Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA; Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
Immunity. 2019 Oct 15;51(4):750-765.e10. doi: 10.1016/j.immuni.2019.08.009. Epub 2019 Sep 3.
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.
控制恶性疟原虫（Pf）疟疾寄生虫血症和炎症的免疫可以通过反复感染获得。对这种复杂免疫反应的有限了解阻碍了疫苗和辅助疗法的发展。我们对寄生虫血症和发烧控制能力不同的儿童进行了前瞻性系统生物学研究。通过整合全血转录组学、流式细胞分析以及血浆细胞因子和抗体谱，我们证明了感染前 B 细胞富集的特征，Th1 和 Th2 细胞相关途径的上调，包括干扰素反应和与控制疟疾发热相关的 p53 激活，与 Pf 特异性免疫球蛋白 G（IgG）和 Fc 受体激活相协调，以控制寄生虫血症。我们的假设生成方法确定了宿主分子，这些分子可能有助于 Pf 感染期间的不同临床结果。作为概念验证，我们已经表明，单核细胞中增强的 p53 表达减轻了疟原虫诱导的炎症，并预测了对发热的保护。
