MALARIA PARASITES USE DNA-HARBOURING VESICLES AS A MECHANISM TO ACTIVATE CYTOSOLIC IMMUNE SENSORS

Yifat Ofir-Birin ¹ Xavier Sisquella ² Matthew A. Pimentel ² Lesley Cheng ³ Paula Abou Karam ¹ Natália G. Sampaio ² Jocelyn Sietsma Penington ² Dympna Connolly ⁷ Tal Giladi ¹ Benjamin James Scicluna ^2,3 Robyn A. Sharples ³ Andreea Waltmann ² Dror Avni ⁴ Eli Schwartz ⁴ Louis Schofield ² Ziv Porat ⁶ Diana Hansen ² Anthony T. Papenfuss ² Emily M. Eriksson ² Motti Gerlic ⁵ Andrew F. Hill ³ Andrew G. Bowie ⁷ Neta Regev-Rudzki ^1,2

¹Department of Biomolecular Sciences,, Weizmann Institute of Science, Rehovot, Israel
²The Walter and Eliza Hall Institute of Medical Research, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
³Department of Biochemistry and Molecular Biology, The University of Melbourne, Australia, Melbourne, Australia
⁴7Molecular Laboratory for the Study of Tropical Diseases, and The Institute of Geographic Medicine & Tropical Diseases,, Sheba Medical Center, Tel Hashomer, Israel
⁵8Faculty of Medicine, Sackler School of Medicine,, Tel Aviv University, Tel Aviv, Israel
⁶Flow Cytometry unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
⁷School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute,, Trinity College Dublin, Dublin, Ireland

The mechanisms whereby pathogens evade the human innate immune system remains unknown in many cases, thus limiting our ability to treat infectious diseases. This is especially true of the malaria parasites, Plasmodium falciparum (Pf), the instigators of one of the most devastating infectious diseases. One subversion mechanism employed by Pf involves stimulating cytosolic Stimulator of Interferon Genes (STING)-dependent signalling in immune cells. STING becomes active upon sensing pathogen DNA, yet the processes involved in enabling Pf DNA access to the cytosolic sensors in immune cells is unclear. Here we reveal that malaria parasites engage host monocyte DNA sensing mechanisms from a distance while growing within red blood cells (RBCs). We show that Pf secretes vesicles from RBCs containing both parasitic small RNA molecules and, remarkably, parasitic genomic DNA. Upon internalization of the DNA-harbouring vesicles by human monocytes, the Pf -DNA is released within the cytosol, leading to STING-dependent DNA sensing. STING subsequently activates the kinase TBK1, which phosphorylates transcription factor IRF3, prompting the translocation of IRF3 to the nucleus and, as a result, immune gene induction. This mechanism may represent a decoy device developed by such lethal parasites to promote their infection.