Lactate production by Staphylococcus aureus biofilm inhibits HDAC11 to reprogramme the host immune response during persistent infection

Heim, Cortney E.; Bosch, Megan E.; Yamada, Kelsey J.; Aldrich, Amy; Chaudhari, Sujata S.; Klinkebiel, David; Gries, Casey M.; Alqarzaee, Abdulelah A.; Li, Yixuan; Thomas, Vinai Chittezham; Seto, Edward; Karpf, Adam R.; Kielian, Tammy

doi:10.1038/s41564-020-0756-3

Cited by 128 publications

(130 citation statements)

References 109 publications

(100 reference statements)

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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%

“…Our laboratory has previously shown in a mouse model of PJI that S. aureus biofilm can actively suppress proinflammatory responses by the preferential recruitment of myeloid-derived suppressor cells (MDSCs) and anti-inflammatory monocytes/macrophages (MΦs) to the site of infection ( 14 , 18 ). These MDSCs produce interleukin 10 (IL-10) to create an immunosuppressive environment that allows for biofilm persistence ( 19 , 20 ). Importantly, MDSC infiltrates are also more pronounced in tissues from patients with PJI than with aseptic loosening, reinforcing the findings in the mouse PJI model ( 21 , 22 ).…”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 99%

Staphylococcus aureus ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity

Bosch

Bertrand

Heim

et al. 2020

mBio

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“…Furthermore, the additional loss of ldh2 was found to augment the latter phenotype 46 , highlighting the importance of fermentative metabolism for S. aureus pathogenicity. In addition to maintaining the cells ability to generate energy under conditions encountered in the abscess, the creation of lactate as a byproduct of fermentation was recently shown to aid in staphylococcal immune evasion 48 . Briefly, bacterial-derived lactate causes alterations of gene expression in host immune cells, e.g.…”

Section: Resultsmentioning

confidence: 99%

Spatially-targeted proteomics of the host-pathogen interface during staphylococcal abscess formation

Guiberson

Weiss

Ryan

et al. 2020

Preprint

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Staphylococcus aureus is a common cause of invasive and life-threatening infections that are often multi-drug resistant. To develop novel treatment approaches, a detailed understanding of the complex host-pathogen interactions during infection is essential. This is particularly true for the molecular processes that govern the formation of tissue abscesses, as these heterogeneous structures are important contributors to staphylococcal pathogenicity. To fully characterize the developmental process leading to mature abscesses, temporal and spatial analytical approaches are required. Spatially targeted proteomic technologies, such as micro liquid extraction surface analysis, offer insight into complex biological systems including detection of bacterial proteins, and their abundance in the host environment. By analyzing the proteomic constituents of different abscess regions across the course of infection, we defined the immune response and bacterial contribution to abscess development through spatial and temporal proteomic assessment. The information gathered was mapped to biochemical pathways to characterize the metabolic processes and immune strategies employed by the host. These data provide insights into the physiological state of bacteria within abscesses and elucidate pathogenic processes at the host-pathogen interface.

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“…When their oxidative metabolism is blocked using a nanoparticle approach for the delivery of the OXPHOS inhibitor oligomycin, significantly increased inflammation and S. aureus clearance are observed [ 16 ]. The ability of biofilm formers to induce host IL-10 production was shown to be due to S. aureus lactate-mediated inhibition of the histone deacetylase 11 (HDAC11), resulting in unchecked HDAC6 activity, an increase in histone 3 (H3) acetylation at the Il-10 promoter and enhanced Il-10 transcription [ 50 ] ( Figure 2 C). These findings share some major host epigenetic features with the fumC -induced depletion of fumarate and suppression of trained immunity, discussed above, linking S. aureus -host metabolic adaptation and epigenetics during persistent infection.…”

Section: Host Metabolism Promotes Infectionmentioning

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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Lactate production by Staphylococcus aureus biofilm inhibits HDAC11 to reprogramme the host immune response during persistent infection

Cited by 128 publications

References 109 publications

Staphylococcus aureus ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity

Staphylococcus aureus ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity

Spatially-targeted proteomics of the host-pathogen interface during staphylococcal abscess formation

Consequences of Metabolic Interactions during Staphylococcus aureus Infection

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