Staphylococcus aureus Protein A Induces Human Regulatory T Cells Through Interaction With Antigen-Presenting Cells

Uebele, Julia; Habenicht, Katharina; Tichá, Olga; Bekeredjian‐Ding, Isabelle

doi:10.3389/fimmu.2020.581713

Cited by 5 publications

(8 citation statements)

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“…In chronic infections, T cells exposure to persistent antigenic load could result in down‐modulation of robust T cell effector function via activation of programmed cell death protein 1 (PD‐1) and T cell exhaustion or through induction of regulatory T cells (Treg) 11–13 . One‐day exposure of RDEB T cells to the pooled microbial Ag led to induction of PD‐1 expression on about 20% of the cells with no substantial differences in the CD8 + T‐cell population (Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

“…Since immune‐inhibitory activity of regulatory T cells (Treg) may also play a role in diminishing T cell‐mediated response, 11 we evaluated the presence of Treg in control and RDEB T cells in similar settings. FACS‐based analysis showed that both control (not shown) and RDEB T cells contain a small (~2%) population of CD4 + CD25 + FOXP3 + Treg among CD4‐gated T cells and that this percentage was increased after 6 days of exposure to microbial and S. aureus Ag up to 10% in the control and 20% in the RDEB T cells (Figure 5F).…”

Section: Resultsmentioning

confidence: 99%

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T‐cell activation and bacterial infection in skin wounds of recessive dystrophic epidermolysis bullosa patients

Alexeev

Huitema

Phillips

et al. 2022

Experimental Dermatology

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Recessive dystrophic epidermolysis bullosa (RDEB) patients develop poorly healing skin wounds that are frequently colonized with microbiota. Because T cells play an important role in clearing such pathogens, we aimed to define the status of adaptive T cell-mediated immunity in RDEB wounds. Using a non-invasive approach for sampling of wound-associated constituents, we evaluated microbial contaminants in cellular fraction and exudates obtained from RDED wounds. Infectivity and intracellular trafficking of inactivated Staphylococcus aureus was accessed in RDEB keratinocytes. S. aureus and microbial antigen-specific activation of RDEB wound-derived T cells were investigated by fluorescence-activated cell sorting-based immune-phenotyping and T-cell functional assays. We found that RDEB wounds and epithelial cells are most frequently infected with Staphylococcus sp. and Pseudomonas sp. and that S. aureus essentially infects more RDEB keratinocytes and RDEB-derived squamous cell carcinoma cells than keratinocytes from healthy donors. The RDEB wound-associated T cells contain populations of CD4 + and CD8 + peripheral memory T cells that respond to soluble microbial antigens by proliferating and secreting interferon gamma (IFNγ). Moreover, CD8 + cytotoxic T lymphocytes recognize S. aureus-infected RDEB keratinocytes and respond by producing interleukin-2 (IL-2) and IFNγ and degranulating and cytotoxically killing infected cells. Prolonged exposure of RDEB-derived T cells to microbial antigens in vitro does not trigger PD-1-mediated T-cell exhaustion but induces differentiation of the CD4 high population into CD4 high CD25 + FoxP3 + regulatory T cells. Our data demonstrated that adaptive T cell-mediated immunity could clear infected cells from wound sites, but these effects might be inhibited by PD-1/ Treg-mediated immuno-suppression in RDEB.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

T‐cell activation and bacterial infection in skin wounds of recessive dystrophic epidermolysis bullosa patients

Alexeev

Huitema

Phillips

et al. 2022

Experimental Dermatology

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“…Beyond the above observations, new information continues to emerge regarding the ways through which S. aureus appears to subvert the human immune system. For example, Uebele et al (Uebele et al, 2020) reported that S. aureus protein A induces Treg numbers through interactions with antigen presenting cells. Askarian et al (Askarian et al, 2018) reviewed the mechanisms through which S. aureus modulates innate immune responses via toll-like (TLR), NOD-like (NLR) and C-type lectin (CLR) receptor interactions.…”

Section: Immune Dysfunctions Imposed By S Aureusmentioning

confidence: 99%

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development

Lung

Chan

Prince

et al. 2022

Front. Cell. Infect. Microbiol.

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Despite meritorious attempts, a S. aureus vaccine that prevents infection or mitigates severity has not yet achieved efficacy endpoints in prospective, randomized clinical trials. This experience underscores the complexity of host-S. aureus interactions, which appear to be greater than many other bacterial pathogens against which successful vaccines have been developed. It is increasingly evident that S. aureus employs strategic countermeasures to evade or exploit human immune responses. From entering host cells to persist in stealthy intracellular reservoirs, to sensing the environmental milieu and leveraging bacterial or host metabolic products to reprogram host immune responses, S. aureus poses considerable challenges for the development of effective vaccines. The fact that this pathogen causes distinct types of infections and can undergo transient genetic, transcriptional or metabolic adaptations in vivo that do not occur in vitro compounds challenges in vaccine development. Notably, the metabolic versatility of both bacterial and host immune cells as they compete for available substrates within specific tissues inevitably impacts the variable repertoire of gene products that may or may not be vaccine antigens. In this respect, S. aureus has chameleon phenotypes that have alluded vaccine strategies thus far. Nonetheless, a number of recent studies have also revealed important new insights into pathogenesis vulnerabilities of S. aureus. A more detailed understanding of host protective immune defenses versus S. aureus adaptive immune evasion mechanisms may offer breakthroughs in the development of effective vaccines, but at present this goal remains a very high bar. Coupled with the recent advances in human genetics and epigenetics, newer vaccine technologies may enable such a goal. If so, future vaccines that protect against or mitigate the severity of S. aureus infections are likely to emerge at the intersection of precision and personalized medicine. For now, the development of S. aureus vaccines or alternative therapies that reduce mortality and morbidity must continue to be pursued.

