Malaria parasites both repress host CXCL10 and use it as a cue for growth acceleration

Ofir-Birin, Yifat; Pilo, Hila Ben Ami; Camacho, Abel Cruz; Rudik, Ariel; Rivkin, Anna; Revach, Or‐Yam; Nir, Netta; Tamin, Tal Block; Karam, Paula Abou; Kiper, Edo; Peleg, Yoav; Nevo, Reinat; Solomon, Aryeh; Havkin-Solomon, Tal; Rojas, Alicia; Rotkopf, Ron; Porat, Ziv; Avni, Dror; Schwartz, Eli; Zillinger, Thomas; Hartmann, Gunther; Pizio, Antonella Di; Quashie, Neils B; Dikstein, Rivka; Gerlic, Motti; Torrecilhas, Ana Claúdia; Levy, Carmit; Hoen, Esther N. M. Nolte‐‘t; Bowie, Andrew; Regev‐Rudzki, Neta

doi:10.1038/s41467-021-24997-7

Cited by 26 publications

(32 citation statements)

References 97 publications

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“…EVs were concentrated using a Vivacell (Ofir-Birin et al, 2021), third of the EV sample was treated with 10 μl/ml Sialidase (Neuraminidase, REF 11080752001, LOT 1005025, Roche). The solution was incubated for 30 min at 37 • C. The remaining two thirds of the EV sample were used as control and were incubated for 30 min at 37 • C. The EV production proceeded to TO staining and an overnight ultracentrifugation step (Sisquella et al, 2017).…”

Section:  Sialidase Treatmentmentioning

confidence: 99%

“…Extracellular Vesicles (EVs) are produced across almost all the living kingdoms (Carrera-Bravo et al, 2021;Malda et al, 2016;Osteikoetxea et al, 2016;Pegtel et al, 2010;Schorey et al, 2015;Wortzel et al, 2019) including parasites (Carrera-Bravo et al, 2021;Montaner et al, 2014;Ofir-Birin & Regev-Rudzki, 2019). They contain a cornucopia of different molecules and transfer functional signals to target cells.…”

Section: Introductionmentioning

confidence: 99%

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Sialylated N‐glycans mediate monocyte uptake of extracellular vesicles secreted from Plasmodium falciparum‐infected red blood cells

Pilo

Khilji

Lühle

et al. 2022

J of Extracellular Bio

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Glycoconjugates on extracellular vesicles (EVs) play a vital role in internalization and mediate interaction as well as regulation of the host immune system by viruses, bacteria, and parasites. During their intraerythrocytic life‐cycle stages, malaria parasites, Plasmodium falciparum (Pf) mediate the secretion of EVs by infected red blood cells (RBCs) that carry a diverse range of parasitic and host‐derived molecules. These molecules facilitate parasite‐parasite and parasite‐host interactions to ensure parasite survival.To date, the number of identified Pf genes associated with glycan synthesis and the repertoire of expressed glycoconjugates is relatively low. Moreover, the role of Pf glycans in pathogenesis is mostly unclear and poorly understood. As a result, the expression of glycoconjugates on Pf‐derived EVs or their involvement in the parasite life‐cycle has yet to be reported.Herein, we show that EVs secreted by Pf‐infected RBCs carry significantly higher sialylated complex N‐glycans than EVs derived from healthy RBCs. Furthermore, we reveal that EV uptake by host monocytes depends on N‐glycoproteins and demonstrate that terminal sialic acid on the N‐glycans is essential for uptake by human monocytes. Our results provide the first evidence that Pf exploits host sialylated N‐glycans to mediate EV uptake by the human immune system cells.

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Section:  Sialidase Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sialylated N‐glycans mediate monocyte uptake of extracellular vesicles secreted from Plasmodium falciparum‐infected red blood cells

Pilo

Khilji

Lühle

et al. 2022

J of Extracellular Bio

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“…One such prominent example is the deadly malaria parasite in humans, Plasmodium falciparum ( Pf ). During their life-cycle, Pf parasites secrete EVs while growing inside human red blood cells (RBCs), which deliver multiple cargo components ( Regev-Rudzki et al., 2013 ; Mantel et al., 2016 ; Sisquella et al., 2017 ; Ye et al., 2018 ; Avalos-Padilla et al, 2021 ; Dekel et al., 2021 ; Ofir-Birin et al., 2021 ). These EVs modulate different host cells by promoting parasitic invasion ( Dekel et al., 2021 ), endothelial cell modulation ( Mantel et al., 2016 ) and immune cell alteration ( Mantel et al., 2013 ; Sisquella et al., 2017 ; Ye et al., 2018 ; Ofir-Birin et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…During their life-cycle, Pf parasites secrete EVs while growing inside human red blood cells (RBCs), which deliver multiple cargo components ( Regev-Rudzki et al., 2013 ; Mantel et al., 2016 ; Sisquella et al., 2017 ; Ye et al., 2018 ; Avalos-Padilla et al, 2021 ; Dekel et al., 2021 ; Ofir-Birin et al., 2021 ). These EVs modulate different host cells by promoting parasitic invasion ( Dekel et al., 2021 ), endothelial cell modulation ( Mantel et al., 2016 ) and immune cell alteration ( Mantel et al., 2013 ; Sisquella et al., 2017 ; Ye et al., 2018 ; Ofir-Birin et al., 2021 ). For instance, it was shown that Pf -derived EVs deliver parasitic genomic DNA (gDNA), recognized by the STING-dependent cytosolic DNA sensing pathway in recipient monocytes ( Sisquella et al., 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Monitoring Distribution Dynamics of EV RNA Cargo Within Recipient Monocytes and Macrophages

