Abstract
ObjectivesMalaria, caused by Plasmodium infection, remains a major global health problem. Monocytes are integral to the immune response, yet their transcriptional and functional responses in primary Plasmodium falciparum infection and in clinical malaria are poorly understood.MethodsThe transcriptional and functional profiles of monocytes were examined in controlled human malaria infection with P. falciparum blood stages and in children and adults with acute malaria. Monocyte gene expression and functional phenotypes were examined by RNA sequencing and flow cytometry at peak infection and compared to pre‐infection or at convalescence in acute malaria.ResultsIn subpatent primary infection, the monocyte transcriptional profile was dominated by an interferon (IFN) molecular signature. Pathways enriched included type I IFN signalling, innate immune response and cytokine‐mediated signalling. Monocytes increased TNF and IL‐12 production upon in vitro toll‐like receptor stimulation and increased IL‐10 production upon in vitro parasite restimulation. Longitudinal phenotypic analyses revealed sustained significant changes in the composition of monocytes following infection, with increased CD14+CD16− and decreased CD14−CD16+ subsets. In acute malaria, monocyte CD64/FcγRI expression was significantly increased in children and adults, while HLA‐DR remained stable. Although children and adults showed a similar pattern of differentially expressed genes, the number and magnitude of gene expression change were greater in children.ConclusionsMonocyte activation during subpatent malaria is driven by an IFN molecular signature with robust activation of genes enriched in pathogen detection, phagocytosis, antimicrobial activity and antigen presentation. The greater magnitude of transcriptional changes in children with acute malaria suggests monocyte phenotypes may change with age or exposure.
Highlights
Malaria remains an important global disease, with an estimated 228 million cases and 405 000 deaths in 2018, the majority caused by Plasmodium falciparum.[1]
Using IPA (Ingenuity Pathway Analysis), we identified DEG enrichment of canonical pathways, including IFN signalling, communication between innate and adaptive immune cells, antigen presentation, neuroinflammation signalling, triggering receptor expressed on myeloid cells-1 (TREM-1) signalling, role of pattern recognition receptors in recognition of bacteria and viruses, activation of IRF by cytosolic pattern recognition receptors, phagosome formation [including FCGR1A (CD64)], FccR-mediated phagocytosis and production of reactive oxygen (RO) species [including CYBB, the gene for NADPH oxidase 2 (NOX2) and NCF1, another subunit of NADPH oxidase] (Figure 2a and c)
Upstream regulators predicted as inhibited included mitogen-activated protein kinase 1 (MAPK1), prostaglandin E2 receptor 4 (PTGER4), suppressor of cytokine signalling 1 (SOCS1) and interleukin 1 receptor antagonist (IL1RN), and tripartite-motif protein 24 (TRIM24), the negative regulator of p53 stability.[21]
Summary
Malaria remains an important global disease, with an estimated 228 million cases and 405 000 deaths in 2018, the majority caused by Plasmodium falciparum.[1]. Blood-stage infection is characterised by cycles of asexual replication leading to RBC rupture and periodic malaria symptoms. Despite recent gains in reducing the burden of malaria, progress has stagnated in the last 3–5 years, with morbidity rising in several highly endemic countries.[1] In areas of unstable malaria transmission, morbidity and mortality affect adults as well as children. Innate and adaptive immune responses mediate both tolerogenic and antiparasitic protective mechanisms that can result in reduced clinical symptoms in future reinfections,[2] yet acquisition of clinical immunity is complex and incompletely understood. Monocytes are integral to innate immune responses and may modulate adaptive immune responses during malaria.[3,4] An increased understanding of monocyte activation and function in subpatent Plasmodium infection may aid the development of strategies to enhance protective responses to improve the morbidity and mortality of malaria and assist in vaccine development
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