kassoum Kayentao, Boubacar Traore, Ewen F. Kirkness, Peter D. Crompton

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Abstract

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 immunoglobulin G (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.
Original languageEnglish (US)
Pages (from-to)750
JournalImmunity
Volume51
Issue number4
DOIs
StatePublished - Oct 15 2019

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Tran, T. M., Guha, R., Portugal, S., Skinner, J., Ongoiba, A., Bhardwaj, J., Jones, M., Moebius, J., Venepally, P., Doumbo, S., DeRiso, E. A., Li, S., Vijayan, K., Anzick, S. L., Hart, G. T., O’Connell, E. M., Doumbo, O. K., Kaushansky, A., Alter, G., ... Crompton, P. D. (2019). A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation. Immunity, 51(4), 750. https://doi.org/10.1016/j.immuni.2019.08.009