Malaria parasite DNA-harbouring vesicles activate cystolic immune sensors.pdf (2.34 MB)
Malaria parasite DNA-harbouring vesicles activate cytosolic immune sensors
journal contributionposted on 2021-06-23, 02:17 authored by X Sisquella, Y Ofir-Birin, MA Pimentel, Lesley SimLesley Sim, P Abou Karam, NG Sampaio, JS Penington, D Connolly, T Giladi, Benjamin J Scicluna, Robyn SharplesRobyn Sharples, A Waltmann, D Avni, E Schwartz, L Schofield, Z Porat, DS Hansen, AT Papenfuss, EM Eriksson, M Gerlic, Andrew HillAndrew Hill, AG Bowie, N Regev-Rudzki
STING is an innate immune cytosolic adaptor for DNA sensors that engage malaria parasite (Plasmodium falciparum) or other pathogen DNA. As P. falciparum infects red blood cells and not leukocytes, how parasite DNA reaches such host cytosolic DNA sensors in immune cells is unclear. Here we show that malaria parasites inside red blood cells can engage host cytosolic innate immune cell receptors from a distance by secreting extracellular vesicles (EV) containing parasitic small RNA and genomic DNA. Upon internalization of DNA-harboring EVs by human monocytes, P. falciparum DNA is released within the host cell cytosol, leading to STING-dependent DNA sensing. STING subsequently activates the kinase TBK1, which phosphorylates the transcription factor IRF3, causing IRF3 to translocate to the nucleus and induce STING-dependent gene expression. This DNA-sensing pathway may be an important decoy mechanism to promote P. falciparum virulence and thereby may affect future strategies to treat malaria.
We thank Malaria Research Reference Reagent Resource Center (MR4) for their generous supply of parasite strains. Special thanks to Prof. Alan Cowman for his contribution to this study and for the scientific environment of his laboratory. We thank Dr Ken Pang, Dr Jacob Baum, Dr Maya Olshina and Ms Natalie Page for scientific discussions, Dr Bradley Coleman (Andrew Hill's lab) for the vesicle assay, Dr Kelly Rogers and Lachlan Whitehead (WEHI imaging facility), Stephen Wilcox (Systems Biology and Personalised Medicine), Dr Eric Hansen (the Advanced Microscopy Facility, Bio21 and the Melbourne Materials Institute (MMI), Mr. Vladimir Kiss (Department of Biomolecular Sciences, Weizmann Institute). M.G. was supported by the Israel Science Foundation (ISF) (grant #1416/15), alpha-1 foundation, Recanati Foundation (TAU), and Individual research grant Varda and Boaz Dotan Research Center. The research of Dr Neta Regev-Rudzki is supported by the Israel Science Foundation (ISF) (619/16 and 119034) and by the Benoziyo Endowment Fund for the Advancement of Science, the Jeanne and Joseph Nissim Foundation for Life Sciences Research and the Samuel M. Soref and Helene K. Soref Foundation. Dr Neta Regev-Rudzki is the incumbent of the Enid Barden and Aaron J. Jade President's Development Chair for New Scientists in Memory of Cantor John Y. Jade. A.B. and D.C. were supported by grants from the National Institutes of Health (AI093752) and Science Foundation Ireland (11/PI/1056).
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Science & TechnologyMultidisciplinary SciencesScience & Technology - Other TopicsRED-BLOOD-CELLSEXTRACELLULAR VESICLESPLASMODIUM-FALCIPARUMSIGNALING PATHWAYSMEDIATED TRANSFERHOST MORTALITYEXOSOMESRESPONSESRECEPTORINFECTIONErythrocytesMonocytesCell LineCell NucleusCytosolHumansPlasmodium falciparumMalaria, FalciparumProtein-Serine-Threonine KinasesMembrane ProteinsDNA, ProtozoanRNA, ProtozoanCryoelectron MicroscopySignal TransductionPhosphorylationInterferon Regulatory Factor-3Immunity, InnatePrimary Cell CultureExtracellular Vesicles