MRNA Sequencing of human monocyte cell lines exposed to Brugia malayi filarial helminth-derived extracellular vesicles.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE263693 | GEO | 2024/08/20
REPOSITORIES: GEO
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Project description:Live microfilariae (Mf) and mf-derived extracellular vesicles (EVs) have been shown to modulate human antigen presenting cell (APC) function, most notably by suppressing the induction of IL-12 (and other pro-inflammatory cytokines) following activation with LPS and interferon-gamma. To explore further how EVs alter human APC function, we studied the effect of mf and EVs on human elutriated monocyte-derived DCs following exposure to Mf, Mf-derived excretrory/secretory (E/S) products, E/S depleted of EVs through ultracentrifugation and purified EVs using RNAseq analysis. In our analyses of the data for the DC, using a false discovery rate (FDR)<0.05, EV-exposed DCs had induced the expression of 212 differentially expressed genes (DEGs) when compared to unexposed DC and 157 when compared to ES-depleted EVs. These genes were enriched in GO biological processes associated with neutrophil degranulation and 15 DEGs associated with KEGG Lysosome pathways. IPA analysis point to immune dysregulation.
2024-08-20 | GSE263690 | GEO
Project description:We report our microarray analysis of Brugia malayi microfilariae-derived miRNA comparing parasite-derived EVs and supernatants Microarray analysis was performed using isolated RNA from three biological replicates of Brugia malayi microfilariae with a focus on the parasite-derived EVs and supernatant
2021-01-12 | GSE157226 | GEO
Project description:Dysregulation of professional APC has been postulated as a major mechanism underlying Ag-specific T cell hyporesponsiveness in patients with patent filarial infection. To address the nature of this dysregulation, dendritic cells (DC) and macrophages generated from elutriated monocytes were exposed to live microfilariae (mf), the parasite stage that circulates in blood and is responsible for most immune dysregulation in filarial infections. DC exposed to mf for 24–96 h showed a marked increase in cell death and caspase-positive cells compared with unexposed DC, while mf exposure did not induce apoptosis in macrophages. Interestingly, 48 h exposure of DC to mf induced mRNA expression of the pro-apoptotic gene TRAIL and both mRNA and protein expression of TNF-alpha. mAb to TRAIL-R2, TNF-R1, or TNF-alpha partially reversed mf-induced cell death in DC, as did knocking down the receptor for TRAIL-R2 using small interfering RNA. Mf also induced gene expression of BH3-interacting domain death agonist (Bid) and protein expression of cytochrome c in DC; mf-induced cleavage of Bid could be shown to induce release of cytochrome c, leading to activation of caspase 9. Our data suggest that mf induce DC apoptosis in a TRAIL- and TNF-alpha-dependent fashion. Keywords: Dendritic Cell, Parasite, Human, Microfilariae
2008-09-17 | GSE12787 | GEO
Project description:We have previously shown that the microfilarial (mf) stage of Brugia malayi can inhibit the mammalian target of rapamycin (mTOR; a conserved serine/threonine kinase critical for immune regulation and cellular growth) in human dendritic cells (DC) and we have proposed that this mTOR inhibition is associated with the DC dysfunction seen in filarial infections. Extracellular vesicles (EVs) contain many proteins and nucleic acids including microRNAs (miRNAs) that might affect a variety of intracellular pathways. Thus, EVs secreted from mf may elucidate the mechanism by which the parasite is able to modulate the host immune response during infection. EVs, purified from mf of Brugia malayi and confirmed by size through nanoparticle tracking analysis, were assessed by miRNA microarrays and shown to be enriched (>2fold, p-value<0.05, FDR=0.05) for miR100, miR71, miR34, and miR7. The microarray analysis compared mf-derived EVs and mf supernatant. After confirming their presence in EVs using qPCR for these miRNA targets, web-based target predictions (using MIRPathv3, TarBAse and MicroT-CD) predicted that miR100 targeted mTOR and its downstream regulatory protein 4E-BP1 respectively. Our previous data with live parasites demonstrated that mf downregulate the phosphorylation of mTOR and its downstream effectors. Additionally, our proteomic analysis of the mf-derived EVs revealed the presence of proteins commonly found in these vesicles. We confirmed internalization of mf-derived EVs by human DCs and monocytes using confocal microscopy and flow cytometry, and further demonstrated through flow cytometry, that mf-derived EVs downregulate the phosphorylation of mTOR in human monocytes (THP-1 cells) to the same degree that rapamycin (a known mTOR inhibitor) does. Our data collectively suggest that mf release EVs that interact with host cells, such as DC, to modulate host responses.
2021-01-12 | PXD021844 | Pride
Project description:Dysregulation of professional APC has been postulated as a major mechanism underlying Ag-specific T cell hyporesponsiveness in patients with patent filarial infection. To address the nature of this dysregulation, dendritic cells (DC) and macrophages generated from elutriated monocytes were exposed to live microfilariae (mf), the parasite stage that circulates in blood and is responsible for most immune dysregulation in filarial infections. DC exposed to mf for 24â96 h showed a marked increase in cell death and caspase-positive cells compared with unexposed DC, while mf exposure did not induce apoptosis in macrophages. Interestingly, 48 h exposure of DC to mf induced mRNA expression of the pro-apoptotic gene TRAIL and both mRNA and protein expression of TNF-alpha. mAb to TRAIL-R2, TNF-R1, or TNF-alpha partially reversed mf-induced cell death in DC, as did knocking down the receptor for TRAIL-R2 using small interfering RNA. Mf also induced gene expression of BH3-interacting domain death agonist (Bid) and protein expression of cytochrome c in DC; mf-induced cleavage of Bid could be shown to induce release of cytochrome c, leading to activation of caspase 9. Our data suggest that mf induce DC apoptosis in a TRAIL- and TNF-alpha-dependent fashion. Experiment Overall Design: Microfilariae and human monocyte derived-DCs were cultuted at a multiplicity of infection of 1:1 for 24hrs for four independent donors. Matching samples exposed to media alone were used for controls The four experimental and 4 control samples were then pooled to create one experoimental and one healthy pool used for microarray analysis.