Alfandari

Pilo

Karam

et al. 2022

Front. Cell. Infect. Microbiol.

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Extracellular vesicles (EVs) are produced by across almost all the living kingdoms and play a crucial role in cell-cell communication processes. EVs are especially important for pathogens, as Plasmodium falciparum (Pf) parasite, the leading causing species in human malaria. Malaria parasites are able to modulate the host immune response from a distance via delivering diverse cargo components inside the EVs, such as proteins and nucleic acids. We have previously shown that imaging flow cytometry (IFC) can be effectively used to monitor the uptake of different cargo components of malaria derived EVs by host human monocytes. Here, we take this approach one step further and demonstrate that we can directly investigate the dynamics of the cargo distribution pattern over time by monitoring its distribution within two different recipient cells of the immune system, monocytes vs macrophages. By staining the RNA cargo of the vesicles and monitor the signal we were able to evaluate the kinetics of its delivery and measure different parameters of the cargo’s distribution post internalization. Interestingly, we found that while the level of the EV uptake is similar, the pattern of the signal for RNA cargo distribution is significantly different between these two recipient immune cells. Our results demonstrate that this method can be applied to study the distribution dynamics of the vesicle cargo post uptake to different types of cells. This can benefit significantly to our understanding of the fate of cargo components post vesicle internalization in the complex interface between pathogen-derived vesicles and their host recipient cells.

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“…In addition, to their role in parasite-parasite communication, EVs have potent immunoregulatory properties. For instance, EVs can stimulate monocytes and macrophages to secrete proinflammatory cytokines and chemokines ( Couper et al, 2010 ; Sisquella et al, 2017 ; Mbagwu et al, 2019 ; Ofir-Birin et al, 2021 ). EVs secreted by mast cells worsen the development of cerebral malaria in the rodent malaria ( Huang et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Validation of Effective Extracellular Vesicles Isolation Methods Adapted to Field Studies in Malaria Endemic Regions

Zoia

Subramanian

Eriksson

et al. 2022

Front. Cell Dev. Biol.

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Malaria affects the poorer regions of the world and is of tremendous health and economic burden for developing countries. Extracellular vesicles (EVs) are small vesicles released by almost any cells in the human body, including malaria infected red blood cells. Recent evidence shows that EVs might contribute to the pathogenesis of malaria. In addition, EVs hold considerable value in biomarker discovery. However, there are still significant gaps in our understanding of EV biology. So far most of our knowledge about EVs in malaria comes from in vitro work. More field studies are required to gain insight into their contribution to the disease and pathogenesis under physiological conditions. However, to perform research on EVs in low-income regions might be challenging due to the lack of appropriate equipment to isolate EVs. Therefore, there is a need to develop and validate EV extraction protocols applicable to poorly equipped laboratories. We established and validated two protocols for EV isolation from cell culture supernatants, rodent and human plasma. We compared polyethylene glycol (PEG) and salting out (SA) with sodium acetate for precipitation of EVs. We then characterized the EVs by Transmission Electron Microscopy (TEM), Western Blot, Size-exclusion chromatography (SEC), bead-based flow cytometry and protein quantification. Both protocols resulted in efficient purification of EVs without the need of expensive material or ultracentrifugation. Furthermore, the procedure is easily scalable to work with large and small sample volumes. Here, we propose that both of our approaches can be used in resource limited countries, therefore further helping to close the gap in knowledge of EVs during malaria.

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Malaria parasites both repress host CXCL10 and use it as a cue for growth acceleration

Cited by 26 publications

References 97 publications

Sialylated N‐glycans mediate monocyte uptake of extracellular vesicles secreted from Plasmodium falciparum‐infected red blood cells

Sialylated N‐glycans mediate monocyte uptake of extracellular vesicles secreted from Plasmodium falciparum‐infected red blood cells

Monitoring Distribution Dynamics of EV RNA Cargo Within Recipient Monocytes and Macrophages

Validation of Effective Extracellular Vesicles Isolation Methods Adapted to Field Studies in Malaria Endemic Regions

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