Malaria parasite DNA-harbouring vesicles activate cytosolic immune sensors

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

doi:10.1038/s41467-017-02083-1

Malaria parasite DNA-harbouring vesicles activate cytosolic immune sensors

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

152 Scopus citations

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.

Original language	English
Article number	1985
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02083-1
State	Published - 1 Dec 2017

Funding

Funders	Funder number
Benoziyo Endowment Fund for the Advancement of Science
Jeanne and Joseph Nissim Foundation for Life Sciences Research
Recanati Foundation
Varda and Boaz Dotan Research Center	119034, 619/16
National Institutes of Health
National Institute of Allergy and Infectious Diseases	R01AI093752
Alpha-1 Foundation
Science Foundation Ireland	11/PI/1056
Israel Science Foundation	1416/15
Tel Aviv University

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-017-02083-1

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Sisquella, X., Ofir-Birin, Y., Pimentel, M. A., Cheng, L., Abou Karam, P., Sampaio, N. G., Penington, J. S., Connolly, D., Giladi, T., Scicluna, B. J., Sharples, R. A., Waltmann, A., Avni, D., Schwartz, E., Schofield, L., Porat, Z., Hansen, D. S., Papenfuss, A. T., Eriksson, E. M., ... Regev-Rudzki, N. (2017). Malaria parasite DNA-harbouring vesicles activate cytosolic immune sensors. Nature Communications, 8(1), Article 1985. https://doi.org/10.1038/s41467-017-02083-1

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title = "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.",

author = "Xavier Sisquella and Yifat Ofir-Birin and Pimentel, {Matthew A.} and Lesley Cheng and {Abou Karam}, Paula and Sampaio, {Nat{\'a}lia G.} and Penington, {Jocelyn Sietsma} and Dympna Connolly and Tal Giladi and Scicluna, {Benjamin J.} and Sharples, {Robyn A.} and Andreea Waltmann and Dror Avni and Eli Schwartz and Louis Schofield and Ziv Porat and Hansen, {Diana S.} and Papenfuss, {Anthony T.} and Eriksson, {Emily M.} and Motti Gerlic and Hill, {Andrew F.} and Bowie, {Andrew G.} and Neta Regev-Rudzki",

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Sisquella, X, Ofir-Birin, Y, Pimentel, MA, Cheng, L, Abou Karam, P, Sampaio, NG, Penington, JS, Connolly, D, Giladi, T, Scicluna, BJ, Sharples, RA, Waltmann, A, Avni, D , Schwartz, E, Schofield, L, Porat, Z, Hansen, DS, Papenfuss, AT, Eriksson, EM, Gerlic, M, Hill, AF, Bowie, AG & Regev-Rudzki, N 2017, 'Malaria parasite DNA-harbouring vesicles activate cytosolic immune sensors', Nature Communications, vol. 8, no. 1, 1985. https://doi.org/10.1038/s41467-017-02083-1

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T1 - Malaria parasite DNA-harbouring vesicles activate cytosolic immune sensors

AU - Sisquella, Xavier

AU - Ofir-Birin, Yifat

AU - Pimentel, Matthew A.

AU - Cheng, Lesley

AU - Abou Karam, Paula

AU - Sampaio, Natália G.

AU - Penington, Jocelyn Sietsma

AU - Connolly, Dympna

AU - Giladi, Tal

AU - Scicluna, Benjamin J.

AU - Sharples, Robyn A.

AU - Waltmann, Andreea

AU - Avni, Dror

AU - Schwartz, Eli

AU - Schofield, Louis

AU - Porat, Ziv

AU - Hansen, Diana S.

AU - Papenfuss, Anthony T.

AU - Eriksson, Emily M.

AU - Gerlic, Motti

AU - Hill, Andrew F.

AU - Bowie, Andrew G.

AU - Regev-Rudzki, Neta

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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SN - 2041-1723

VL - 8

JO - Nature Communications

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Malaria parasite DNA-harbouring vesicles activate cytosolic immune sensors

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Funding

UN SDGs

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