Neutrophil extracellular traps drive inflammatory pathogenesis in malaria

Knackstedt, Sebastian Lorenz; Georgiadou, Athina; Apel, Falko; Abu-Abed, Ulrike; Moxon, Christopher A.; Cunnington, Aubrey J.; Raupach, Bärbel; Cunningham, Deirdre; Langhorne, Jean; Krüger, Renate; Barrera, Valentina; Harding, Simon; Berg, Åse; Patel, Sam; Otterdal, Kari; Mordmüller, Benjamin; Schwarzer, Evelin; Brinkmann, Volker; Zychlinsky, Arturo; Amulic, Borko

doi:10.1126/sciimmunol.aaw0336

Cited by 113 publications

(143 citation statements)

References 97 publications

Supporting

Mentioning

130

Contrasting

Order By: Relevance

“…We also observed an increase in the percentage of neutrophils among white blood cells and in the expression of neutrophil-specific genes in P. vivax infections, regardless of STH co-infection, confirming previous evidence that neutrophil activation is an important response to malaria (Aitken et al 2018). Indeed, a strong neutrophil response with the formation of extracellular traps is observed in acute P. falciparum patients (Knackstedt et al 2019). However, a previous study (Vallejo et al 2018) described a decrease in neutrophils and neutrophil specific genes in P. vivax infections, but this was only observed in first-time infections, possibly accounting for the differences with our results.…”

Section: Discussioncontrasting

confidence: 84%

The immune response and microbiota profiles during co-infection with P. vivax and soil-transmitted helminths

Easton

Raciny-Aleman²,

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

Co-infection with soil-transmitted helminths (STH) and Plasmodium spp. parasites is a common occurrence in tropical low-income countries, but the consequences of this interaction remain poorly understood. Here, we performed a multi-omic analysis on peripheral blood and fecal samples from 130 individuals in Tierralta, Córdoba, Colombia who were infected with P. vivax alone (n = 33), co-infected with P. vivax and STH (n = 27), infected with STH alone (n = 39) or were infected with neither P. vivax nor STH (n = 31). In addition to Complete Blood Count (CBC) with differential, transcriptional profiling of peripheral blood samples was performed by RNA-Seq, fecal microbial communities were determined by 16S ribosomal RNA gene sequencing and circulating cytokine levels were measured by bead-based immunoassays. Differences in blood cell counts were driven primarily by P. vivax infection, including an increased percentage of neutrophils that was associated with a transcriptional signature of neutrophil activation in the blood. P. vivax infection was also associated with increased levels of IL-6, IL-8 and IL-10, and these cytokine levels were not affected by STH co-infection. Surprisingly, P. vivax infection was more strongly associated with changes in the microbiome than STH infection. Children infected with P. vivax exhibited elevated Bacteroides and reduced Prevotella and Clostridiaceae, but these differences were not observed in individuals co-infected with STH. We also observed that P. vivax parasitemia was higher in the STH-infected population. When we used machine learning to identify the most important predictors of P. vivax parasite burden from all measured variables, bacterial taxa were the strongest predictors of parasitemia levels. In contrast, circulating TGF-β was the strongest predictor of T. trichiura egg burden. This study provides unexpected evidence that the gut microbiota may have a stronger link with P. vivax than with STH infection.

show abstract

Section: Discussioncontrasting

confidence: 84%

The immune response and microbiota profiles during co-infection with P. vivax and soil-transmitted helminths

Easton

Raciny-Aleman²,

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition to contributing to the protection, activation of immune cells, when dysregulated, also promote disease pathogenesis. While neutrophils can mediate parasite killing when activated [19], they also release molecules such as proteases or neutrophil extracellular traps (NETs), which can also be very destructive to host tissues [20,21]. Pro-inflammatory mediators, such as IFN-γ and tumor necrosis factor (TNF), that support parasite killing and clearance can cause uncontrolled inflammation and lead to the sequestration of infected erythrocytes.…”

Section: Introductionmentioning

confidence: 99%

Comparison of leucocyte profiles between healthy children and those with asymptomatic and symptomatic Plasmodium falciparum infections

