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Plasmodium falciparum (P. falciparum) induces trained innate immune responses in vitro, where initial stimulation of adherent PBMCs with P. falciparum-infected RBCs (iRBCs) results in hyperresponsiveness to subsequent ligation of TLR2. This response correlates with the presence of T and B lymphocytes in adherent PBMCs, suggesting that innate immune training is partially due to adaptive immunity. We found that T cell-depleted PBMCs and purified monocytes alone did not elicit hyperproduction of IL-6 and TNF-α under training conditions. Analysis of P. falciparum-trained PBMCs showed that DCs did not develop under control conditions, and IL-6 and TNF-α were primarily produced by monocytes and DCs. Transwell experiments isolating purified monocytes from either PBMCs or purified CD4+ T cells, but allowing diffusion of secreted proteins, enabled monocytes trained with iRBCs to hyperproduce IL-6 and TNF-α after TLR restimulation. Purified monocytes stimulated with IFN-γ hyperproduced IL-6 and TNF-α, whereas blockade of IFN-γ in P. falciparum-trained PBMCs inhibited trained responses. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) on monocytes from patients with malaria showed persistently open chromatin at genes that appeared to be trained in vitro. Together, these findings indicate that the trained immune response of monocytes to P. falciparum is not completely cell intrinsic but depends on soluble signals from lymphocytes.
Introduction
Plasmodium falciparum (P. falciparum) remains one of the deadliest diseases in the world today. In 2020, WHO reported that there were an estimated 241 million cases of malaria that took the lives of 627,000 individuals - most of these were children under the age of 5 (1). The features of the acute uncomplicated disease include high-spiking fevers, profound malaise, headache, and other systemic signs of inflammation (2-4). These symptoms suggest that parasite products (pathogen-associated molecular patterns) engage the myeloid compartment, activating a panel of innate immune sensors that drive cytokine production and inflammation (5).
Patients with malaria have an increased risk of developing invasive bacterial infection, and these bacterial coinfections substantially increase the risk of mortality (6, 7). A longitudinal study conducted in Kenya found that greater than 50% of all the bacteremia cases in the region were attributable to malaria infection (8). The mechanisms underlying this increased susceptibility to bacteremia are not fully understood. Researchers have hypothesized that acute malaria infection primes innate inflammatory pathways,...