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Title: Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway
Authors: Weijian Ye
Marvin Chew
Jue Hou
Fritz Lai
Stije J. Leopold
Hooi Linn Loo
Aniruddha Ghose
Ashok K. Dutta
Qingfeng Chen
Eng Eong Ooi
Nicholas J. White
Arjen M. Dondorp
Peter Preiser
Jianzhu Chen
Singapore-MIT Alliance
Massachusetts Institute of Technology
A-Star, Institute of Molecular and Cell Biology
National University of Singapore
Mahidol University
Chittagong Medical College Hospital
Nuffield Department of Clinical Medicine
Nanyang Technological University
Keywords: Biochemistry, Genetics and Molecular Biology;Immunology and Microbiology
Issue Date: 1-Oct-2018
Citation: PLoS Pathogens. Vol.14, No.10 (2018)
Abstract: © 2018 Ye et al. 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.
ISSN: 15537374
Appears in Collections:Scopus 2018

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