Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway

Natural killer (NK) cells provide the first line of defense against malaria parasite infection. However, the molecular mechanisms through which NK cells are activated by parasites are largely unknown, so is the molecular basis underlying the variation in NK cell responses to malaria infection in the...

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Main Authors: Ye, W, Chew, M, Hou, J, Lai, F, Leopold, S, Loo, H, Ghose, A, Dutta, A, Chen, Q, Ooi, E, White, N, Dondorp, A, Preiser, P, Chen, J
Format: Journal article
Language:English
Published: Public Library of Science 2018
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author Ye, W
Chew, M
Hou, J
Lai, F
Leopold, S
Loo, H
Ghose, A
Dutta, A
Chen, Q
Ooi, E
White, N
Dondorp, A
Preiser, P
Chen, J
author_facet Ye, W
Chew, M
Hou, J
Lai, F
Leopold, S
Loo, H
Ghose, A
Dutta, A
Chen, Q
Ooi, E
White, N
Dondorp, A
Preiser, P
Chen, J
author_sort Ye, W
collection OXFORD
description Natural killer (NK) cells provide the first line of defense against malaria parasite infection. However, the molecular mechanisms through which NK cells are activated by parasites are largely unknown, so is the molecular basis underlying the variation in NK cell responses to malaria infection in the human population. Here, we compared transcriptional profiles of responding and non-responding NK cells following exposure to Plasmodium-infected red blood cells (iRBCs) and identified MDA5, a RIG-I-like receptor involved in sensing cytosolic RNAs, to be differentially expressed. Knockout of MDA5 in responding human NK cells by CRISPR/cas9 abolished NK cell activation, IFN-γ secretion, lysis of iRBCs. Similarly, inhibition of TBK1/IKKε, an effector molecule downstream of MDA5, also inhibited activation of responding NK cells. Conversely, activation of MDA5 by liposome-packaged poly I:C restored non-responding NK cells to lyse iRBCs. We further show that microvesicles containing large parasite RNAs from iRBCs activated NK cells by fusing with NK cells. These findings suggest that NK cells are activated through the MDA5 pathway by parasite RNAs that are delivered to the cytoplasm of NK cells by microvesicles from iRBCs. The difference in MDA5 expression between responding and non-responding NK cells following exposure to iRBCs likely contributes to the variation in NK cell responses to malaria infection in the human population
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spelling oxford-uuid:8b536bed-a0b3-494f-9dd9-6d1ac5ca6b482022-03-26T22:37:23ZMicrovesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathwayJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8b536bed-a0b3-494f-9dd9-6d1ac5ca6b48EnglishSymplectic Elements at OxfordPublic Library of Science2018Ye, WChew, MHou, JLai, FLeopold, SLoo, HGhose, ADutta, AChen, QOoi, EWhite, NDondorp, APreiser, PChen, JNatural killer (NK) cells provide the first line of defense against malaria parasite infection. However, the molecular mechanisms through which NK cells are activated by parasites are largely unknown, so is the molecular basis underlying the variation in NK cell responses to malaria infection in the human population. Here, we compared transcriptional profiles of responding and non-responding NK cells following exposure to Plasmodium-infected red blood cells (iRBCs) and identified MDA5, a RIG-I-like receptor involved in sensing cytosolic RNAs, to be differentially expressed. Knockout of MDA5 in responding human NK cells by CRISPR/cas9 abolished NK cell activation, IFN-γ secretion, lysis of iRBCs. Similarly, inhibition of TBK1/IKKε, an effector molecule downstream of MDA5, also inhibited activation of responding NK cells. Conversely, activation of MDA5 by liposome-packaged poly I:C restored non-responding NK cells to lyse iRBCs. We further show that microvesicles containing large parasite RNAs from iRBCs activated NK cells by fusing with NK cells. These findings suggest that NK cells are activated through the MDA5 pathway by parasite RNAs that are delivered to the cytoplasm of NK cells by microvesicles from iRBCs. The difference in MDA5 expression between responding and non-responding NK cells following exposure to iRBCs likely contributes to the variation in NK cell responses to malaria infection in the human population
spellingShingle Ye, W
Chew, M
Hou, J
Lai, F
Leopold, S
Loo, H
Ghose, A
Dutta, A
Chen, Q
Ooi, E
White, N
Dondorp, A
Preiser, P
Chen, J
Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway
title Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway
title_full Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway
title_fullStr Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway
title_full_unstemmed Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway
title_short Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway
title_sort microvesicles from malaria infected red blood cells activate natural killer cells via mda5 pathway
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