Malaria parasite DNA-harbouring vesicles activate cytosolic immune sensors

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.

Schistosomal extracellular vesicle‐enclosed miRNAs modulate host T helper cell differentiation

“…Cells were imaged using an inverted confocal microscope or multispectral IFC (ImageS-treamX Mark II imaging flow cytometer; Amnis Corp, Seattle, WA, part of EMD Millipore) as previously described in Sisquella et al [88]. As a control, the unused schistosomal-growing medium was also labeled.…”

Extracellular Vesicles: A Prevalent Tool for Microbial Gene Delivery?

“…It has recently been revealed that, in addition to RNA and proteins, vesicles from different eukaryotic systems also harbor DNA molecules. The size of the vesicular DNA, from both eukaryotic and prokaryotic origin, typically ranges from hundreds of bp to over 20 kb and its source can be chromosomal, episomal, or even mitochondial . These exciting discoveries raise the possibility that secreted vesicles can serve as mediators of genetic material exchange among microbes, thus offering a potential explanation for observed HGT events between eukaryotic cells.…”

“…A malaria study revealed that, in fact, the eukaryotic parasite delivers vesicles harboring not just episomal genes, but also parasitic genomic DNA . Further support for an EV‐mediated HGT event in malaria comes from a study by Sundararaman and co‐workers .…”

Histamine releasing factor and elongation factor 1 alpha secreted via malaria parasites extracellular vesicles promote immune evasion by inhibiting specific T cell responses

“…In support of these observations, P. falciparum iRBCs‐derived EVs have been shown to stimulate the cells of the innate immune system in vitro by activating a proinflammatory and anti‐inflammatory cytokine response in macrophages and by strongly activating neutrophils to spontaneously move even in the absence of a chemotactic gradient (Mantel et al, ). Recently, Regev‐Rudzki and colleagues revealed a previously unidentified aspect: P. falciparum strains deliver genomic DNA via EVs to alter the immune response (Sisquella et al, ).…”

“…In contrast, microvesicles are formed by budding and shedding from the plasma membrane and are larger with greater size heterogeneity. EVs carry diverse content such as RNA (Baglio et al, ; Ridder et al, ), DNA (Sansone et al, ; Sisquella et al, ; Thakur et al, ), proteins (Simpson, Lim, Moritz, & Mathivanan, ; Torrecilhas, Schumacher, Alves, & Colli, ), and lipids (Record, Silvente‐Poirot, Poirot, & Wakelam, ; Verderio, Gabrielli, & Giussani, ), which can be delivered to target cells.…”