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Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst.

ABSTRACT: Neutrophils are critical in the host defense against Staphylococcus aureus, a major human pathogen. However, even in the setting of a robust neutrophil response, S. aureus can evade immune clearance. Here, we demonstrate that S. aureus impairs neutrophil function by triggering the production of the anti-inflammatory metabolite itaconate. The enzyme that synthesizes itaconate, Irg1, is selectively expressed in neutrophils during S. aureus pneumonia. Itaconate inhibits neutrophil glycolysis and oxidative burst, which impairs survival and bacterial killing. In a murine pneumonia model, neutrophil Irg1 expression protects the lung from excessive inflammation but compromises bacterial clearance. S. aureus is thus able to evade the innate immune response by targeting neutrophil metabolism and inducing the production of the anti-inflammatory metabolite itaconate.

SUBMITTER: Tomlinson KL

PROVIDER: S-EPMC10387506 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst.

Tomlinson Kira L KL Riquelme Sebastián A SA Baskota Swikrity Upadhyay SU Drikic Marija M Monk Ian R IR Stinear Timothy P TP Lewis Ian A IA Prince Alice S AS

Cell reports 20230131 2

Neutrophils are critical in the host defense against Staphylococcus aureus, a major human pathogen. However, even in the setting of a robust neutrophil response, S. aureus can evade immune clearance. Here, we demonstrate that S. aureus impairs neutrophil function by triggering the production of the anti-inflammatory metabolite itaconate. The enzyme that synthesizes itaconate, Irg1, is selectively expressed in neutrophils during S. aureus pneumonia. Itaconate inhibits neutrophil glycolysis and ox ...[more]

PMID: 36724077

Similar Datasets

Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst

Project description:Neutrophils are critical in the host defense against Staphylococcus aureus, a major human pathogen. However, even in the setting of a robust neutrophil response, S. aureus can cause persistent infection. Here we demonstrate that S. aureus impairs neutrophil function by triggering the production of the anti-inflammatory metabolite, itaconate. The enzyme that synthesizes itaconate, Irg1, is selectively expressed in neutrophils during S. aureus pneumonia. Itaconate inhibits neutrophil glycolysis and oxidative burst, which impairs survival and bacterial killing. In a murine pneumonia model, neutrophil Irg1 expression protects critical lung cell populations from oxidative stress but compromises bacterial clearance. S. aureus is thus able to evade innate immune clearance by targeting neutrophil metabolism and inducing the production of the antiinflammatory metabolite itaconate.

2023-01-01 | GSE215195 | GEO

Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst

Project description:Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst

| PRJNA889172 | ENA

Suppressing neutrophil itaconate production attenuates Mycoplasma pneumoniae pneumonia.

Project description:Mycoplasma pneumoniae is a common cause of community-acquired pneumonia in which neutrophils play a critical role. Immune-responsive gene 1 (IRG1), responsible for itaconate production, has emerged as an important regulator of inflammation and infection, but its role during M. pneumoniae infection remains unknown. Here, we reveal that itaconate is an endogenous pro-inflammatory metabolite during M. pneumoniae infection. Irg1 knockout (KO) mice had lower levels of bacterial burden, lactate dehydrogenase (LDH), and pro-inflammatory cytokines compared with wild-type (WT) controls after M. pneumoniae infection. Neutrophils were the major cells producing itaconate during M. pneumoniae infection in mice. Neutrophil counts were positively correlated with itaconate concentrations in bronchoalveolar lavage fluid (BALF) of patients with severe M. pneumoniae pneumonia. Adoptive transfer of Irg1 KO neutrophils, or administration of β-glucan (an inhibitor of Irg1 expression), significantly attenuated M. pneumoniae pneumonia in mice. Mechanistically, itaconate impaired neutrophil bacterial killing and suppressed neutrophil apoptosis via inhibiting mitochondrial ROS. Moreover, M. pneumoniae induced Irg1 expression by activating NF-κB and STAT1 pathways involving TLR2. Our data thus identify Irg1/itaconate pathway as a potential therapeutic target for the treatment of M. pneumoniae pneumonia.

| S-EPMC11567624 | biostudies-literature

Staphylococcus aureus stimulates neutrophil targeting chemokine expression in keratinocytes through an autocrine IL-1alpha signaling loop.