2008-10-25 | E-GEOD-12787 | biostudies-arrayexpress
Project description:Filarial nematodes are arthropod-borne nematodes that cause a variety of economically important diseases such as onchocerciasis (river blindness), lymphatic filariasis, and heartworm disease. The most widespread filarial disease of humans is lymphatic filariasis, caused by worms in the genera Wuchereria and Brugia. Lymphatic filariasis is an economic and social burden in endemic countries and affects approximately 119 million people worldwide (Michael, 1997). In humans, the worms live in and block the lymph vessels, causing improper flow of lymph, and inflammation of the lymphatic system. The symptoms are fever, swollen limbs and genitals, generalized malaise, and can progress to a debilitating condition known as elephantiasis This research focuses on the transmission of these worms to the disseminating mosquito host, and it is based on the interesting observation that mf must be at least 7 days old to successfully infect the mosquito (de Hollanda, 1982). Newborn mf that have not ‘matured’ cannot successfully penetrate the midgut of the mosquito, and subsequently cannot develop to the L3 stage (Fuhrman, 1987). Previous work done by another group 20 years ago suggests that the molecular makeup of the worm surface changes during this maturation process (Furman, 1983 a and b). We used microarray analysis to characterize changes in gene expression that take place during the mf maturation process. Understanding the gene expression changes that occur as the mf mature will allow us to understand the nature of the philological transition that allows mf to move from the human to the mosquito host. With this information in hand, we can eventually identify parasite molecules that could be targeted to either stop parasite reproduction or prevent transmission of the mf to the mosquito. This would stop parasite transmission in endemic areas.
2009-10-01 | GSE14940 | GEO
Project description:Parasitic nematodes that cause elephantiasis and river blindness threaten hundreds of millions of people in the developing world. We have sequenced the approximately 90 megabase (Mb) genome of the human filarial parasite Brugia malayi and predict approximately 11,500 protein coding genes in 71 Mb of robustly assembled sequence. Comparative analysis with the free-living, model nematode Caenorhabditis elegans revealed that, despite these genes having maintained little conservation of local synteny during approximately 350 million years of evolution, they largely remain in linkage on chromosomal units. More than 100 conserved operons were identified. Analysis of the predicted proteome provides evidence for adaptations of B. malayi to niches in its human and vector hosts and insights into the molecular basis of a mutualistic relationship with its Wolbachia endosymbiont. These findings offer a foundation for rational drug design.
| S-EPMC2613796 | biostudies-literature
Project description:Filarial nematodes are arthropod-borne nematodes that cause a variety of economically important diseases such as onchocerciasis (river blindness), lymphatic filariasis, and heartworm disease. The most widespread filarial disease of humans is lymphatic filariasis, caused by worms in the genera Wuchereria and Brugia. Lymphatic filariasis is an economic and social burden in endemic countries and affects approximately 119 million people worldwide (Michael, 1997). In humans, the worms live in and block the lymph vessels, causing improper flow of lymph, and inflammation of the lymphatic system. The symptoms are fever, swollen limbs and genitals, generalized malaise, and can progress to a debilitating condition known as elephantiasis This research focuses on the transmission of these worms to the disseminating mosquito host, and it is based on the interesting observation that mf must be at least 7 days old to successfully infect the mosquito (de Hollanda, 1982). Newborn mf that have not âmaturedâ cannot successfully penetrate the midgut of the mosquito, and subsequently cannot develop to the L3 stage (Fuhrman, 1987). Previous work done by another group 20 years ago suggests that the molecular makeup of the worm surface changes during this maturation process (Furman, 1983 a and b). We used microarray analysis to characterize changes in gene expression that take place during the mf maturation process. Understanding the gene expression changes that occur as the mf mature will allow us to understand the nature of the philological transition that allows mf to move from the human to the mosquito host. With this information in hand, we can eventually identify parasite molecules that could be targeted to either stop parasite reproduction or prevent transmission of the mf to the mosquito. This would stop parasite transmission in endemic areas. Two biological replicates were performed each with two technical replicates.
2010-05-22 | E-GEOD-14940 | biostudies-arrayexpress
Project description:Lymphatic filariasis (LF) threatens nearly 20% of the world’s population and has handicapped one-third of the 120 million people currently infected. Current control and eventual elimination of LF rely on mass drug administration (MDA) programs with three drugs: ivermectin (IVM), albendazole (ALB), and diethylcarbamazine (DEC). Only the mechanism of action of albendazole is well-understood. . To gain a better insight into antifilarial drug action, we treated gerbils with patent B. malayi infections with 6 mg/kg DEC, 1 mg/kg ALB, or 0.15 mg/kg IVM to mirror the doses used in human MDA programs. These treatments had no effect on the numbers of worms present in the peritoneal cavity of infected animals. Adults and Mf were collected 1 and 7 days post-treatment and RNA was isolated for transcriptomic analysis. The experiment was repeated three times. Preliminary analysis of the effects of IVM, ALB, and DEC on adult males and females revealed treatment-specific changes in transcripts related to collagen expression, reproduction, embryogenesis, larval development, and lifespan determination. Similar data are currently being collected for the microfilariae.
2017-05-26 | GSE99334 | GEO