Abstract
The endosymbiotic bacteria, Wolbachia, induce neutrophilic responses to the human helminth pathogen Onchocerca volvulus. The formation of Neutrophil Extracellular Traps (NETs), has been implicated in anti-microbial defence, but has not been identified in human helminth infection. Here, we demonstrate NETs formation in human onchocerciasis. Extracellular NETs and neutrophils were visualised around O. volvulus in nodules excised from untreated patients but not in nodules from patients treated with the anti-Wolbachia drug, doxycycline. Whole Wolbachia or microspheres coated with a synthetic Wolbachia lipopeptide (WoLP) of the major nematode Wolbachia TLR2/6 ligand, peptidoglycan associated lipoprotein, induced NETosis in human neutrophils in vitro. TLR6 dependency of Wolbachia and WoLP NETosis was demonstrated using purified neutrophils from TLR6 deficient mice. Thus, we demonstrate for the first time that NETosis occurs during natural human helminth infection and demonstrate a mechanism of NETosis induction via Wolbachia endobacteria and direct ligation of Wolbachia lipoprotein by neutrophil TLR2/6.
Highlights
The endosymbiotic bacteria, Wolbachia, induce neutrophilic responses to the human helminth pathogen Onchocerca volvulus
As the presence of neutrophils and neutrophil extracellular traps” (NETs) were associated with the presence of Wolbachia in onchocercomata, we investigated whether whole Wolbachia bacteria freshly isolated from the culture supernatant of a Wolbachia infected Aedes albopictus cell line (C6/36 [wAlbB]) induced NETosis when co-cultured with human neutrophils
For the first time, that neutrophil infiltrates surrounding O. volvulus adult parasites in nodules are frequently contained within a DNA net-like material decorated with neutrophil-derived granule molecules and citrullinated histones as markers of NETosis
Summary
The endosymbiotic bacteria, Wolbachia, induce neutrophilic responses to the human helminth pathogen Onchocerca volvulus. Onchocerciasis (river blindness) is a parasitic disease affecting 37 million people worldwide, causing debilitating skin and eye pathology and accounting for an estimated global loss of 1 million Disability-Adjusted-Life-Years[1] It is caused by the migrating progeny (microfilariae-mf) of the filarial nematode Onchocerca volvulus, released by adult females residing in subcutaneous nodules (onchocercomata). Neutrophils are the major component of the early inflammatory infiltrate around damaged mf in the cornea and skin[3,4,5,6] Their recruitment and activation, with subsequent development of tissue pathology or systemic adverse reactions to microfilaricidal drug treatment, depend on the presence of Wolbachia[3,4,5,7,8,9,10].
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