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Age is an intrinsic driver of inflammatory responses to malaria

ABSTRACT: Age is a critical factor influencing the host immune response and disease pathogenesis. In malaria, the risk of severe disease increases with age in non-immune individuals. Malaria disease is in part driven by inflammation, but the specific cells and mechanisms contributing to age-dependent disease risk are incompletely understood. Here, we assessed inflammatory cytokines in malaria in non-immune children and adults, and the phenotypic, functional and transcriptional differences of innate immune cell responders to malaria parasites in malaria-naïve children and adults. During naturally acquired malaria, age was associated with increased plasma levels of inflammatory chemokines CCL2, CCL3, CXCL8, CXLC9, along with CRP, and IDO, which were associated with clinical symptoms. In malaria naïve individuals, classical monocyte and Vδ2+ δ T cell responses from adults were characterized by increased inflammatory cytokine production, and higher transcriptional activation following stimulation with malaria parasites. Classical monocyte responses in adults were dominated by CCL2 production, while in children the response had increased IL-10 production and enrichment in IL-10 signaling pathways upon parasite stimulation. This heightened inflammatory response in adults was not mitigated by regulatory T cells (Tregs). Taken together, these findings identify cellular mechanisms of age-dependent host responses that play crucial roles in driving inflammatory responses in malaria.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270553 | GEO | 2024/12/02

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.

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Age is an intrinsic driver of inflammatory responses to malaria

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