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Age-Related Differences in Monocyte DNA Methylation and Immune Function in Healthy Kenyan Adults and Children

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157611 | GEO | 2021/03/11

REPOSITORIES: GEO

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Project description:Malaria represents a major public health problem in Africa [1]. In the East African highlands, even in high-altitude areas previously considered too cold to support vector population and parasite transmission [2], frequent malaria epidemics have been reported since the 1980M-bM-^@M-^Ys [3]. Plasmodium falciparum infections have been detected in areas as high as 1,600-2,400m above sea level in Africa [4], albeit there is a marked gradient of parasite prevalence along the altitude transect [5-7]. Both the historical absence of malaria in the African highlands and now the intensive malaria control efforts put in place after the recent outbreaks have reduced malaria prevalence and incidence [8], rendering the East African highlands particularly prone to epidemic malaria due to the lack of the protective immunity, and causing significant human mortality amongst all age groups [9]. Therefore, malaria transmission monitoring in the East African highlands becomes a particularly important public health issue.Despite the overall lower immunity of the population in these historically malaria-free areas, the many successive outbreaks since the 1980M-bM-^@M-^Ys may have generated some level of immunity against P. falciparum amongst highland residents. The antibody response to Plasmodium is cumulative and long lasting, developing after repeated exposures to the parasite and persisting for months or years after infection was resolved. The antibody response to Plasmodium varies amongst individuals of different age groups (i.e. toddlers, children and adults) as well as amongst individuals of same age groups from areas of different parasite prevalence [10]. The repertoire of targets of the antibody response also expands after multiple infections, with the number of recognized antigens being correlated to parasite prevalence, age and immunity to clinical malaria [11,12]. Serological studies bring forth indirect evidence of human exposure to the parasite, and can reliably assess its prevalence and transmission intensity in an endemic area [13-15]. However, the vast majority of serological studies of malaria have been, hereto, limited to a small number of the parasiteM-bM-^@M-^Ys antigens. The work we present here is an expansion of the study published by Badu et al. [16], in which the antibody response to the 19kDa fragment of merozoite surface protein 1 (MSP-119) was examined in populations from two endemic areas in the western Kenyan highlands. There, the tremendous variations of malaria transmission intensity in a small spatial scale are caused by substantial differences in altitude, topography and other environmental conditions [6,7,17,18]. We now expand our antibody profiling survey to include 854 P. falciparum proteins by using high-throughput proteomic microarray technology. Protein microarrays have been used to explore the humoral response to P. falciparum in other African settings [19-24], but this is the broadest characterization of the antibody responses of the population of western Kenyan highlands to date. In the present study we: i) determined the serological reactivity against P. falciparum (Pf) in subjects residing in a low transmission area, and detected hotspots of transmission; ii) examined the dynamics of antibody response to hundreds of Pf proteins generated by sera from toddlers, older children and adults residing in two endemic areas differing in transmission intensities, during two distinct malaria seasons, and compared the intensity, breadth and antigenic targets of these responses; and iii) identified candidate Pf antigenic markers that could provide more sensitive serological surveillance to detect micro-geographic variations in malaria transmission levels and differentiate hotspots of infection in low endemic areas. (references provided in the 'readme.txt') Antibody profiling was performed on sera from residents of western Kenyan highlands against Plasmodium falciparum. One-hundred and ten age-stratified serum samples collected during the dry and the wet seasons, from residents of two locations with differing parasite transmission levels (uphill and valley bottom), and 10 unexposed USA controls were probed on a protein microarray displaying 854 unique proteins of P. falciparum.

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Project description:Malaria represents a major public health problem in Africa [1]. In the East African highlands, even in high-altitude areas previously considered too cold to support vector population and parasite transmission [2], frequent malaria epidemics have been reported since the 1980’s [3]. Plasmodium falciparum infections have been detected in areas as high as 1,600-2,400m above sea level in Africa [4], albeit there is a marked gradient of parasite prevalence along the altitude transect [5-7]. Both the historical absence of malaria in the African highlands and now the intensive malaria control efforts put in place after the recent outbreaks have reduced malaria prevalence and incidence [8], rendering the East African highlands particularly prone to epidemic malaria due to the lack of the protective immunity, and causing significant human mortality amongst all age groups [9]. Therefore, malaria transmission monitoring in the East African highlands becomes a particularly important public health issue.Despite the overall lower immunity of the population in these historically malaria-free areas, the many successive outbreaks since the 1980’s may have generated some level of immunity against P. falciparum amongst highland residents. The antibody response to Plasmodium is cumulative and long lasting, developing after repeated exposures to the parasite and persisting for months or years after infection was resolved. The antibody response to Plasmodium varies amongst individuals of different age groups (i.e. toddlers, children and adults) as well as amongst individuals of same age groups from areas of different parasite prevalence [10]. The repertoire of targets of the antibody response also expands after multiple infections, with the number of recognized antigens being correlated to parasite prevalence, age and immunity to clinical malaria [11,12]. Serological studies bring forth indirect evidence of human exposure to the parasite, and can reliably assess its prevalence and transmission intensity in an endemic area [13-15]. However, the vast majority of serological studies of malaria have been, hereto, limited to a small number of the parasite’s antigens. The work we present here is an expansion of the study published by Badu et al. [16], in which the antibody response to the 19kDa fragment of merozoite surface protein 1 (MSP-119) was examined in populations from two endemic areas in the western Kenyan highlands. There, the tremendous variations of malaria transmission intensity in a small spatial scale are caused by substantial differences in altitude, topography and other environmental conditions [6,7,17,18]. We now expand our antibody profiling survey to include 854 P. falciparum proteins by using high-throughput proteomic microarray technology. Protein microarrays have been used to explore the humoral response to P. falciparum in other African settings [19-24], but this is the broadest characterization of the antibody responses of the population of western Kenyan highlands to date. In the present study we: i) determined the serological reactivity against P. falciparum (Pf) in subjects residing in a low transmission area, and detected hotspots of transmission; ii) examined the dynamics of antibody response to hundreds of Pf proteins generated by sera from toddlers, older children and adults residing in two endemic areas differing in transmission intensities, during two distinct malaria seasons, and compared the intensity, breadth and antigenic targets of these responses; and iii) identified candidate Pf antigenic markers that could provide more sensitive serological surveillance to detect micro-geographic variations in malaria transmission levels and differentiate hotspots of infection in low endemic areas. (references provided in the 'readme.txt')

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Age-Related Differences in Monocyte DNA Methylation and Immune Function in Healthy Kenyan Adults and Children

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