Extracellular vesicles released from the filarial parasite Brugia malayi downregulate the host mTOR pathway.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Brugia malayi
/ immunology
Cell Cycle Proteins
/ metabolism
Dendritic Cells
/ immunology
Down-Regulation
Extracellular Vesicles
/ metabolism
Filariasis
/ immunology
Humans
MicroRNAs
/ metabolism
Microfilariae
/ immunology
Monocytes
/ metabolism
Phosphorylation
Proteomics
THP-1 Cells
TOR Serine-Threonine Kinases
/ genetics
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
28
04
2020
accepted:
13
10
2020
entrez:
7
1
2021
pubmed:
8
1
2021
medline:
18
5
2021
Statut:
epublish
Résumé
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 (accession number GSE157226) and shown to be enriched (>2-fold, 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. 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 (data are available via ProteomeXchange with identifier PXD021844). 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.
Identifiants
pubmed: 33411714
doi: 10.1371/journal.pntd.0008884
pii: PNTD-D-20-00708
pmc: PMC7790274
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Cell Cycle Proteins
0
EIF4EBP1 protein, human
0
MicroRNAs
0
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0008884Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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