Exposure of Pseudomonas aeruginosa to bactericidal hypochlorous acid during neutrophil phagocytosis is compromised in cystic fibrosis

Dickerhof, Nina; Isles, Vivienne; Pattemore, Philip; Hampton, Mark B.

doi:10.1074/jbc.ra119.009934

Cited by 42 publications

(57 citation statements)

References 67 publications

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“…The CFTR has been shown to be expressed on the cellular surface of neutrophils, indicating that their dysregulation is primarily caused by the absence of a functioning CFTR protein, as opposed to just being a secondary effect of mutated CFTR in epithelial cells [123]. Typically, the CFTR is recruited to phagosomes in neutrophils, assisting in the killing of phagocytosed pathogens by moving Cl − ions into the phagolysosome to produce hypochlorous acid (HOCl) [124,125]; however, in neutrophils with CF mutations, the dysfunctional CFTR compromises the ability of neutrophils to kill pathogens due to defective HOCl production in these compartments [124,126,127]. Although another study was unable to find impaired phagocytosis of P. aeruginosa in neutrophils with CF mutations, they did find that phagocytosis is impaired in monocytes from patients with CF [128].…”

Section: Neutrophilsmentioning

confidence: 99%

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Lara-Reyna

Holbrook

Jarosz-Griffiths

et al. 2020

Cell. Mol. Life Sci.

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Cystic fibrosis (CF) is one of the most common life-limiting recessive genetic disorders in Caucasians, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF is a multi-organ disease that involves the lungs, pancreas, sweat glands, digestive and reproductive systems and several other tissues. This debilitating condition is associated with recurrent lower respiratory tract bacterial and viral infections, as well as inflammatory complications that may eventually lead to pulmonary failure. Immune cells play a crucial role in protecting the organs against opportunistic infections and also in the regulation of tissue homeostasis. Innate immune cells are generally affected by CFTR mutations in patients with CF, leading to dysregulation of several cellular signalling pathways that are in continuous use by these cells to elicit a proper immune response. There is substantial evidence to show that airway epithelial cells, neutrophils, monocytes and macrophages all contribute to the pathogenesis of CF, underlying the importance of the CFTR in innate immune responses. The goal of this review is to put into context the important role of the CFTR in different innate immune cells and how CFTR dysfunction contributes to the pathogenesis of CF, highlighting several signalling pathways that may be dysregulated in cells with CFTR mutations.

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Section: Neutrophilsmentioning

confidence: 99%

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Lara-Reyna

Holbrook

Jarosz-Griffiths

et al. 2020

Cell. Mol. Life Sci.

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“…HOCl production by phagocytic cells is one of the central mechanisms to protect host organisms from pathogenic bacteria, including E. coli and P. aeruginosa [32][33][34] . In turn, bacteria have to deal with this intense oxidative insult, with the involvement of Cys-based proteins [35][36][37].…”

Section: Discussionmentioning

confidence: 99%

“…1C) were performed in a cellular context. Therefore, we investigated PaYbbN, as P. aeruginosa is exposed to HOCl during host-pathogen interactions [32,33].…”

Section: Hocl Stressesmentioning

confidence: 99%

Investigation on the requirements for YbbN/CnoX displaying thiol-disulfide oxidoreductase and chaperone activities

