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Transcriptional profiling and immunophenotyping show sustained activation of blood monocytes in subpatent Plasmodium falciparum infection.

ABSTRACT: Objectives: Malaria, 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. Methods: The transcriptional and functional profile 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. Results: In 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, 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 was greater in children. Conclusions: Monocyte 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 suggest monocyte phenotypes may change with age or exposure.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154317 | GEO | 2020/07/14

REPOSITORIES: GEO

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Project description:Genome wide DNA methylation profiling of isolated monocyte samples from healthy Kenyan children, the same children during an episode of acute malaria, healthy Kenyan adults, and healthy adults from the United States. The Illumina Infinium MethylationEPIC BeadChip microarray was used to obtain DNA methylation profiles across approximately 860,000 CpGs in negatively selected monocyte samples. Samples included monocytes from 8 children from western Kenya obtained while healthy and matching samples from the same 8 Kenyan children obtained during an episode of acute uncomplicated Plasmodium falciparum malaria, 8 healthy malaria-immune adults from western Kenya, and 8 healthy malaria-naive adults from the US. Abstract -- Background: Age-related changes in adaptive and innate immune cells have been associated with a decline in effective immunity and chronic, low-grade inflammation. Epigenetic, transcriptional, and functional changes in monocytes occur with aging, though most studies to date have focused on differences between young adults and the elderly in populations with European ancestry; few data exist regarding changes that occur in circulating monocytes during the first few decades of life or in African populations. We analyzed DNA methylation profiles, cytokine production, and inflammatory gene expression profiles in monocytes from young adults and children from western Kenya. Results: We identified several hypo- and hyper-methylated CpG sites in monocytes from Kenyan young adults vs. children that replicated findings in the current literature of differential DNA methylation in monocytes from elderly persons vs. young adults across diverse populations. Differentially methylated CpG sites were also noted in gene regions important to inflammation and innate immune responses. Monocytes from Kenyan young adults vs. children displayed increased production of IL-8, IL-10, and IL-12p70 in response to TLR4 and TLR2/1 stimulation as well as distinct inflammatory gene expression profiles. Conclusions: These findings complement previous reports of age-related methylation changes in isolated monocytes and provide novel insights into the role of age-associated changes in innate immune functions.

Project description:We aimed at finding differently expressed genes in whole blood cells of African children with asymptomatic Plasmodium falciparum infection (A), uncomplicated malaria (U), severe malarial anemia (A) and cerebral malaria (Ce) compared one to another and to healthy children (Co). Understanding malarial immunopathology in the human host represents and enormous challenge for transcriptomic research. In this work, we used microarray and real-time RT-PCR technology to pursue deeper knowledge about the mechanisms underlying this disease in African children. To this end, we investigated the genomic transcriptional profiles in whole blood of healthy children and children with asymptomatic infection, uncomplicated malaria, malaria associated with severe anemia and cerebral malaria and compared them with previously published microarray results. We were able to discriminate between the different presentations of P. falciparum infection using supervised and unsupervised clustering of microarray data and unsupervised double-hierarchical clustering of real-time RT-PCR results of a set of 22 genes known to be expressed in at least one of the principal blood cell lineages. We further found considerable overlap between genes regulated in Kenyan and Gabonese children with symptomatic malaria, in contrast to adults with acute malaria from Cameroon. Different signatures for transcription factor binding sites in promoters of genes either up-regulated in symptomatic disease, specifically up-regulated in uncomplicated malaria or specifically down-regulated in cerebral malaria point out that similar gene expression in each of these clinical presentations is probably a result of common regulation at the transcriptional level. Immunoglobulin production, complement regulation and IFN beta signalling emerged as most discrepant features between uncomplicated malaria and all other investigated presentations, correlating with IRF7 and ISRE binding signatures in the corresponding genes. Down-regulation of several genes in cerebral malaria seems instead to be a response to hypoxia orchestrated by AhRF, GABP and HIF1 transcription factors. ARG1, BPI, CD163, IFI27, HP and TNFAIP6 transcript levels correlated positively with lactatemia and inversely with hemoglobin concentration and should be evaluated as prognostic markers to direct early therapeutic measures and prevent malarial disease evolution and death.

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Transcriptional profiling and immunophenotyping show sustained activation of blood monocytes in subpatent Plasmodium falciparum infection.

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