Monocyte metabolic reprogramming promotes pro-inflammatory activity and Staphylococcus aureus biofilm clearance

Yamada, Kelsey J.; Heim, Cortney E.; Xi, Xinyuan; Attri, Kuldeep S.; Wang, Dezhen; Zhang, Wenting; Singh, Pankaj K.; Bronich, Tatiana K.; Kielian, Tammy

doi:10.1371/journal.ppat.1008354

Cited by 57 publications

(74 citation statements)

References 85 publications

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“…A critical role for S. aureus atpA in attenuating the host immune response in vivo was demonstrated by the finding that Δ atpA elicited heightened proinflammatory mediator production in a mouse model of S. aureus PJI. This coincided with a significant reduction in MDSCs concomitant with increased monocyte and MΦ recruitment, a relationship that our prior studies have established coincides with biofilm clearance ( 18 , 20 , 22 , 27 , 42 ).…”

Section: Discussionsupporting

confidence: 75%

“…aureus ATP synthase attenuates MDSC and M⌽ inflammatory responses to biofilm. Previous studies from our laboratory have demonstrated that S. aureus biofilm skews leukocytes to an anti-inflammatory state, which promotes bacterial persistence (18,19,27). To determine if S. aureus ATP synthase-dependent pathways play a role in this process, primary bone marrow-derived MDSCs and M⌽s were cocultured with ΔatpA biofilm to quantify cytokine production.…”

Section: Resultsmentioning

confidence: 99%

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Staphylococcus aureus ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity

Bosch

Bertrand

Heim

et al. 2020

mBio

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Staphylococcus aureus is a major cause of prosthetic joint infection (PJI), which is characterized by biofilm formation. S. aureus biofilm skews the host immune response toward an anti-inflammatory profile by the increased recruitment of myeloid-derived suppressor cells (MDSCs) that attenuate macrophage proinflammatory activity, leading to chronic infection. A screen of the Nebraska Transposon Mutant Library identified several hits in the ATP synthase operon that elicited a heightened inflammatory response in macrophages and MDSCs, including atpA, which encodes the alpha subunit of ATP synthase. An atpA transposon mutant (ΔatpA) had altered growth kinetics under both planktonic and biofilm conditions, along with a diffuse biofilm architecture that was permissive for leukocyte infiltration, as observed by confocal laser scanning microscopy. Coculture of MDSCs and macrophages with ΔatpA biofilm elicited significant increases in the proinflammatory cytokines interleukin 12p70 (IL-12p70), tumor necrosis factor alpha (TNF-α), and IL-6. This was attributed to increased leukocyte survival resulting from less toxin and protease production by ΔatpA biofilm as determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The enhanced inflammatory response elicited by ΔatpA biofilm was cell lysis-dependent since it was negated by polyanethole sodium sulfanate treatment or deletion of the major autolysin, Atl. In a mouse model of PJI, ΔatpA-infected mice had decreased MDSCs concomitant with increased monocyte/macrophage infiltrates and proinflammatory cytokine production, which resulted in biofilm clearance. These studies identify S. aureus ATP synthase as an important factor in influencing the immune response during biofilm-associated infection and bacterial persistence. IMPORTANCE Medical device-associated biofilm infections are a therapeutic challenge based on their antibiotic tolerance and ability to evade immune-mediated clearance. The virulence determinants responsible for bacterial biofilm to induce a maladaptive immune response remain largely unknown. This study identified a critical role for S. aureus ATP synthase in influencing the host immune response to biofilm infection. An S. aureus ATP synthase alpha subunit mutant (ΔatpA) elicited heightened proinflammatory cytokine production by leukocytes in vitro and in vivo, which coincided with improved biofilm clearance in a mouse model of prosthetic joint infection. The ability of S. aureus ΔatpA to augment host proinflammatory responses was cell lysis-dependent, as inhibition of bacterial lysis by polyanethole sodium sulfanate or a ΔatpAΔatl biofilm did not elicit heightened cytokine production. These studies reveal a critical role for AtpA in shaping the host immune response to S. aureus biofilm.

