Staphylococcus aureusinduces a muted host response in human blood that blunts the recruitment of neutrophils

Author:

Zwack Erin E.1,Chen Ze1,Devlin Joseph C.1,Li Zhi2,Zheng Xuhui1,Weinstock Ada3ORCID,Lacey Keenan A.1,Fisher Edward A.13,Fenyö David24ORCID,Ruggles Kelly V.25,Loke P’ng16,Torres Victor J.17ORCID

Affiliation:

1. Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016

2. Institute for Systems Genetics, New York University Grossman School of Medicine, New York, NY 10016

3. Department of Medicine Cardiology, New York University Grossman School of Medicine, New York, NY 10016

4. Department for Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016

5. Division of Translational Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016

6. Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892

7. Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016

Abstract

Staphylococcus aureusis an opportunistic pathogen and chief among bloodstream-infecting bacteria.S. aureusproduces an array of human-specific virulence factors that may contribute to immune suppression. Here, we defined the response of primary human phagocytes following infection withS. aureususing RNA-sequencing (RNA-Seq). We found that the overall transcriptional response toS. aureuswas 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 withS. aureusresulted in the down-regulation of genes related to innate immune response and cytokine and chemokine signaling. This muted transcriptional response was conserved across diverseS. aureusclones but absent in blood exposed to heat-killedS. aureusor blood infected with the less virulent staphylococcal speciesStaphylococcus epidermidis. Notably, this signature was also present in patients withS. aureusbacteremia. We identified the master regulatorS. aureusexoprotein expression (SaeRS) and the SaeRS-regulated pore-forming toxins as key mediators of the transcriptional suppression. TheS. aureus–mediated suppression of chemokine and cytokine transcription was reflected by circulating protein levels in the plasma. Wild-typeS. aureuselicited a soluble milieu that was restrictive in the recruitment of human neutrophils compared with strains lackingsaeRS. Thus,S. aureusblunts the inflammatory response resulting in impaired neutrophil recruitment, which could promote the survival of the pathogen during invasive infection.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

Division of Intramural Research, National Institute of Allergy and Infectious Diseases

HHS | NIH | National Heart, Lung, and Blood Institute

Cystic Fibrosis Foundation

Burroughs Wellcome Fund

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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