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Updated: Feb 17, 2026
Author Spotlight: Identifying Compensatory Pathways in Malaria Parasites Containing Hypomorphic Allele of Essential Protein Kinases
Published on: November 22, 2024
Malaria parasite DNA-harbouring vesicles activate cytosolic immune sensors
Xavier Sisquella1,2, Yifat Ofir-Birin3, Matthew A Pimentel1,2
1The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
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.
Insights
Malaria parasites release extracellular vesicles containing DNA to activate host STING immune responses. This discovery reveals a novel mechanism of parasite virulence and potential therapeutic targets for malaria.
Area of Science:
- Innate immunity
- Molecular biology
- Parasitology
Background:
- STING (stimulator of interferon genes) is a cytosolic DNA sensor crucial for innate immunity.
- Plasmodium falciparum, the malaria parasite, infects red blood cells, posing a challenge for its DNA to be detected by immune cells.
- The mechanism by which parasite DNA engages host cytosolic DNA sensors remains unclear.
Purpose of the Study:
- To elucidate how Plasmodium falciparum DNA activates host cytosolic DNA sensors.
- To investigate the role of extracellular vesicles (EVs) in mediating parasite DNA sensing.
- To understand the downstream signaling pathway initiated by parasite DNA detection.
Main Methods:
- Analysis of extracellular vesicles secreted by malaria parasites.
- Incubation of human monocytes with DNA-containing EVs.
- Assessment of STING-TBK1-IRF3 signaling pathway activation.
- Gene expression analysis of STING-dependent pathways.
Main Results:
- Malaria parasites release EVs containing Plasmodium falciparum genomic DNA and small RNA.
- Human monocytes internalize these EVs, releasing parasite DNA into the cytosol.
- Parasite DNA triggers STING-dependent activation of TBK1 and IRF3.
- This leads to the induction of STING-dependent gene expression.
Conclusions:
- Extracellular vesicles facilitate the distant engagement of host cytosolic DNA sensors by malaria parasites.
- The parasite DNA sensing pathway involving STING, TBK1, and IRF3 is activated by Plasmodium falciparum.
- This mechanism may represent a virulence strategy for the malaria parasite, impacting treatment strategies.
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