Understanding immune responses in children who remain aparasitemic despite exposure to Plasmodium falciparum malaria

Abstract

Reliable immune correlates of protection against Plasmodium falciparum (Pf) malaria remain elusive, partly because sustained protection from parasitemia through natural exposure is rarely observed. In a prospective cohort study in an area of intense malaria transmission in Mali, we identified a subset of young children who remained aparasitemic during 7 months of active and passive surveillance, despite boosting of Pf-specific IgG. To identify immune responses associated with apparent elite control of infection, we carried out CITE-seq of PBMCs from 7 pairs of age- and sex- matched aparasitemic and parasitemic children. We included Pf antigens MSP1- and AMA1- specific B cell tetramers in the CITE-seq cocktail and sequenced B cell receptors (BCRs) from these cells. To identify epigenetic changes, we performed scATAC-seq on additional samples. Immune cell types from aparasitemic children exhibited markedly different transcriptional states and epigenetic landscapes. Notably, CD14+ monocytes in aparasitemic children showed enrichment of inflammatory signatures including TNFα signaling via NF-κB along with differently accessible chromatin in the target genes of these pathways. We also identified 44 antigen-specific B cells, primarily from aparasitemic children, and cloned their BCRs into expression plasmids to produce Pf-specific monoclonal antibodies in vitro to test their ability to control parasite growth and enhance the opsonophagocytosis capacity of monocytes.