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Role and plasticity of Th1 and Th17 responses in immunity to Staphylococcus aureus.

ABSTRACT: The human commensal Staphylococcus aureus (SA) is a leading cause of skin/soft tissue and surgical-site infections, and bacteremia. Functional antibodies and T-cell-mediated immunity, particularly Th1/Th17 responses, are thought to mediate protection. Vaccine development may be hindered by modulation of vaccine-induced T cells by pathogen-activated immunoregulatory responses, e.g., via IL-10.We screened SA proteins for CD4+ T-cell-activating and IL-10/IL-17-inducing capacities using healthy donor-derived PBMCs. Responses were characterized (Th1/Th17/Th22/immunosuppressive IL-10-producing cells) using intracellular cytokine staining and flow cytometry. Phenotypic plasticity of Th1/Th17 cells was evaluated under pro- or anti-inflammatory conditions using modulatory cytokines. The impact of vaccination on SA-specific memory responses was assessed using samples from a clinical trial evaluating AS03-adjuvanted and non-adjuvanted multicomponent (CPS5/CPS8/?-toxin/ClfA) vaccines (NCT01160172).The donors exhibited SA-specific memory T-cell responses, indicative of pre-existing immunity to SA. We identified effective activators of Th1 responses (EbhA/IsaA/SdrE/MntC/Aaa/?-toxin), and Th17 and Th1/Th17 responses (EbhA/IsaA/SdrE and, to a lesser extent, ?-toxin), but not of Th22 responses or IL-10 production. MRPII, IsdA, and ClfA were inefficient CD4+ T-cell activators in our assays. IL-10, likely produced by innate immune cells, influenced mainly Th1 cells by suppressing IFN-? production. The memory CD4+ T-cells observed after long-term stimulation with ?-toxin and ClfA indicated that vaccination with these proteins had induced expansion of pre-existing Th1 but not Th17 responses, without apparent adjuvant effect, confirming the trial data. The Th1/Th17-driving proteins (EbhA/IsaA/SdrE) shared low IL-10-promoting abilities and restricted phenotypic plasticity under pro- and anti-inflammatory conditions.Given the complex immunopathology and multiple virulence factors, identification of Th1/Th17-driving antigens, adjuvants and administration routes, and delineation of the role of memory responses, may advance vaccine development.

SUBMITTER: Ferraro A

PROVIDER: S-EPMC6930085 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Role and plasticity of Th1 and Th17 responses in immunity to Staphylococcus aureus.

Ferraro Alessandra A Buonocore Sofia M SM Auquier Philippe P Nicolas Isabelle I Wallemacq Hugues H Boutriau Dominique D van der Most Robbert G RG

Human vaccines & immunotherapeutics 20191031 12

The human commensal Staphylococcus aureus (SA) is a leading cause of skin/soft tissue and surgical-site infections, and bacteremia. Functional antibodies and T-cell-mediated immunity, particularly Th1/Th17 responses, are thought to mediate protection. Vaccine development may be hindered by modulation of vaccine-induced T cells by pathogen-activated immunoregulatory responses, e.g., via IL-10.We screened SA proteins for CD4+ T-cell-activating and IL-10/IL-17-inducing capacities ...[more]

PMID: 31149870

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Project description:The opportunistic pathogen Staphylococcus aureus (S. aureus) is a major cause of nosocomial- and community-acquired infections. In addition, many antibiotic-resistant strains are emerging worldwide, thus, there is an urgent unmet need to pinpoint novel therapeutic and prophylactic strategies. In the present study, we characterized the impact of infection with the pandemic methicillin-resistant USA300 S. aureus strain on human primary dendritic cells (DC), key initiators and regulators of immune responses. In particular, among staphylococcal virulence factors, the function of EsxA and EsxB, two small acidic dimeric proteins secreted by the type VII-like secretion system Ess (ESAT-6-like secretion system), was investigated in human DC setting. A comparative analysis of bacterial entry, replication rate as well as DC maturation, apoptosis, signaling pathway activation and cytokine production was performed by using wild type (wt) USA300 and three isogenic mutants carrying the deletion of esxA (?esxA), esxB (?esxB), or both genes (?esxAB). The S. aureus mutant lacking only the EsxA protein (?esxA) stimulated a stronger pro-apoptotic phenotype in infected DC as compared to wt USA300, ?esxAB, and ?esxB strains. When the mutant carrying the esxB deletion (?esxB) was analyzed, a higher production of both regulatory and pro-inflammatory mediators was found in the infected DC with respect to those challenged with the wt counterpart and the other esx mutants. In accordance with these data, supernatant derived from ?esxB-infected DC promoted a stronger release of both IFN-? and IL-17 from CD4+ T cells as compared with those conditioned with supernatants derived from wild type USA300-, ?esxAB-, and ?esxA-infected cultures. Although, the interaction of S. aureus with human DC is not yet fully understood, our data suggest that both cytokine production and apoptotic process are modulated by Esx factors, thus indicating a possible role of these proteins in the modulation of DC-mediated immunity to S. aureus.

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Role and plasticity of Th1 and Th17 responses in immunity to Staphylococcus aureus.

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Role and plasticity of Th1 and Th17 responses in immunity to <i>Staphylococcus aureus</i>.

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