EssE Promotes Staphylococcus aureus ESS-Dependent Protein Secretion To Modify Host Immune Responses during Infection

Abstract

Staphylococcus aureus, an invasive pathogen of humans and animals, requires a specialized ESS pathway 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 interleukin-12 (IL-12) (p40/p70) and the suppression of RANTES (CCL5), activators of T H 1 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 (EsxA/ESAT-6-like secretion system) pathway for the secretion of small subsets of proteins lacking canonical signal peptides. The molecular mechanisms for ESSdependent 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 EssEmediated secretion contributes to the production or the suppression of specific cytokines during host infection, thereby modifying immune responses toward this pathogen.

A membrane-depolarizing toxin substrate of theStaphylococcus aureusType VII secretion system mediates intra-species competition

“…Despite the ess locus forming part of the core S. aureus genome, these four substrate proteins are not conserved across S. aureus isolates, being found in only approximately 50% of sequenced strains 19 . Furthermore, inactivation of the T7SS in S. aureus strain ST398 shows a similar decrease in kidney abscess formation as that seen for T7 mutants in Newman and USA300 2, 4, 20 , despite the fact that recognizable homologues of EsxB/EsxC/EsxD/EsaD are not encoded by this strain 19 . This strongly suggests that there are further S. aureus T7 substrates that are yet to be identified.…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 3)

“…Данный интерлейкин функционирует как провоспалительный цитокин, который вызывает два основных эффекта: способ-ствует рекрутированию CD4 + Т-лимфоцитов, преи-мущественно Th 1 -клеток, и ингибирует Тh 2 -клетки. Также IL-16 индуцирует хемотаксис эозинофилов и дендритных клеток [3,63].…”

“…Во время заболеваний, вызванных Staphylococcus aureus, наблюдается повышение экспрессии IL-12, который вместе с IL-17 играет доминиру-ющую роль в патогенезе стафилококковой ин-фекции [3,79]. Quang- Tam В то же время существуют данные, что IL-12 способствует стафилококковой колонизации [106] и препятствует благоприятному течению Staphylococcus aureus-индуцированного абсцес-са головного мозга [40], а назначение препаратов биологической терапии (в частности, устекину-маба), подавляющих активность IL-12, пациентам с неконтролируемым воспалением, вызванным Staphylococcus aureus, приводит к выздоровлению пациентов [49].…”

EssD, a Nuclease Effector of the Staphylococcus aureus ESS Pathway

“…aureus EssD nuclease activity affects IL-12 signaling during bloodstream infection. Anderson et al reported that the surge of IL-12 cytokine signaling associated with S. aureus bloodstream infection in mice requires EssE-mediated secretion of ESS pathway effectors (25). We wondered whether the EssD nuclease activity of S. aureus USA300 is also required for the induction of IL-12 signaling.…”

“…In S. aureus, the ESS pathway contributes to the stimulation of IL-12 (p40) and IL-12 (p35) production and secretion during mouse infection (25). This immunomodulatory activity is thought to contribute to S. aureus virulence and persistence within deepseated abscess lesions (7,26).…”