文章基本信息

标题：Staphylococcus aureus induces a muted host response in human blood that blunts the recruitment of neutrophils
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作者：Erin E. Zwack ; Ze Chen ; Joseph C. Devlin 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：31
DOI：10.1073/pnas.2123017119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance We show here that infection of human blood with Staphylococcus aureus triggers a suppressing transcriptional signature. The signature was conserved across S. aureus lineages and present in bacteremic patients infected with S. aureus. In contrast to S. aureus, we show that Staphylococcus epidermidis did not elicit the suppressing signature, implicating S. aureus virulence factors as drivers of the suppression. Indeed, the master regulator of virulence, S. aureus exoprotein expression (SaeRS), and the SaeRS-regulated toxins were found to be responsible for the “muted” transcriptional response. The S. aureus–elicited suppressing response resulted in impaired production of chemokines and decreased recruitment of neutrophils. Thus, we describe a previously unappreciated immunosuppressive strategy employed by S. aureus to interfere with the host antimicrobial response. Staphylococcus aureus is an opportunistic pathogen and chief among bloodstream-infecting bacteria. S. aureus produces an array of human-specific virulence factors that may contribute to immune suppression. Here, we defined the response of primary human phagocytes following infection with S. aureus using RNA-sequencing (RNA-Seq). We found that the overall transcriptional response to S. aureus was weak both in the number of genes and in the magnitude of response. Using an ex vivo bacteremia model with fresh human blood, we uncovered that infection with S. aureus resulted in the down-regulation of genes related to innate immune response and cytokine and chemokine signaling. This muted transcriptional response was conserved across diverse S. aureus clones but absent in blood exposed to heat-killed S. aureus or blood infected with the less virulent staphylococcal species Staphylococcus epidermidis. Notably, this signature was also present in patients with S. aureus bacteremia. We identified the master regulator S. aureus exoprotein expression (SaeRS) and the SaeRS-regulated pore-forming toxins as key mediators of the transcriptional suppression. The S. aureus–mediated suppression of chemokine and cytokine transcription was reflected by circulating protein levels in the plasma. Wild-type S. aureus elicited a soluble milieu that was restrictive in the recruitment of human neutrophils compared with strains lacking saeRS. Thus, S. aureus blunts the inflammatory response resulting in impaired neutrophil recruitment, which could promote the survival of the pathogen during invasive infection.
关键词：enbacteremiaimmunosuppressionhuman leukocytesStaphylococcus aureusMRSA