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

Tomlinson, Kira L.; Lung, Tania Wong Fok; Dach, Felix; Annavajhala, Medini K.; Gabryszewski, Stanislaw J.; Groves, Ryan A.; Drikic, Marija; Francoeur, Nancy; Sridhar, Shwetha Hara; Smith, Melissa; Khanal, Sara; Britto, Clemente J.; Sebra, Robert; Lewis, Ian A.; Uhlemann, Anne‐Catrin; Kahl, Barbara C.; Prince, Alice

doi:10.1038/s41467-021-21718-y

Cited by 98 publications

(78 citation statements)

References 54 publications

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“…Tomlinson et al investigated the immunometabolic response of S. aureus [137]. Their data showed that S. aureus induced the production of the immunoregulatory metabolite itaconate in airway immune cells by stimulating mitochondrial oxidative stress.…”

Section: Biofilm Formation-an Adaptive Mechanism Of S Aureus In Cystic Fibrosismentioning

confidence: 99%

Staphylococcus aureus and Cystic Fibrosis—A Close Relationship. What Can We Learn from Sequencing Studies?

et al. 2021

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Staphylococcus aureus is next to Pseudomonas aeruginosa the most isolated pathogen from the airways of cystic fibrosis (CF) patients, who are often infected by a dominant S. aureus clone for extended periods. To be able to persist, the pathogen has to adapt to the hostile niche of the airways to counteract host defence, antibiotic therapy and the competition with coinfecting pathogens. S. aureus is equipped with many virulence factors including adhesins, toxins that are localized on the chromosome, on plasmids or are phage-related. S. aureus is especially versatile and adaptation and evolution of the pathogen occurs by the acquisition of new genes by horizontal gene transfer (HGT), changes in nucleotides (single nucleotide variations, SNVs) that can cause a selective advantage for the bacteria and become fixed in subpopulations. Methicillin-resistant S. aureus are a special threat to CF patients due to the more severe lung disease occurring in infected patients. Today, with decreasing costs for sequencing, more and more studies using S. aureus isolates cultured from CF patients are being published, which use whole genome sequencing (WGS), multilocus sequence typing (MLST) or spa-sequence typing (spa-typing) to follow the population dynamics of S. aureus, elucidate the underlying mechanisms of phenotypic variants, newly acquired resistance or adaptation to the host response in this particular niche. In the first part of this review, an introduction to the genetic make-up and the pathogenesis of S. aureus with respect to CF is provided. The second part presents an overview of recent studies and their findings using genotypic methods such as single or multilocus sequencing and whole genome sequencing, which identify factors contributing to the adaptation of S. aureus and its evolution in the airways of individuals with CF.

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Section: Biofilm Formation-an Adaptive Mechanism Of S Aureus In Cystic Fibrosismentioning

confidence: 99%

Staphylococcus aureus and Cystic Fibrosis—A Close Relationship. What Can We Learn from Sequencing Studies?

et al. 2021

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“…A recent study of the role of itaconate in S. aureus endophthalmitis indicates that TLR2 signaling is not sufficient, as heat-killed S. aureus, lipoteichoic acid, and peptidoglycan do not stimulate IRG1 expression to the same extent as live bacteria (63). Instead, IRG1 expression can be mitigated by administration of a mitochondrial ROS scavenger, suggesting that host mitochondrial stress and/or oxidants promote IRG1 expression during S. aureus infection (56).…”

Section: S Aureus Induces An Itaconate-dominated Immunometabolic Responsementioning

confidence: 99%

“…Mitochondrial ROS production and itaconate accumulation in the murine airway depend on S. aureus glycolysis, demonstrating that bacterial metabolism itself stimulates itaconate generation during S. aureus lung infection (56). The exact mechanism that connects bacterial metabolism to host metabolic reprogramming still needs to be determined.…”

Section: S Aureus Induces An Itaconate-dominated Immunometabolic Responsementioning

confidence: 99%

“…As a Gram-positive pathogen lacking LPS, S. aureus induces a distinct immunometabolic response from the one detailed above for P. aeruginosa . During S. aureus infection, itaconate, but not succinate, accumulates in the airway ( 22 , 56 ) ( Figure 3 ). This itaconate-dominated response is accompanied by a distinct cytokine profile, characterized by diminished levels of some pro-inflammatory cytokines, like IL-1β and IL-6, but not others, like TNFα ( 56 ).…”

Section: S Aureus Induces An Itaconate-dominated Immunometabolic Responsementioning

confidence: 99%

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Immunometabolites Drive Bacterial Adaptation to the Airway

2021

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Pseudomonas aeruginosa and Staphylococcus aureus are both opportunistic pathogens that are frequently associated with chronic lung infections. While bacterial virulence determinants are critical in initiating infection, the metabolic flexibility of these bacteria promotes their persistence in the airway. Upon infection, these pathogens induce host immunometabolic reprogramming, resulting in an airway milieu replete with immune-signaling metabolites. These metabolites are often toxic to the bacteria and create a steep selection pressure for the emergence of bacterial isolates adapted for long-term survival in the inflamed lung. In this review, we discuss the main differences in the host immunometabolic response to P. aeruginosa and S. aureus, as well as how these pathogens alter their own metabolism to adapt to airway metabolites and cause persistent lung infections.

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“…Itaconate is abundantly produced by macrophages and the host airway after infection with P. aeruginosa [21,41]. Itaconate is toxic to many bacterial species, such as Staphylococcus aureus, Mycobacterium tuberculosis and Legionella pneumophila [45][46][47] targeting the activity of both isocitrate lyase (aceA) [48] and aldolase, major metabolic nodes that control the function of the anti-oxidant glyoxylate shunt [49,50] and glycolysis, respectively (Figure 2). However, several important airway pathogens, including P. aeruginosa, M. tuberculosis and Aspergillus species can also metabolize itaconate [51].…”

Section: P Aeruginosa Induces and Assimilates Host Itaconate To Cause Long-term Diseasementioning

confidence: 99%

Pseudomonas aeruginosa Consumption of Airway Metabolites Promotes Lung Infection

Riquelme

2021

Pathogens

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Prevailing dogma indicates that the lung of cystic fibrosis (CF) individuals is infected by multiple pathogens due to the abundant accumulation of mucus, which traps most of inhaled organisms. However, this hypothesis does not explain how specific opportunists, like Pseudomonas aeruginosa, are selected in the CF lung to cause chronic disease. This strongly suggests that other factors than mucus are accrued in the human airway and might predispose to bacterial disease, especially by P. aeruginosa. In this review we discuss the role of macrophage metabolites, like succinate and itaconate, in P. aeruginosa pneumonia. We analyze how dysfunction of the CF transmembrane conductance regulator (CFTR) favors release of these metabolites into the infected airway, and how P. aeruginosa exploits these elements to induce transcriptomic and metabolic changes that increase its capacity to cause intractable disease. We describe the host and pathogen pathways associated with succinate and itaconate catabolism, mechanisms of bacterial adaptation to these determinants, and suggest how both experimental settings and future therapies should consider macrophage metabolites abundance to better study P. aeruginosa pathogenesis.

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

Cited by 98 publications

References 54 publications

Staphylococcus aureus and Cystic Fibrosis—A Close Relationship. What Can We Learn from Sequencing Studies?

Staphylococcus aureus and Cystic Fibrosis—A Close Relationship. What Can We Learn from Sequencing Studies?

Immunometabolites Drive Bacterial Adaptation to the Airway

Pseudomonas aeruginosa Consumption of Airway Metabolites Promotes Lung Infection

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