Project description:Staphylococcus aureus is a significant human pathogen that can colonize the skin. Neutrophils are well known to be involved in clearance of the bacterium. This study focused on exploring the role that human keratinocytes have as first responders to bacterial challenges. IL-1alpha and IL-1beta increased mRNA production and protein secretion of the neutrophil chemotactic CXCL1, CXCL2, and IL-8 in keratinocytes. S. aureus and the bacterial cell wall components lipoteichoic acid (LTA) and peptidoglycan (PGN) induced similar expression profiles in a Toll-like receptor (TLR)-2-dependent manner. Interestingly, the S. aureus-induced mRNA levels peaked at later time points than those induced by IL-1. The S. aureus-activated chemokine production was preceded by significant IL-1alpha and IL-1beta secretion. Expression of IL-1alpha was significantly higher than that of IL-1beta. Inhibition of IL-1RI using neutralizing antibodies revealed that S. aureus-derived LTA and PGN-induced chemokine expression requires IL-1RI engagement. Surprisingly, we further found that chemokine secretion is dependent upon endocrine IL-1alpha, but not IL-1beta, signaling. Our data show that the innate immune response of keratinocytes is regulated differently than those of other cell types. This may represent a fail-safe system that protects the host against genetic variation and immune evasion mechanisms developed by pathogens.

| S-EPMC2886182 | biostudies-literature

Staphylococcus aureus SaeR/S-regulated factors reduce human neutrophil reactive oxygen species production.

Project description:Neutrophils are the first line of defense after a pathogen has breached the epithelial barriers, and unimpaired neutrophil functions are essential to clear infections. Staphylococcus aureus is a prevalent human pathogen that is able to withstand neutrophil killing, yet the mechanisms used by S. aureus to inhibit neutrophil clearance remain incompletely defined. The production of reactive oxygen species (ROS) is a vital neutrophil antimicrobial mechanism. Herein, we test the hypothesis that S. aureus uses the SaeR/S two-component gene regulatory system to produce virulence factors that reduce neutrophil ROS production. With the use of ROS probes, the temporal and overall production of neutrophil ROS was assessed during exposure to the clinically relevant S. aureus USA300 (strain LAC) and its isogenic mutant LACΔsaeR/S Our results demonstrated that SaeR/S-regulated factors do not inhibit neutrophil superoxide (O2-) production. However, subsequent neutrophil ROS production was significantly reduced during exposure to LAC compared with LACΔsaeR/S In addition, neutrophil H2O2 production was reduced significantly by SaeR/S-regulated factors by a mechanism independent of catalase. Consequently, the reduction in neutrophil H2O2 resulted in decreased production of the highly antimicrobial agent hypochlorous acid/hypochlorite anion (HOCl/-OCl). These findings suggest a new evasion strategy used by S. aureus to diminish a vital neutrophil antimicrobial mechanism.

| S-EPMC5069094 | biostudies-literature

Staphylococcus aureus agr genotypes with enterotoxin production capabilities can resist neutrophil bactericidal activity.

Project description:Staphylococcus aureus pathogenicity is mainly due to the production of a number of secreted and cell surface-associated proteins under the regulation of the agr gene. A region of the agr gene was used to subgroup S. aureus strains according to restriction fragment length polymorphisms. Additionally, strains were subtyped according to the coagulase gene in order to strengthen discriminatory power. Virulence capabilities of agr genotype subgroups were evaluated using an in vitro neutrophil bactericidal assay, which showed that prevalent genotypes were significantly better at evading this primary host defense. Multiplex PCR was then used to detect enterotoxin genes among the genotype subgroups in order to determine possible virulence candidates that enable strains to combat neutrophil killing. The prevalent genotype strains were found to possess higher production capabilities for enterotoxin A than did low-prevalence strains. The significance of enterotoxin A production capabilities in affecting pathogenicity of S. aureus strains was evaluated and found to have a profound effect on neutrophil killing abilities. The use of a large epidemiological database as a tool for subgrouping strains with varying degrees of pathogenicity has allowed the identification of relevant and previously undefined virulence factors that affect a pathogen's capability to overcome host immune defenses.

| S-EPMC97853 | biostudies-literature

Staphylococcus aureus induces an itaconate-dominated immunometabolic response that drives biofilm formation.

