Weijian YeMarvin ChewJue HouFritz LaiStije J. LeopoldHooi Linn LooAniruddha GhoseAshok K. DuttaQingfeng ChenEng Eong OoiNicholas J. WhiteArjen M. DondorpPeter PreiserJianzhu ChenSingapore-MIT AllianceMassachusetts Institute of TechnologyA-Star, Institute of Molecular and Cell BiologyNational University of SingaporeMahidol UniversityChittagong Medical College HospitalNuffield Department of Clinical MedicineNanyang Technological University2019-08-232019-08-232018-10-01PLoS Pathogens. Vol.14, No.10 (2018)15537374155373662-s2.0-85054465440https://repository.li.mahidol.ac.th/handle/20.500.14594/45047© 2018 Ye et al. http://creativecommons.org/licenses/by/4.0/. 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyImmunology and MicrobiologyArticleSCOPUS10.1371/journal.ppat.1007298