RESUMEN
Despite continuous exposure and development of specific immunity, Staphylococcus aureus (Sa) remains one of the leading causes of severe infections worldwide. Although innate immune defense mechanisms are well understood, the role of the T cell response has not been fully elucidated. Here, we demonstrate that Sa and one of its major virulence factors protein A (SpA) induce human regulatory T cells (Tregs), key players in immune tolerance. In human PBMC and MoDC/T cell cocultures CD4+CD25+CD127dim Tregs were induced upon stimulation with Sa and to a lower extent with SpA alone. Treg induction was strongly, but not exclusively, dependent on SpA, and independent of antigen presentation or T cell epitope recognition. Lastly, soluble factors in the supernatant of SpA-stimulated MoDC were sufficient to trigger Treg formation, while supernatants of MoDC/T cell cocultures containing Sa-triggered Tregs displayed T cell suppressive activity. In summary, our findings identify a new immunosuppressory function of SpA, which leads to release of soluble, Treg-inducing factors and might be relevant to establish colonization.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Antígenos Bacterianos/inmunología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Linfocitos T Reguladores/inmunología , Células Cultivadas , Epítopos de Linfocito T/inmunología , Humanos , Tolerancia Inmunológica/inmunología , Leucocitos Mononucleares/inmunologíaRESUMEN
Lipoproteins (Lpp) of Gram-positive bacteria are major players in alerting our immune system. Here, we show that the TLR2 response induced by commensal species Staphylococcus aureus and Staphylococcus epidermidis is almost ten times lower than that induced by noncommensal Staphylococcus carnosus, and this is at least partially due to their different modifications of the Lpp lipid moieties. The N terminus of the lipid moiety is acylated with a long-chain fatty acid (C17) in S. aureus and S. epidermidis, while it is acylated with a short-chain fatty acid (C2) in S. carnosus. The long-chain N-acylated Lpp, recognized by TLR2-TLR1 receptors, silences innate and adaptive immune responses, while the short-chain N-acetylated Lpp, recognized by TLR2-TLR6 receptors, boosts it.
Asunto(s)
Adaptación Fisiológica/inmunología , Proteínas Bacterianas/metabolismo , Inmunidad Innata/fisiología , Lípidos/química , Lipoproteínas/metabolismo , Staphylococcus aureus/fisiología , Staphylococcus epidermidis/fisiología , Ácidos Grasos/metabolismo , Células HEK293 , Humanos , Transducción de Señal , Células TH1/inmunología , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Intracellular persistence of Staphylococcus aureus favors bacterial spread and chronic infections. Here, we provide evidence for the existence of human CD4+ and CD8+ T cell memory against staphylococcal antigens. Notably, the latter could provide a missing link in our understanding of immune control of intracellular S. aureus. The analyses showed that pulsing of monocyte-derived dendritic cells (MoDC) with native staphylococcal protein antigens induced release of Th2-associated cytokines and mediators linked to T regulatory cell development (G-CSF, IL-2 and IL-10) from both CD4+ and CD8+ T cells, thus revealing a state of tolerance predominantly arising from preformed memory T cells. Furthermore, G-CSF was identified as a suppressor of CD8+ T cell-derived IFNγ secretion, thus confirming a tolerogenic role of this cytokine in the regulation of T cell responses to S. aureus. Nevertheless, delivery of in vitro transcribed mRNA-encoded staphylococcal antigens triggered Th1-biased responses, e.g. IFNγ and TNF release from both naïve and memory T cells. Collectively, our data highlight the potential of mRNA-adjuvanted antigen presentation to enable inflammatory responses, thus overriding the existing Th2/Treg-biased memory T cell response to native S. aureus antigens.