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Section: Discussionsupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Staphylococcus aureus ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity

Bosch

Bertrand

Heim

et al. 2020

mBio

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“…Monocytes that are associated with biofilm infections are polarized toward an anti-inflammatory state (Le et al, 2018;Yamada et al, 2020). Directed uptake by monocytes of nanoparticles coated with the mitochondrial oxidative phosphate inhibitor oligomycin reprogrammed metabolism toward pro-inflammatory glycolysis (Yamada et al, 2020). These macrophages reduced biofilm density in vitro and in vivo in a mouse model of biomaterial-associated bone infection.…”

Section: Discussionmentioning

confidence: 99%

Surface Proteins of Staphylococcus epidermidis

Foster

2020

Front. Microbiol.

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Staphylococcus epidermidis is a ubiquitous commensal of human skin. The widespread use of indwelling medical devices in modern medicine provides an opportunity for it to cause infections. Disease causing isolates can come from many different genetic backgrounds. Multiply antibiotic resistant strains have spread globally. S. epidermidis has a smaller repertoire of cell wall anchored (CWA) surface proteins than Staphylococcus aureus. Nevertheless, these CWA proteins promote adhesion to components of the extracellular matrix including collagen, fibrinogen, and fibronectin and contribute to the formation of biofilm. The A domain of the accumulation associated protein Aap can promote adhesion to unconditioned biomaterial but must be removed proteolytically to allow accumulation to proceed by homophilic Zn 2+-dependent interactions. Mature biofilm contains amyloid structures formed by Aap and the small basic protein (Sbp). The latter contributes to the integrity of both protein and polysaccharide biofilm matrices. Several other CWA proteins can also promote S. epidermidis biofilm formation.

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“…The metabolic preferences of the monocytes recruited during the immune response to S. aureus also influence the outcome of the infection [16]. In contrast to the S. aureus isolates from the skin that induce host glycolysis and inflammation, the strains from prosthetic joint infections, which are prolific biofilm formers, promote oxidative phosphorylation in the recruited macrophage-monocyte population [16]. These immune cells have anti-inflammatory properties including IL-10 and arginase production.…”

Section: Host Metabolism Promotes Infectionmentioning

confidence: 99%

“…The simultaneous changes in host and staphylococcal metabolism during S. aureus infection have a major impact on the clearance of infection [ 6 , 9 , 15 , 16 ]. In the pathogenesis of pneumonia, aspirated bacteria must rapidly adjust their metabolic activity to consume nutrients now available in the airway that differ from those in the sites of initial colonization in the nares.…”

Section: Introductionmentioning

confidence: 99%

Consequences of Metabolic Interactions during Staphylococcus aureus Infection

Prince

Lung

2020

Toxins

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Staphylococcus aureus is a metabolically flexible pathogen that causes infection in diverse settings. An array of virulence factors, including the secreted toxins, enables S. aureus to colonize different environmental niches and initiate infections by any of several discrete pathways. During these infections, both S. aureus and host cells compete with each other for nutrients and remodel their metabolism for survival. This metabolic interaction/crosstalk determines the outcome of the infection. The reprogramming of metabolic pathways in host immune cells not only generates adenosine triphosphate (ATP) to meet the cellular energy requirements during the infection process but also activates antimicrobial responses for eventual bacterial clearance, including cell death pathways. The selective pressure exerted by host immune cells leads to the emergence of bacterial mutants adapted for chronicity. These host-adapted mutants are often characterized by substantial changes in the expression of their own metabolic genes, or by mutations in genes involved in metabolism and biofilm formation. Host-adapted S. aureus can rewire or benefit from the metabolic activities of the immune cells via several mechanisms to cause persistent infection. In this review, we discuss how S. aureus activates host innate immune signaling, which results in an immune metabolic pressure that shapes S. aureus metabolic adaptation and determines the outcome of the infection.

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Monocyte metabolic reprogramming promotes pro-inflammatory activity and Staphylococcus aureus biofilm clearance

Cited by 57 publications

References 85 publications

Staphylococcus aureus ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity

Staphylococcus aureus ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity

Surface Proteins of Staphylococcus epidermidis

Consequences of Metabolic Interactions during Staphylococcus aureus Infection

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