Staphylococcus aureus SaeR/S-Regulated Factors Decrease Monocyte-Derived Tumor Necrosis Factor–α to Reduce Neutrophil Bactericidal Activity

Sward, Eli W.; Fones, Elizabeth M.; Spaan, Russel R; Pallister, Kyler B.; Haller, Brandon L; Guerra, Fermin E.; Zurek, Oliwia W.; Nygaard, Tyler K.; Voyich, Jovanka M.

doi:10.1093/infdis/jix652

Cited by 5 publications

(3 citation statements)

References 47 publications

(86 reference statements)

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“…We observed increases in bacterial biomass of up to a log 10 difference of 1.26 (in a control experiment with no neutrophils added) and reductions up to Ϫ2.35 (an experiment with neutrophils in which the GFP area was reduced to its limit of detection). The magnitude of these decreases in bacterial biomass is comparable to the results of neutrophil challenges to planktonic bacteria at similar neutrophil/bacterium ratios (34, 35). The dependence of bacterial biomass on the neutrophil/bacterium ratio plotted in Fig.…”

Section: Resultssupporting

confidence: 70%

Direct Microscopic Observation of Human Neutrophil-Staphylococcus aureus Interaction In Vitro Suggests a Potential Mechanism for Initiation of Biofilm Infection on an Implanted Medical Device

et al. 2019

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The ability of human neutrophils to clear newly attached Staphylococcus aureus bacteria from a serum-coated glass surface was examined in vitro using time-lapse confocal scanning laser microscopy. Quantitative image analysis was used to measure the temporal change in bacterial biomass, neutrophil motility, and fraction of the surface area policed by neutrophils. In control experiments in which the surface was inoculated with bacteria but no neutrophils were added, prolific bacterial growth was observed. Neutrophils were able to control bacterial growth but only consistently when the neutrophil/bacterium number ratio exceeded approximately 1. When preattached bacteria were given a head start and allowed to grow for 3 h prior to neutrophil addition, neutrophils were unable to maintain control of the nascent biofilm. In these head-start experiments, aggregates of bacterial biofilm with areas of 50 μm2 or larger formed, and the growth of such aggregates continued even when multiple neutrophils attacked a cluster. These results suggest a model for the initiation of a biofilm infection in which a delay in neutrophil recruitment to an abiotic surface allows surface-attached bacteria time to grow and form aggregates that become protected from neutrophil clearance. Results from a computational model of the neutrophil-biofilm surface contest supported this conceptual model and highlighted the stochastic nature of the interaction. Additionally, we observed that both neutrophil motility and clearance of bacteria were impaired when oxygen tension was reduced to 0% or 2% O2.

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Section: Resultssupporting

confidence: 70%

Direct Microscopic Observation of Human Neutrophil-Staphylococcus aureus Interaction In Vitro Suggests a Potential Mechanism for Initiation of Biofilm Infection on an Implanted Medical Device

et al. 2019

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“…S5 ). Consistent with our data, TNFα has previously been shown to be produced in higher amounts by saeRS mutants than WT after 3 h of infection of whole blood ( 35 ). While IL-1β belongs to the transcriptional suppression signature cluster, IL-1β protein requires processing in order to be secreted ( 36 ); thus, we see higher IL-1β secretion in WT S. aureus infection than buffer treatment.…”

Section: Resultssupporting

confidence: 92%

Staphylococcus aureusinduces a muted host response in human blood that blunts the recruitment of neutrophils

Zwack

Chen

Devlin

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Staphylococcus aureus is an opportunistic pathogen and chief among bloodstream-infecting bacteria. S. aureus produces an array of human-specific virulence factors that may contribute to immune suppression. Here, we defined the response of primary human phagocytes following infection with S. aureus using RNA-sequencing (RNA-Seq). We found that the overall transcriptional response to S. aureus was weak both in the number of genes and in the magnitude of response. Using an ex vivo bacteremia model with fresh human blood, we uncovered that infection with S. aureus resulted in the down-regulation of genes related to innate immune response and cytokine and chemokine signaling. This muted transcriptional response was conserved across diverse S. aureus clones but absent in blood exposed to heat-killed S. aureus or blood infected with the less virulent staphylococcal species Staphylococcus epidermidis . Notably, this signature was also present in patients with S. aureus bacteremia. We identified the master regulator S. aureus exoprotein expression (SaeRS) and the SaeRS-regulated pore-forming toxins as key mediators of the transcriptional suppression. The S. aureus –mediated suppression of chemokine and cytokine transcription was reflected by circulating protein levels in the plasma. Wild-type S. aureus elicited a soluble milieu that was restrictive in the recruitment of human neutrophils compared with strains lacking saeRS . Thus, S. aureus blunts the inflammatory response resulting in impaired neutrophil recruitment, which could promote the survival of the pathogen during invasive infection.

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“…However, most of the studies were limited to a few cytokine profiles, and therefore, we aimed to analyze multiple markers. Our results obtained in mice are in line with several other analyses, which show the release of TNF-α, 25–27 IL-1α, 28 IL-1β 29 and IL-6 30 in response to severe IAV and staphylococcal (co-)infections, particularly at the late stages of infection. However, we show that these cytokines are already produced at early stages of infection and are mostly restricted to the lungs.…”

Section: Discussionsupporting

confidence: 91%

Cytokine Profiling in Influenza A Virus and Staphylococcal (Co-)Infections

Tölken¹,

Paulikat²,

Cuypers³

et al. 2022

Infect Microb Dis

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Influenza A virus and Staphylococcus aureus are common causative agents of pneumonia. Co-infections with these two pathogens frequently occur and are characterized, among others, by higher morbidity and mortality due to hyper-inflammation of the lungs. Here, we aimed to profile systemic and local cytokine composition at early acute stages of pneumonia in a murine model. All mice recovered from single influenza A virus and/or staphylococcal infections. In contrast, co-infections led to a severe clinical outcome. While distinct cytokine patterns were detected in lungs of single-pathogen-infected animals, co-infections combined both virus- and bacteria-driven responses. However, analyses of infected human primary monocytic cells as well as bronchial epithelial cells did not reflect murine profiles. Based on infectious dose, mainly bacteria-driven responses were noted. The impact of single cells to cytokine composition of the lungs and translation of murine studies to humans remains uncertain and warrants further studies.

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Staphylococcus aureus SaeR/S-Regulated Factors Decrease Monocyte-Derived Tumor Necrosis Factor–α to Reduce Neutrophil Bactericidal Activity

Abstract: Our findings identify an immune evasion strategy used by S. aureus to impede neutrophil priming and subsequent bactericidal activity.

Cited by 5 publications

References 47 publications

Direct Microscopic Observation of Human Neutrophil-Staphylococcus aureus Interaction In Vitro Suggests a Potential Mechanism for Initiation of Biofilm Infection on an Implanted Medical Device

Direct Microscopic Observation of Human Neutrophil-Staphylococcus aureus Interaction In Vitro Suggests a Potential Mechanism for Initiation of Biofilm Infection on an Implanted Medical Device

Staphylococcus aureusinduces a muted host response in human blood that blunts the recruitment of neutrophils

Cytokine Profiling in Influenza A Virus and Staphylococcal (Co-)Infections

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