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

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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.
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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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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

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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

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KW - neutrophil activation

KW - neutrophil extracellular traps

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U2 - 10.1093/infdis/jiy661

DO - 10.1093/infdis/jiy661

M3 - Article

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EP - 2004

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

SN - 0022-1899

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