All bacterial infections occur within a polymicrobial environment, from which a pathogen population emerges to establish disease within a host. Emphasis has been placed on prevention of pathogen dominance by competing microflora acting as probiotics1. Here we show that the virulence of the human pathogen Staphylococcus aureus is augmented by native, polymicrobial, commensal skin flora and individual species acting as ‘proinfectious agents’. The outcome is pathogen proliferation, but not commensal. Pathogenesis augmentation can be mediated by particulate cell wall peptidoglycan, reducing the S. aureus infectious dose by over 1,000-fold. This phenomenon occurs using a range of S. aureus strains and infection models and is not mediated by established receptor-mediated pathways including Nod1, Nod2, Myd88 and the NLPR3 inflammasome. During mouse sepsis, augmentation depends on liver-resident macrophages (Kupffer cells) that capture and internalize both the pathogen and the proinfectious agent, leading to reduced production of reactive oxygen species, pathogen survival and subsequent multiple liver abscess formation. The augmented infection model more closely resembles the natural situation and establishes the role of resident environmental microflora in the initiation of disease by an invading pathogen. As the human microflora is ubiquitous2, its role in increasing susceptibility to infection by S. aureus highlights potential strategies for disease prevention.

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This work was funded by the Wellcome Trust (099957/Z/12/Z, 089981), Innovate UK (27486-188210), the Swedish Research Council (2013-09302), an MRC programme grant to S.A.R. (MR/M004864/1), an MRC grant to S.J.F. (MR/R001111/1) and the University of Sheffield 2022 Futures programme via the Florey Institute. Imaging used the Wolfson Light Microscopy Facility (supported by MRC grant MR/K015753/1). P.K. is supported by Alberta Innovates Health Solutions (AIHS), the Canadian Institutes of Health Research (CIHR) and the Canada Research Chairs Program. B.G.J.S. is partially funded by a postdoctoral fellowship from CIHR. The authors acknowledge use of the Bateson Centre aquarium, Biological Services Unit, Core Histology Service and the Flow Cytometry Facility at the University of Sheffield. The authors thank the International Microbiome Centre from the University of Calgary for assistance, the Bateson Centre aquarium staff for assistance with zebrafish husbandry, L. Prince, D. Yang, J. Hooker, F. Wright and A. Hendriks for advice and assistance, F. Götz for providing SA113lgt::ermB and M. Gunzer and A. Hasenberg for providing Ly6G-tdTomato reporter mice.

Author information

Author notes

  1. These authors contributed equally: Emma Boldock, Bas G. J. Surewaard, Daria Shamarina.


  1. Florey Institute, University of Sheffield, Sheffield, UK

    • Emma Boldock
    • , Daria Shamarina
    • , Paul Morris
    • , Stephen A. Renshaw
    •  & Simon J. Foster
  2. Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, UK

    • Emma Boldock
    • , Daria Shamarina
    • , Alexander Williams
    • , Eric J. G. Pollitt
    • , Piotr Szkuta
    • , Tomasz K. Prajsnar
    •  & Simon J. Foster
  3. Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

    • Emma Boldock
    • , Paul Morris
    • , Tomasz K. Prajsnar
    •  & Stephen A. Renshaw
  4. Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Canada

    • Bas G. J. Surewaard
    •  & Paul Kubes
  5. Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands

    • Bas G. J. Surewaard
    •  & Jos A. G. van Strijp
  6. Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden

    • Manli Na
    • , Ying Fei
    • , Abukar Ali
    •  & Tao Jin
  7. Department of Microbiology and Immunology, The Affiliated Hospital of GuiZhou Medical University, GuiZhou Sheng, China

    • Ying Fei
  8. Bateson Centre, University of Sheffield, Sheffield, UK

    • Tomasz K. Prajsnar
    •  & Stephen A. Renshaw
  9. Western Canadian Microbiome Centre, Cumming School of Medicine, University of Calgary, Calgary, Canada

    • Kathy D. McCoy
  10. Department of Rheumatology, Sahlgrenska University Hospital, Gothenburg, Sweden

    • Tao Jin
  11. MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK

    • David H. Dockrell


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E.B., B.G.J.S., D.S., M.N., Y.F., A.A., A.W., E.J.G.P., P.S., P.M. and T.K.P. performed and analysed the experiments. K.D.M., T.J., D.H.D., J.A.G.S., P.K., S.A.R. and S.J.F. contributed to study design and data analysis. E.B. and S.J.F. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Simon J. Foster.

Supplementary Information

  1. Supplementary Information

    Supplementary Figures 1–4

  2. Reporting Summary

  3. Supplementary Video 1

    Capture of S. aureus and PGN by Kupffer cells. Kupffer cells (F4/80, purple) capture most intravenous injected S. aureus (5 × 107 c.f.u., BSG1) from the circulation in female C57BL/6J mice. Neutrophils (Ly6g; red). Bacteria were injected 1 min after initiation of 20 min time interval visualized by SD-IVM. Videos represent one out of three independent experiments. Scale bar, 50 µm.

  4. Supplementary Video 2

    Kupffer cells (F4/80, purple) capture most intravenous injected S. aureus + PGN from the circulation in female C57BL/6J mice. Neutrophils (Ly6g; red). Bacteria were injected 1 min after initiation of 20 min time interval visualized by SD-IVM. Videos represent one out of three independent experiments. Scale bar, 50 µm.

  5. Supplementary Video 3

    Oxidative burst associated with S. aureus and PGN within Kupffer cells. SD-IVM video of mouse livers with labelled Kupffer cells (F4/80, purple), injected with pHrodo S. aureus bioparticles (red) additionally labelled with AF647 (blue) as a reference fluorophore, and OxyBURST (green) without co-injection of 500 µg PGN. Panels show individual label channels and a merge. S. aureus bioparticles were injected 1 min after initiation of 50 min time interval visualized by SD-IVM. Videos represent one out of three independent experiments. Scale bar, 25 µm.

  6. Supplementary Video 4

    Oxidative burst associated with S. aureus and PGN within Kupffer cells. SD-IVM video of mouse livers with labelled Kupffer cells (F4/80, purple), injected with pHrodo S. aureus bioparticles (red) additionally labelled with AF647 (blue) as a reference fluorophore, and OxyBURST (green) with co-injection of 500 µg PGN. Panels show individual label channels and a merge. S. aureus bioparticles were injected 1 min after initiation of 50 min time interval visualized by SD-IVM. Videos represent one out of three independent experiments. Scale bar, 25 µm.

  7. Supplementary Video 5

    Co-phagocytosis of S. aureus and latex beads in the zebrafish embryo model of infection. In vivo imaging of 9,000 latex beads (green) and S. aureus SH1000-mCherry (red, 1,500 c.f.u.) 2 hpi. Imaging for 5 minutes. Video represents one out of two independent experiments. Scale bar, 10 μm.

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