Publications

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

Tran TM, Guha R, Portugal S, Skinner J, Ongoiba A, Bhardwaj J, Jones M, Moebius J, Venepally P, Doumbo S, DeRiso EA, Li S, Vijayan K, Anzick SL, Hart GT, O'Connell EM, Doumbo OK, Kaushansky A, Alter G, Felgner PL, Lorenzi H, Kayentao K, Traore B, Kirkness EF, Crompton PD

PMID: 31492649

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.