Project description:Staphylococcus aureus is a prominent human pathogen that readily adapts to host immune defenses. Here, we show that, in contrast to Gram-negative pathogens, S. aureus induces a distinct airway immunometabolic response dominated by the release of the electrophilic metabolite, itaconate. The itaconate synthetic enzyme, IRG1, is activated by host mitochondrial stress, which is induced by staphylococcal glycolysis. Itaconate inhibits S. aureus glycolysis and selects for strains that re-direct carbon flux to fuel extracellular polysaccharide (EPS) synthesis and biofilm formation. Itaconate-adapted strains, as illustrated by S. aureus isolates from chronic airway infection, exhibit decreased glycolytic activity, high EPS production, and proficient biofilm formation even before itaconate stimulation. S. aureus thus adapts to the itaconate-dominated immunometabolic response by producing biofilms, which are associated with chronic infection of the human airway.

| S-EPMC7930111 | biostudies-literature

Selective activation of PFKL suppresses the phagocytic oxidative burst.

Project description:In neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading pathogens. However, excessive NOX2 activity can exacerbate inflammation, as in acute respiratory distress syndrome (ARDS). Here, we use two unbiased chemical proteomic strategies to show that small-molecule LDC7559, or a more potent designed analog NA-11, inhibits the NOX2-dependent oxidative burst in neutrophils by activating the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) and dampening flux through the pentose phosphate pathway. Accordingly, neutrophils treated with NA-11 had reduced NOX2-dependent outputs, including neutrophil cell death (NETosis) and tissue damage. A high-resolution structure of PFKL confirmed binding of NA-11 to the AMP/ADP allosteric activation site and explained why NA-11 failed to agonize phosphofructokinase-1 platelet type (PFKP) or muscle type (PFKM). Thus, NA-11 represents a tool for selective activation of PFKL, the main phosphofructokinase-1 isoform expressed in immune cells.

| S-EPMC8802628 | biostudies-literature

Effect of Antiretroviral Therapy on Neutrophil Oxidative Burst in Children.

Project description:ObjectiveTo ascertain the effect of human immunodeficiency virus (HIV) infection, as well as, antiretroviral therapy (ART) on neutrophil oxidative burst in children.MethodsFifty-five children living with HIV infection (30 receiving ART for ≥ 2 y, 25 treatment-naïve) and 30 healthy controls, aged 18 mo-18 y, were assessed for hemogram and neutrophil oxidative burst. The treatment-naïve children were followed up and the above tests were repeated after 6 mo of ART.ResultsMean (SD) serum MPO activity at 6 mo after ART [32.1 (± 19.9) U/L] was comparable to that at disease onset [17.2 (± 23.0) U/L], although it was significantly higher compared to that in children on ART ≥ 2 y [13.3 (± 15.8) U/L] and controls [12.1 (± 11.9) U/L]. Median fluorescence intensity (MFI) of unstimulated DHR was highest at 6 mo after ART and in the treatment-naïve group, which was significantly higher than in the controls, as well as, children receiving ART ≥ 2 y. Stimulation index was highest in the control group [442.4 (341.9-562.9)], which was comparable to that in children on ART ≥ 2 y [304.2 (153.2-664.8)], but was significantly higher than the treatment-naïve cohort [266.1 (148.2-339.4)] and children on ART for 6 mo [318.8 (154.9-395.6)].ConclusionA hyperinflammatory state caused by an increased serum myeloperoxidase enzyme activity and increased basal neutrophil oxidative burst was seen in untreated HIV infection and during initial 6 mo of ART. ART given for ≥ 2 y normalized the impaired neutrophilic phagocytic functions.

| S-EPMC9364305 | biostudies-literature

Antibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus.

Project description:The pathogen Staphylococcus aureus can readily develop antibiotic resistance and evade the human immune system, which is associated with reduced levels of neutrophil recruitment. Here, we present a class of antibacterial peptides with potential to act both as antibiotics and as neutrophil chemoattractants. The compounds, which we term 'antibiotic-chemoattractants', consist of a formylated peptide (known to act as chemoattractant for neutrophil recruitment) that is covalently linked to the antibiotic vancomycin (known to bind to the bacterial cell wall). We use a combination of in vitro assays, cellular assays, infection-on-a-chip and in vivo mouse models to show that the compounds improve the recruitment, engulfment and killing of S. aureus by neutrophils. Furthermore, optimizing the formyl peptide sequence can enhance neutrophil activity through differential activation of formyl peptide receptors. Thus, we propose antibiotic-chemoattractants as an alternate approach for antibiotic development.

| S-EPMC8546149 | biostudies-literature

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