Circulating Neutrophil Extracellular Traps and Neutrophil Activation Are Increased in Proportion to Disease Severity in Human Malaria

Steven Kho, Gabriela Minigo, Benediktus Andries, Leo Leonardo, Pak Prayoga, Jeanne R. Poespoprodjo, Enny Kenangalem, Ric N. Price, Tonia Woodberry, Nicholas M. Anstey, Tsin W. Yeo

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: Neutrophil activation results in Plasmodium parasite killing in vitro, but neutrophil products including neutrophil extracellular traps (NETs) mediate host organ damage and may contribute to severe malaria. The role of NETs in the pathogenesis of severe malaria has not been examined.

    Methods: In Papua, Indonesia, we enrolled adults with symptomatic Plasmodium falciparum (n = 47 uncomplicated, n = 8 severe), Plasmodium vivax (n = 37), or Plasmodium malariae (n = 14) malaria; asymptomatic P falciparum (n = 19) or P vivax (n = 21) parasitemia; and healthy adults (n = 23) without parasitemia. Neutrophil activation and NETs were quantified by immunoassays and microscopy and correlated with parasite biomass and disease severity.

    Results: In patients with symptomatic malaria, neutrophil activation and NET counts were increased in all 3 Plasmodium species. In falciparum malaria, neutrophil activation and NET counts positively correlated with parasite biomass (Spearman rho = 0.41, P = .005 and r2 = 0.26, P = .002, respectively) and were significantly increased in severe disease. In contrast, NETs were inversely associated with parasitemia in adults with asymptomatic P falciparum infection (r2 = 0.24, P = .031) but not asymptomatic P vivax infection.

    Conclusions: Although NETs may inhibit parasite growth in asymptomatic P falciparum infection, neutrophil activation and NET release may contribute to pathogenesis in severe falciparum malaria. Agents with potential to attenuate these processes should be evaluated.

    Original languageEnglish
    Pages (from-to)1994-2004
    Number of pages11
    JournalThe Journal of infectious diseases
    Volume219
    Issue number12
    DOIs
    Publication statusPublished - 15 Jun 2019

    Fingerprint

    Neutrophil Activation
    Malaria
    Parasitemia
    Parasites
    Plasmodium
    Falciparum Malaria
    Biomass
    Infection
    Plasmodium malariae
    Plasmodium vivax
    Indonesia
    Extracellular Traps
    Plasmodium falciparum
    Immunoassay
    Microscopy
    Neutrophils
    Growth

    Cite this

    Kho, Steven ; Minigo, Gabriela ; Andries, Benediktus ; Leonardo, Leo ; Prayoga, Pak ; Poespoprodjo, Jeanne R. ; Kenangalem, Enny ; Price, Ric N. ; Woodberry, Tonia ; Anstey, Nicholas M. ; Yeo, Tsin W. / Circulating Neutrophil Extracellular Traps and Neutrophil Activation Are Increased in Proportion to Disease Severity in Human Malaria. In: The Journal of infectious diseases. 2019 ; Vol. 219, No. 12. pp. 1994-2004.
    @article{6f87a43dc5204085afb109d79467434a,
    title = "Circulating Neutrophil Extracellular Traps and Neutrophil Activation Are Increased in Proportion to Disease Severity in Human Malaria",
    abstract = "Background: Neutrophil activation results in Plasmodium parasite killing in vitro, but neutrophil products including neutrophil extracellular traps (NETs) mediate host organ damage and may contribute to severe malaria. The role of NETs in the pathogenesis of severe malaria has not been examined.Methods: In Papua, Indonesia, we enrolled adults with symptomatic Plasmodium falciparum (n = 47 uncomplicated, n = 8 severe), Plasmodium vivax (n = 37), or Plasmodium malariae (n = 14) malaria; asymptomatic P falciparum (n = 19) or P vivax (n = 21) parasitemia; and healthy adults (n = 23) without parasitemia. Neutrophil activation and NETs were quantified by immunoassays and microscopy and correlated with parasite biomass and disease severity.Results: In patients with symptomatic malaria, neutrophil activation and NET counts were increased in all 3 Plasmodium species. In falciparum malaria, neutrophil activation and NET counts positively correlated with parasite biomass (Spearman rho = 0.41, P = .005 and r2 = 0.26, P = .002, respectively) and were significantly increased in severe disease. In contrast, NETs were inversely associated with parasitemia in adults with asymptomatic P falciparum infection (r2 = 0.24, P = .031) but not asymptomatic P vivax infection.Conclusions: Although NETs may inhibit parasite growth in asymptomatic P falciparum infection, neutrophil activation and NET release may contribute to pathogenesis in severe falciparum malaria. Agents with potential to attenuate these processes should be evaluated.",
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    author = "Steven Kho and Gabriela Minigo and Benediktus Andries and Leo Leonardo and Pak Prayoga and Poespoprodjo, {Jeanne R.} and Enny Kenangalem and Price, {Ric N.} and Tonia Woodberry and Anstey, {Nicholas M.} and Yeo, {Tsin W.}",
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    Circulating Neutrophil Extracellular Traps and Neutrophil Activation Are Increased in Proportion to Disease Severity in Human Malaria. / Kho, Steven; Minigo, Gabriela; Andries, Benediktus; Leonardo, Leo; Prayoga, Pak; Poespoprodjo, Jeanne R.; Kenangalem, Enny; Price, Ric N.; Woodberry, Tonia; Anstey, Nicholas M.; Yeo, Tsin W.