Meireles

Yokomizo

Netto

2020

Preprint

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YbbN/CnoX are proteins that display a Trx domain linked to a tetratricopeptide (TPR) domain, which are involved in protein-protein interactions and protein folding processes. YbbN from Escherichia coli (EcYbbN) displays a co-chaperone (holdase) activity that is induced by HOCl (bleach). EcYbbN contains a SQHC motif within the Trx domain and displays no thiol-disulfide oxidoreductase activity.EcYbbN also presents a second Cys residue at Trx domain (Cys63) 24 residues away from SQHF motif that can form mixed disulfides with substrates. Here, we compared EcYbbN with two other YbbN proteins: from Xylella fastidiosa (XfYbbN) and from Pseudomonas aeruginosa (PaYbbN). While EcYbbN displays two Cys residues along a SQHC[N24]C motif; XfYbbN and PaYbbN present two and three Cys residues in the CAPC[N24]V and CAPC[N24]C motifs, respectively. These three proteins are representatives of evolutionary conserved YbbN subfamilies. In contrast to EcYbbN, both XfYbbN and PaYbbN: (1) reduced an artificial disulfide (5,5′-dithiobis-(2-nitrobenzoic acid) = DTNB); and (2) supported the peroxidase activity of Peroxiredoxin Q from X. fastidiosa, suggesting that in vivo these proteins might function similarly to the canonical Trx enzymes. Indeed, XfYbbN was reduced by XfTrx reductase with a high catalytic efficiency (kcat/Km=1.27 x 10 7 M -1 .s -1 ), like the canonical XfTrx (XfTsnC). Furthermore, EcYbbN (as described before) and XfYbbN, but not PaYbbN displayed HOCl -induced holdase activity. Remarkably, EcYbbN gained disulfide reductase activity while lost the HOCl-activated chaperone function when the SQHC was replaced by CQHC. In contrast,the XfYbbN C40A mutant lost the disulfide reductase activity, while kept its HOCl-induced chaperone function. Finally, we generated a P. aeruginosa strain with the ybbN gene deleted, which did not present increased sensitivity to heat shock or to oxidants or to reductants. Altogether, our results suggest that different YbbN/CnoX proteins display distinct properties and activities, depending on the presence of the three conserved Cys residues. Graphical AbstractAbbreviations TPR, tetratricopeptide repeat; NADPH, nicotinamide adenine dinucleotide phosphate; Trx, thioredoxin; DTNB, 5,5-dithio-bis-(2-nitrobenzoic acid). KeywordsThioredoxin, tetratricopeptide-repeat domain, oxidoreductase activity, chaperone/holdase activity. S C C C C C Highlights-CXXC motif is required for the thiol-disulfide reductase activity of YbbN proteins. -XfYbbN and PaYbbN display thiol-disulfide oxidoreductase activity -The affinities of XfTrxR for XfYbbN and XfTsnC (canonical Trx) are comparable -XfYbbN and EcYbbN, but not PaYbbN, display holdase activity induced by hypochlorous acid -Engineering EcYbbN/CnoX by inserting a Cys residue in the SQHC motif resulted in a gain of function (thiol-disulfide oxidoreductase activity) and abolished the HOCl-induced holdase activity.

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“…Furthermore, expression of the cAMP-activated chloride channel (CFTR) has been demonstrated in neutrophils on mRNA and protein level, although at rather low levels [ 143 , 144 ]. Involvement of CFTR in bacterial killing activity of neutrophils via its contribution to the generation of hypochlorite (HOCl) in the phagolysosome has been discussed [ 144 , 145 , 146 , 147 ]. However, the exact underlying mechanisms need further investigation.…”

Section: Sepsis-induced Neutrophil Dysfunction and Its Correlationmentioning

confidence: 99%

Ion and Water Transport in Neutrophil Granulocytes and Its Impairment during Sepsis

Messerer

Schmidt

Frick

et al. 2021

IJMS

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Neutrophil granulocytes are the vanguard of innate immunity in response to numerous pathogens. Their activity drives the clearance of microbe- and damage-associated molecular patterns, thereby contributing substantially to the resolution of inflammation. However, excessive stimulation during sepsis leads to cellular unresponsiveness, immunological dysfunction, bacterial expansion, and subsequent multiple organ dysfunction. During the short lifespan of neutrophils, they can become significantly activated by complement factors, cytokines, and other inflammatory mediators. Following stimulation, the cells respond with a defined (electro-)physiological pattern, including depolarization, calcium influx, and alkalization as well as with increased metabolic activity and polarization of the actin cytoskeleton. Activity of ion transport proteins and aquaporins is critical for multiple cellular functions of innate immune cells, including chemotaxis, generation of reactive oxygen species, and phagocytosis of both pathogens and tissue debris. In this review, we first describe the ion transport proteins and aquaporins involved in the neutrophil ion–water fluxes in response to chemoattractants. We then relate ion and water flux to cellular functions with a focus on danger sensing, chemotaxis, phagocytosis, and oxidative burst and approach the role of altered ion transport protein expression and activity in impaired cellular functions and cell death during systemic inflammation as in sepsis.

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Exposure of Pseudomonas aeruginosa to bactericidal hypochlorous acid during neutrophil phagocytosis is compromised in cystic fibrosis

Cited by 42 publications

References 67 publications

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Investigation on the requirements for YbbN/CnoX displaying thiol-disulfide oxidoreductase and chaperone activities

Ion and Water Transport in Neutrophil Granulocytes and Its Impairment during Sepsis

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