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“…TNF-a or IL-10, has been observed; (c) the frequency of coinfection with Respiratory Syncytial Virus, influenza A virus, Influenza B virus, Parainfluenzae, Mycoplasma pneumoniae, Pseudomonas aeruginosa, Haemophilus influenza or Klebsiella pneumoniae is expected to be lower compared to earlier variants [since all these pathogens induce "low Treg" reaction (1)];(d) in Omicron associated pneumonia, the frequency of coinfection with Staphylococcus aureus, Streptococcus pneumonia, and Adenoviruses is expected to increase since each of these three pathogens induces "high Treg" reaction (15)(16)(17)(18). For the same reason, corticosteroids are not expected to be efficient in the treatment of pneumonia associated with these pathogens.…”

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confidence: 99%

“…Even if Omicron related inflammation persists, it is plausibly attenuated and may be considered a “high Treg” inflammation. Under this assumption, the binary model of chronic diseases ( 14 ) predicts: (a) for the vast majority of Omicron variant cases, corticosteroid treatment is not recommended (since corticosteroids are Treg promoters ( 1 )); (b) corticosteroids may be effective in Omicron related severe disease only if a surge in the blood levels of cytokines like IFN-γ, IL-1, IL-6, TNF-α or IL-10, has been observed ; (c) the frequency of coinfection with Respiratory Syncytial Virus, influenza A virus , Influenza B virus , Parainfluenzae , Mycoplasma pneumoniae , Pseudomonas aeruginosa , Haemophilus influenza or Klebsiella pneumoniae is expected to be lower compared to earlier variants [since all these pathogens induce “low Treg” reaction ( 1 )];(d) in Omicron associated pneumonia, the frequency of coinfection with Staphylococcus aureus , Streptococcus pneumonia , and Adenoviruses is expected to increase since each of these three pathogens induces “high Treg” reaction ( 15 – 18 ). For the same reason, corticosteroids are not expected to be efficient in the treatment of pneumonia associated with these pathogens.…”

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confidence: 99%

SARS-CoV-2 Omicron (B.1.1.529) Variant: Corticosteroids Treatment/Respiratory Coinfection

Elkoshi

2022

Front. Immunol.

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In a recent publication, the binary model of chronic diseases was applied to SARS-CoV-2 infection (1). The efficiency of corticosteroids in the treatment of severe COVID-19 was explained by their ability to promote Treg expansion while sparing SARS-CoV-2 specific CD8 + T cells. In addition, the model deciphered the coinfection of several respiratory pathogens and severe COVID-19 disease afflicted by early variants of the SAS-CoV-2 virus. The high prevalence of these coinfections was explained by the pro-inflammatory and "low Treg" nature shared by respiratory pathogens and severe ("chronic") COVID-19 triggered by these early variants.Early assessment of the clinical severity of SARS-CoV-2 Omicron variant (B.1.1.529) in South Africa suggested lower odds of severe disease compared to the Delta variant (2). Another study conducted in South Africa pointed to a reduced mortality during the Omicron wave compared to earlier waves of . Similarly, a Canadian study comparing the Omicron and Delta variants presented a reduced severity with the Omicron variant (4). A cohort analysis with nested test negative design study, investigating Omicron severity in Scotland, concludes that "Omicron is associated with a two-thirds reduction in the risk of COVID-19 hospitalization when compared to Delta" (5). A US retrospective study comparing COVID-19 outcomes before and after the emergence of Omicron indicates a significantly less severe outcome during the Omicron wave (6). Corrected estimates adjusted for under-ascertainment of reinfection, demonstrate about 25% reduction in the probability of hospitalization of an unvaccinated person with no history of SARS-CoV-2 infection when Omicron is compared to the Delta variant (7, 8). Although the question of the relative severity of Omicron infection is still under discussion in the literature (9), Omicron seems milder than earlier variants (10). With the earlier variants of SARS-CoV-2, a severe disease was related to a surge of pro-inflammatory cytokines, the so called "cytokine storm" (11). This "chronic" high pro-inflammatory state correlated with low Treg levels (1). The seemingly lower intrinsic severity with Omicron may suggest a lower extent of cytokine storm with this variant. In line with this, the Omicron variant demonstrated attenuated lung infection in several rodent models (12,13). In the overwhelming majority of patients, this variant of concern presumably triggers an acute immune reaction which eventually decays. Resolution of this acute inflammation results in low levels of pro-inflammatory cytokines, along with relatively high levels of regulatory T cells (1). Even if Omicron related inflammation persists, it is plausibly attenuated and may be considered a "high Treg" inflammation. Under this assumption, the binary model of chronic diseases (14) predicts: (a) for the vast majority of Omicron variant cases, corticosteroid treatment is not recommended (since corticosteroids are Treg promoters (1)); (b) corticosteroids may be effective in Omicron related severe disease only if...

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Staphylococcus aureus Protein A Induces Human Regulatory T Cells Through Interaction With Antigen-Presenting Cells

Cited by 5 publications

References 71 publications

T‐cell activation and bacterial infection in skin wounds of recessive dystrophic epidermolysis bullosa patients

T‐cell activation and bacterial infection in skin wounds of recessive dystrophic epidermolysis bullosa patients

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development

SARS-CoV-2 Omicron (B.1.1.529) Variant: Corticosteroids Treatment/Respiratory Coinfection

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