Wolbachia endosymbionts induce neutrophil extracellular trap formation in human onchocerciasis

Tamarozzi, Francesca; Turner, Joseph D.; Pionnier, Nicolas; Midgley, Angela; Guimarães, Ana Flávia Bereta Coelho; Johnston, Kelly L.; Edwards, Steven W.; Taylor, Mark J.

doi:10.1038/srep35559

Cited by 38 publications

(44 citation statements)

References 44 publications

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“…NETs were recently demonstrated to be involved in the defense against incoming larvae of Strongyloides stercoralis 50. In human filarial nematode Onchocerca volvulus infections, NET formations were found around the adult worm containing nodules and the mechanism of NET formation was linked to the presence of Wolbachia and TLR2/651. The prominent role of neutrophils during the skin phase of L. sigmodontis infection in our study is in accordance with the study of Porthouse et al ., which showed that the very early immune response against incoming Brugia pahangi larvae is dominated by neutrophils and IL-652.…”

Section: Discussionsupporting

confidence: 92%

NOD2 dependent neutrophil recruitment is required for early protective immune responses against infectious Litomosoides sigmodontis L3 larvae

Ajendra

Specht

Ziewer

et al. 2016

Sci Rep

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Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) recognizes muramyl dipeptide (MDP) of bacterial cell walls, triggering NFκB-induced pro-inflammation. As most human pathogenic filariae contain Wolbachia endobacteria that synthesize the MDP-containing cell wall precursor lipid II, NOD2’s role during infection with the rodent filaria Litomosoides sigmodontis was investigated. In NFκB reporter-cells, worm-extract containing Wolbachia induced NOD2 and NOD1. NOD2-deficient mice infected with L. sigmodontis had significantly more worms than wildtype controls early in infection. Increased worm burden was not observed after subcutaneous infection, suggesting that protective NOD2-dependent immune responses occur within the skin. Flow cytometry demonstrated that neutrophil recruitment to the skin was impaired in NOD2−/− mice after intradermal injection of third stage larvae (L3), and blood neutrophil numbers were reduced after L. sigmodontis infection. PCR array supported the requirement of NOD2 for recruitment of neutrophils to the skin, as genes associated with neutrophil recruitment and activation were downregulated in NOD2−/− mice after intradermal L3 injection. Neutrophil depletion before L. sigmodontis infection increased worm recovery in wildtype mice, confirming that neutrophils are essential against invading L3 larvae. This study indicates that NOD-like receptors are implemented in first-line protective immune responses against filarial nematodes.

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Section: Discussionsupporting

confidence: 92%

NOD2 dependent neutrophil recruitment is required for early protective immune responses against infectious Litomosoides sigmodontis L3 larvae

Ajendra

Specht

Ziewer

et al. 2016

Sci Rep

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“…Interestingly, many filarial species harbor obligate bacterial endosymbionts ( Wolbachia ) which were recently shown to trigger NETosis ( 65 ). So far, it remains unclear whether microfilariae-triggered NETosis may interfere with antifilarial treatments.…”

Section: Discussionmentioning

confidence: 99%

Dirofilaria immitis Microfilariae and Third-Stage Larvae Induce Canine NETosis Resulting in Different Types of Neutrophil Extracellular Traps

et al. 2018

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Heartworm disease is a zoonotic vector-borne disease caused by Dirofilaria immitis mainly affecting canids. Infectious third-stage larvae (L3) are transmitted to the definitive hosts via culicid mosquitoes; adult nematodes reside in the pulmonary arteries and in the right heart releasing unsheathed first-stage larvae (microfilariae) into the bloodstream leading to chronic and sometimes fatal disease. So far, early innate immune reactions triggered by these different D. immitis stages in the canine host have scarcely been investigated. Therefore, D. immitis microfilariae and L3 were analyzed for their capacity to induce neutrophil extracellular traps (NETs) in canine polymorphonuclear neutrophils (PMN). Overall, scanning electron microscopy analysis revealed both larval stages as strong inducers of canine NETosis. Co-localization of PMN-derived extracellular DNA with granulocytic histones, neutrophil elastase, or myeloperoxidase in parasite-entrapping structures confirmed the classical characteristics of NETosis. Quantitative analyses showed that both larval stages triggered canine NETs in a time-dependent but dose-independent manner. Moreover, parasite-induced NET formation was not influenced by the parasites viability since heat-inactivated microfilariae and L3 also induced NETs. In addition, parasite/PMN confrontation promoted significant entrapment but not killing of microfilariae and L3. Both, NETosis and larval entrapment was significantly reversed via DNase I treatments while treatments with the NADPH oxidase inhibitor diphenyleneiodonium failed to significantly influence these reactions. Interestingly, different types of NETs were induced by microfilariae and L3 since microfilarial stages merely induced spread and diffuse NETs while the larger L3 additionally triggered aggregated NET formation.

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“…The onchocercomata (subcutaneous nodules) of patients contain worms positive for Wolbachia and exhibited high numbers of NETs. 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: 97%

In vivo evidence for extracellular DNA trap formation

et al. 2020

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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.

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Wolbachia endosymbionts induce neutrophil extracellular trap formation in human onchocerciasis

Cited by 38 publications

References 44 publications

NOD2 dependent neutrophil recruitment is required for early protective immune responses against infectious Litomosoides sigmodontis L3 larvae

NOD2 dependent neutrophil recruitment is required for early protective immune responses against infectious Litomosoides sigmodontis L3 larvae

Dirofilaria immitis Microfilariae and Third-Stage Larvae Induce Canine NETosis Resulting in Different Types of Neutrophil Extracellular Traps

In vivo evidence for extracellular DNA trap formation

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