Asunto(s)
Antígenos Bacterianos/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Presentación de Antígeno , Citocinas/inmunología , Factor Estimulante de Colonias de Granulocitos/inmunología , Humanos , Tolerancia Inmunológica , Interleucina-10/inmunología , Interleucina-2/inmunología , Infecciones Estafilocócicas/microbiología , Linfocitos T Reguladores/inmunología , Células Th2/inmunologíaRESUMEN
The innate immune system harbors a multitude of different receptor systems and cells that are constantly prepared to sense and eliminate invading microbial pathogens. Staphylococcus aureus enters the body on its exposed epithelial surfaces, e.g., on skin and mucosa. The initial interaction with epithelial cells is governed by Toll-like receptor (TLR)-2-mediated local production of soluble mediators, including cytokines, chemokines, and antimicrobial peptides. The overall goal is to achieve a steady state of immune mediators and colonizing bacteria. Following cell and tissue invasion clearance of bacteria depends on intracellular microbial sensors and subsequent activation of the inflammasomes. Tissue-resident mast cells and macrophages recruit neutrophils, macrophages, and NK cells. This inflammatory response supports the generation of IL-17 producing NKT, γδ T cells, and T helper cells. Local dendritic cells migrate to the lymph nodes and fine-tune the adaptive immune response. The scope of this chapter is to provide an overview on the major cell types and receptors involved in innate immune defense against S. aureus. By segregating the different stages of infection from epithelial barrier to intracellular and systemic infection, this chapter highlights the different qualities of the innate immune response to S. aureus at different stages of invasiveness.
Asunto(s)
Inmunidad Innata , Staphylococcus aureus , CitocinasRESUMEN
PURPOSE OF REVIEW: Multidrug resistance of bacterial pathogens has confronted physicians around the world with the threat of inefficacy of the antibiotic regime, which is particularly important for patients with sepsis. Antibiotic resistance has revived search for alternative nonantibiotic strategies. Among them, prophylaxis by vaccination is an appealing concept. RECENT FINDINGS: This review provides a compact overview on available vaccines against community-acquired pathogens such as pneumococci (in synergy with influenza) and meningococci and provides an overview on the ongoing developments of vaccines targeting typical nosocomial pathogens such as Clostridium difficile, Staphylococcus aureus, Acintetobacter baumannii, Klebsiella pneumonia, and Pseudomonas aeruginosa. SUMMARY: The effects achieved by some conjugated vaccines (e.g. against Haemophilus influenzae B and Streptococcus pneumoniae) are encouraging. Their widespread use has resulted in a decrease or almost elimination of invasive diseases by the covered pneumococcal serotypes or Haemophilus influenzae B, respectively. These vaccines confer not only individual protection but also exploit herd protection effects. However, a multitude of failures reflects the obstacles on the way to effective and well tolerated bacterial vaccines. Regional differences in strain prevalence and variability of antigens that limit cross-protectivity remain major obstacles. However, promising candidates are in clinical development.
Asunto(s)
Infecciones Comunitarias Adquiridas/microbiología , Infecciones Comunitarias Adquiridas/prevención & control , Infección Hospitalaria/microbiología , Infección Hospitalaria/prevención & control , Unidades de Cuidados Intensivos , Vacunas Conjugadas/uso terapéutico , Farmacorresistencia Bacteriana Múltiple , Humanos , Staphylococcus aureusRESUMEN
Porphyromonas gingivalis is an important member of the anaerobic oral flora. Its presence fosters growth of periodontal biofilm and development of periodontitis. In this study, we demonstrated that lipophilic outer membrane vesicles (OMV) shed from P. gingivalis promote monocyte unresponsiveness to live P. gingivalis but retain reactivity to stimulation with bacterial DNA isolated from P. gingivalis or AIM2 ligand poly(dA·dT). OMV-mediated tolerance of P. gingivalis is characterized by selective abrogation of tumor necrosis factor (TNF). Neutralization of interleukin-10 (IL-10) during OMV challenge partially restores monocyte responsiveness toP. gingivalis; full reactivity toP. gingivalis can be restored by inhibition of mTOR signaling, which we previously identified as the major signaling pathway promoting Toll-like receptor 2 and Toll-like receptor 4 (TLR2/4)-mediated tolerance in monocytes. However, despite previous reports emphasizing a central role of TLR2 in innate immune recognition of P. gingivalis, our current findings highlight a selective role of TLR4 in the promotion of OMV-mediated TNF tolerance: only blockade of TLR4-and not of TLR2-restores responsiveness toP. gingivalis Of further note, OMV-mediated tolerance is preserved in the presence of cytochalasin B and chloroquine, indicating that triggering of surface TLR4 is sufficient for this effect. Taking the results together, we propose that P. gingivalis OMV contribute to local immune evasion of P. gingivalis by hampering the host response.