Staphylococcus aureus, an invasive pathogen of humans and animals, requires a specialized ESS secretion system to secrete proteins (EsxA, EsxB, EsxC and EsxD) during infection. Expression of ess genes is required for S. aureus establishment of persistent abscess lesions following bloodstream infection, however the mechanisms whereby effectors of the ESS pathway implement their virulence strategies were heretofore not known. Here, we show that EssE forms a complex with other members of the ESS secretion pathway and its substrates, promoting the secretion of EsxA, EsxB, EsxC, EsxD and EssD. During bloodstream infection of mice, the S. aureus essE mutant displays defects in host cytokine responses, specifically in the production of IL-12 (p40/p70) and the suppression of RANTES (CCL5), activators of TH1 T cell responses and immune cell chemotaxis, respectively. Thus, essE-mediated secretion of protein effectors via the ESS pathway may enable S. aureus to manipulate host immune responses by modifying the production of cytokines.
IMPORTANCE Staphylococcus aureus and other firmicutes evolved a specialized ESS pathway (EsxA/ESAT-6 like Secretion System) for the secretion of small subsets of proteins lacking canonical signal peptides. The molecular mechanisms for ESS-dependent secretion and their functional purpose are still unknown. We demonstrate here that S. aureus EssE functions as a membrane assembly platform for elements of the secretion machinery and their substrates. Furthermore, S. aureus EssE-mediated secretion contributes to the production or the suppression of specific cytokines during host infection, thereby modifying immune responses towards this pathogen.
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