Prah

Amoah

Gibbins

et al. 2020

Malar J

Self Cite

View full text Add to dashboard Cite

Background The immune mechanisms that determine whether a Plasmodium falciparum infection would be symptomatic or asymptomatic are not fully understood. Several studies have been carried out to characterize the associations between disease outcomes and leucocyte numbers. However, the majority of these studies have been conducted in adults with acute uncomplicated malaria, despite children being the most vulnerable group. Methods Peripheral blood leucocyte subpopulations were characterized in children with acute uncomplicated (symptomatic; n = 25) or asymptomatic (n = 67) P. falciparum malaria, as well as malaria-free (uninfected) children (n = 16) from Obom, a sub-district of Accra, Ghana. Leucocyte subpopulations were enumerated by flow cytometry and correlated with two measures of parasite load: (a) plasma levels of P. falciparum histidine-rich protein 2 (PfHRP2) as a proxy for parasite biomass and (b) peripheral blood parasite densities determined by microscopy. Results In children with symptomatic P. falciparum infections, the proportions and absolute cell counts of total (CD3 +) T cells, CD4 + T cells, CD8 + T cells, CD19 + B cells and CD11c + dendritic cells (DCs) were significantly lower as compared to asymptomatic P. falciparum-infected and uninfected children. Notably, CD15 + neutrophil proportions and cell counts were significantly increased in symptomatic children. There was no significant difference in the proportions and absolute counts of CD14 + monocytes amongst the three study groups. As expected, measures of parasite load were significantly higher in symptomatic cases. Remarkably, PfHRP2 levels and parasite densities negatively correlated with both the proportions and absolute numbers of peripheral leucocyte subsets: CD3 + T, CD4 + T, CD8 + T, CD19 + B, CD56 + NK, γδ + T and CD11c + cells. In contrast, both PfHRP2 levels and parasite densities positively correlated with the proportions and absolute numbers of CD15 + cells. Conclusions Symptomatic P. falciparum infection is correlated with an increase in the levels of peripheral blood neutrophils, indicating a role for this cell type in disease pathogenesis. Parasite load is a key determinant of peripheral cell numbers during malaria infections.

show abstract

“…NETs were found in zones adjacent to the nematode cuticle, whereas nodules derived from patients treated with the anti-Wolbachia drugs, doxycycline + ivermectin were depleted for Wolbachia and lacked NETs 65 . More recently it was reported that NETs would drive inflammation in malaria by releasing soluble NET components to facilitate parasite sequestration and tissue destruction, and inhibition of NETs as a treatment strategy in vascular infections was recommended 16 .…”

Section: Nets In Viral Fungal and Parasitic Infectionsmentioning

confidence: 99%

“…In addition to neutrophils, other granulocyte types can also form extracellular DNA traps, such as eosinophils (eosinophil extracellular traps, EETs) 9,10 and basophils (basophil extracellular traps, BETs) 11 . Over the last decade, a number of stimuli, microbial and noninfectious stimuli, able to induce extracellular trap formation have been identified [12][13][14][15][16] . It should be noted that there is an ongoing scientific dispute whether NET formation requires cell death or not [17][18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

In vivo evidence for extracellular DNA trap formation

et al. 2020

View full text Add to dashboard Cite

Extracellular DNA trap formation is a cellular function of neutrophils, eosinophils, and basophils that facilitates the immobilization and killing of invading microorganisms in the extracellular milieu. To form extracellular traps, granulocytes release a scaffold consisting of mitochondrial DNA in association with granule proteins. As we understand more about the molecular mechanism for the formation of extracellular DNA traps, the in vivo function of this phenomenon under pathological conditions remains an enigma. In this article, we critically review the literature to summarize the evidence for extracellular DNA trap formation under in vivo conditions. Extracellular DNA traps have not only been detected in infectious diseases but also in chronic inflammatory diseases, as well as in cancer. While on the one hand, extracellular DNA traps clearly exhibit an important function in host defense, it appears that they can also contribute to the maintenance of inflammation and metastasis, suggesting that they may represent an interesting drug target for such pathological conditions. Facts •The demonstration of extracellular DNA traps in vivo requires sections of affected tissues, which are to be investigated with special staining techniques. These structures are seen in multiple inflammatory and cancer diseases.Is there a simple biomarker that reflects extracellular DNA trap formation?• What is the contribution of extracellular microbe killing compared to intracellular killing following phagocytosis?• The mechanism of DNA trap formation is unknown.

show abstract

Neutrophil extracellular traps drive inflammatory pathogenesis in malaria

Cited by 113 publications

References 97 publications

The immune response and microbiota profiles during co-infection with P. vivax and soil-transmitted helminths

The immune response and microbiota profiles during co-infection with P. vivax and soil-transmitted helminths

Comparison of leucocyte profiles between healthy children and those with asymptomatic and symptomatic Plasmodium falciparum infections

In vivo evidence for extracellular DNA trap formation

Contact Info

Product

Resources

About