    In: The Journal of infectious diseases, Vol. 219, No. 12, 15.06.2019, p. 1994-2004.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Circulating Neutrophil Extracellular Traps and Neutrophil Activation Are Increased in Proportion to Disease Severity in Human Malaria

    AU - Kho, Steven

    AU - Minigo, Gabriela

    AU - Andries, Benediktus

    AU - Leonardo, Leo

    AU - Prayoga, Pak

    AU - Poespoprodjo, Jeanne R.

    AU - Kenangalem, Enny

    AU - Price, Ric N.

    AU - Woodberry, Tonia

    AU - Anstey, Nicholas M.

    AU - Yeo, Tsin W.

    PY - 2019/6/15

    Y1 - 2019/6/15

    N2 - Background: Neutrophil activation results in Plasmodium parasite killing in vitro, but neutrophil products including neutrophil extracellular traps (NETs) mediate host organ damage and may contribute to severe malaria. The role of NETs in the pathogenesis of severe malaria has not been examined.Methods: In Papua, Indonesia, we enrolled adults with symptomatic Plasmodium falciparum (n = 47 uncomplicated, n = 8 severe), Plasmodium vivax (n = 37), or Plasmodium malariae (n = 14) malaria; asymptomatic P falciparum (n = 19) or P vivax (n = 21) parasitemia; and healthy adults (n = 23) without parasitemia. Neutrophil activation and NETs were quantified by immunoassays and microscopy and correlated with parasite biomass and disease severity.Results: In patients with symptomatic malaria, neutrophil activation and NET counts were increased in all 3 Plasmodium species. In falciparum malaria, neutrophil activation and NET counts positively correlated with parasite biomass (Spearman rho = 0.41, P = .005 and r2 = 0.26, P = .002, respectively) and were significantly increased in severe disease. In contrast, NETs were inversely associated with parasitemia in adults with asymptomatic P falciparum infection (r2 = 0.24, P = .031) but not asymptomatic P vivax infection.Conclusions: Although NETs may inhibit parasite growth in asymptomatic P falciparum infection, neutrophil activation and NET release may contribute to pathogenesis in severe falciparum malaria. Agents with potential to attenuate these processes should be evaluated.

    AB - Background: Neutrophil activation results in Plasmodium parasite killing in vitro, but neutrophil products including neutrophil extracellular traps (NETs) mediate host organ damage and may contribute to severe malaria. The role of NETs in the pathogenesis of severe malaria has not been examined.Methods: In Papua, Indonesia, we enrolled adults with symptomatic Plasmodium falciparum (n = 47 uncomplicated, n = 8 severe), Plasmodium vivax (n = 37), or Plasmodium malariae (n = 14) malaria; asymptomatic P falciparum (n = 19) or P vivax (n = 21) parasitemia; and healthy adults (n = 23) without parasitemia. Neutrophil activation and NETs were quantified by immunoassays and microscopy and correlated with parasite biomass and disease severity.Results: In patients with symptomatic malaria, neutrophil activation and NET counts were increased in all 3 Plasmodium species. In falciparum malaria, neutrophil activation and NET counts positively correlated with parasite biomass (Spearman rho = 0.41, P = .005 and r2 = 0.26, P = .002, respectively) and were significantly increased in severe disease. In contrast, NETs were inversely associated with parasitemia in adults with asymptomatic P falciparum infection (r2 = 0.24, P = .031) but not asymptomatic P vivax infection.Conclusions: Although NETs may inhibit parasite growth in asymptomatic P falciparum infection, neutrophil activation and NET release may contribute to pathogenesis in severe falciparum malaria. Agents with potential to attenuate these processes should be evaluated.

    KW - Plasmodium

    KW - malaria

    KW - neutrophil activation

    KW - neutrophil extracellular traps

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    U2 - 10.1093/infdis/jiy661

    DO - 10.1093/infdis/jiy661

    M3 - Article

    VL - 219

    SP - 1994

    EP - 2004

    JO - Journal of Infectious Diseases

    JF - Journal of Infectious Diseases

    SN - 0022-1899

    IS - 12

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