Peritoneal GATA6+ macrophages function as a portal for Staphylococcus aureus dissemination
Selina K. Jorch, … , Michael J. Hickey, Paul Kubes
Selina K. Jorch, … , Michael J. Hickey, Paul Kubes
Published September 23, 2019
Citation Information: J Clin Invest. 2019;129(11):4643-4656. https://doi.org/10.1172/JCI127286.
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Research Article Infectious disease

Peritoneal GATA6+ macrophages function as a portal for Staphylococcus aureus dissemination

Abstract

Essentially all Staphylococcus aureus (S. aureus) bacteria that gain access to the circulation are plucked out of the bloodstream by the intravascular macrophages of the liver — the Kupffer cells. It is also thought that these bacteria are disseminated via the bloodstream to other organs. Our data show that S. aureus inside Kupffer cells grew and escaped across the mesothelium into the peritoneal cavity and immediately infected GATA-binding factor 6–positive (GATA6+) peritoneal cavity macrophages. These macrophages provided a haven for S. aureus, thereby delaying the neutrophilic response in the peritoneum by 48 hours and allowing dissemination to various peritoneal and retroperitoneal organs including the kidneys. In mice deficient in GATA6+ peritoneal macrophages, neutrophils infiltrated more robustly and reduced S. aureus dissemination. Antibiotics administered i.v. did not prevent dissemination into the peritoneum or to the kidneys, whereas peritoneal administration of vancomycin (particularly liposomal vancomycin with optimized intracellular penetrance capacity) reduced kidney infection and mortality, even when administered 24 hours after infection. These data indicate that GATA6+ macrophages within the peritoneal cavity are a conduit of dissemination for i.v. S. aureus, and changing the route of antibiotic delivery could provide a more effective treatment for patients with peritonitis-associated bacterial sepsis.

Authors

Selina K. Jorch, Bas G.J. Surewaard, Mokarram Hossain, Moritz Peiseler, Carsten Deppermann, Jennifer Deng, Ania Bogoslowski, Fardau van der Wal, Abdelwahab Omri, Michael J. Hickey, Paul Kubes

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Figure 2

S.aureus infects macrophages inside the peritoneal cavity.

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S.aureus infects macrophages inside the peritoneal cavity. (A–C) Flow c...
(A–C) Flow cytometry analyses of peritoneal lavage at indicated time points after infection. The LPM and SPM gating strategy is shown in Supplemental Figure 3. (A) Total counts of free GFP S. aureus, mean ± SEM (n = 2–4 from 2 independent experiments). (B) S. aureus cell localization inside the peritoneal cavity, mean percentage (n = 6 from 3 independent experiments). (C) Quantitative analyses for total cell count of LPMs, SPMs, monocytes, and neutrophils over infection time. Boxes extend from the 25th to 75th percentiles, whiskers show minimum to maximum, and lines indicate the median. n = 3–8 from at least 2 independent experiments, Kruskal-Wallis with Dunn’s post test, *P < 0.05 and **P < 0.01. (D and E) Peritoneal cells were harvested 46 hours after GFP S. aureus bloodstream infection, and F4/80+ macrophages or Ly6G+ neutrophils were isolated, cultured, and imaged ex vivo. (D) Representative images of time-lapse videos are shown (Supplemental Video 3). (E) Analysis of time-lapse videos, 4 FOV per mouse (n = 4 from 2 independent experiments).