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Extracellular traps released by antimicrobial TH17 cells contributes to host defense

ABSTRACT: Herein, we used C. acnes as a model to elucidate the antimicrobial machinery of the TH17 subset. We generated C. acnes-specific antimicrobial TH17 clones (AMTH17) with varying antimicrobial activity against C. acnes, to enable us to study mechanisms by which TH17 cells kill bacteria. We show that C. acnes-induced AMTH17 clones represent a subset of CD4+ TEM and TEMRA cells. RNA-seq analysis of AMTH17 indicate transcripts encoding antimicrobial molecules such as GNLY, GZMB, PRF1 and histone H2B, whose expression correlates with killing activity. Additionally, we validated that AMTH17-mediated killing is a general mechanism that can target C. acnes and other bacterial species. Scanning electron microscopy reveal that AMTH17s can release T cell extracellular traps composed of lysine and arginine-rich histones such as H2B and H4 that entangle C. acnes. This study identifies a functionally distinct subpopulation of TH17 cells with an ability to secrete antimicrobial proteins and form extracellular T cell traps to capture and kill bacteria.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144852 | GEO | 2021/12/01

REPOSITORIES: GEO

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Project description:Staphylococcus aureus is one of the first and most prevalent pathogens cultured from the airways of cystic fibrosis (CF) patients, which can persist there for extended periods. Airway infections in CF patients are characterized by a strong inflammatory response of highly recruited neutrophils. One killing mechanism of neutrophils is the formation of neutrophil extracellular traps (NETs), which capture and eradicate bacteria by extracellular fibers of neutrophil chromatin decorated with antimicrobial granule proteins. S. aureus secretes nuclease, which can degrade NETs. We hypothesized, that S. aureus adapts to the airways of CF patients during persistent infection by escaping from NET-mediated killing via an increase of nuclease activity. Sputum samples of CF patients with chronic S. aureus infection were visualized by confocal microscopy after immuno-fluorescence staining for NET-specific markers, S. aureus bacteria and overall DNA structures. Nuclease activity was analyzed in sequential isogenic long persisting S. aureus isolates, as confirmed by whole genome sequencing, from an individual CF patient using a FRET-based nuclease activity assay. Additionally, some of these isolates were selected and analyzed by qRT-PCR to determine the expression of nuc1 and regulators of interest. NET-killing assays were performed with clinical S. aureus isolates to evaluate killing and bacterial survival depending on nuclease activity. To confirm the role of nuclease during NET-mediated killing, a clinical isolate with low nuclease activity was transformed with a nuclease expression vector (pCM28nuc). Furthermore, two sputa from an individual CF patient were subjected to RNA-sequence analysis to evaluate the activity of nuclease in vivo. In sputa, S. aureus was associated to extracellular DNA structures. Nuclease activity in clinical S. aureus isolates increased in a time-and phenotype-dependent manner. In the clinical isolates, the expression of nuc1 was inversely correlated to the activity of agr and was independent of saeS. NET-mediated killing was significantly higher in S. aureus isolates with low compared to isolates with high nuclease activity. Importantly, transformation of the clinical isolate with low nuclease activity with pCM28nuc conferred protection against NET-mediated killing confirming the beneficial role of nuclease for protection against NETs. Also, nuclease expression in in vivo sputa was high, which underlines the important role of nuclease within the highly inflamed CF airways. In conclusion, our data show that S. aureus adapts to the neutrophil-rich environment of CF airways with increasing nuclease expression most likely to avoid NET-killing during long-term persistence.

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Extracellular traps released by antimicrobial TH17 cells contributes to host defense

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