Abstract

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.

Details

Title
Malaria parasite DNA-harbouring vesicles activate cytosolic immune sensors
Author
Sisquella, Xavier 1 ; Ofir-Birin, Yifat 2 ; Pimentel, Matthew A 1 ; Cheng, Lesley 3 ; Paula Abou Karam 2 ; Sampaio, Natália G 1   VIAFID ORCID Logo  ; Jocelyn Sietsma Penington 4   VIAFID ORCID Logo  ; Connolly, Dympna 5 ; Giladi, Tal 2 ; Scicluna, Benjamin J 3 ; Sharples, Robyn A 3 ; Waltmann, Andreea 1 ; Avni, Dror 6 ; Schwartz, Eli 7 ; Schofield, Louis 8 ; Porat, Ziv 9 ; Hansen, Diana S 1 ; Papenfuss, Anthony T 1   VIAFID ORCID Logo  ; Eriksson, Emily M 1 ; Motti Gerlic 10   VIAFID ORCID Logo  ; Hill, Andrew F 3   VIAFID ORCID Logo  ; Bowie, Andrew G 5 ; Regev-Rudzki, Neta 2 

1  The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Grattan Street, Parkville, VIC, Australia 
2  Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel 
3  Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, Australia; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia 
4  The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia 
5  School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Dublin, Ireland 
6  The Institute of Geographic Medicine & Tropical Diseases and The laboratory for Tropical Diseases Research, Sheba Medical Center, Tel Hashomer, Israel 
7  The Institute of Geographic Medicine & Tropical Diseases and The laboratory for Tropical Diseases Research, Sheba Medical Center, Tel Hashomer, Israel; Faculty of Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 
8  The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Grattan Street, Parkville, VIC, Australia; Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, QLD, Australia 
9  Flow Cytometry unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel 
10  Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 
Pages
1-15
Publication year
2017
Publication date
Dec 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-02083-1
ProQuest document ID
1983424254
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.