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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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 3

A lack of peritoneal macrophages results in more neutrophil recruitment and less dissemination of S. aureus to the kidneys.

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A lack of peritoneal macrophages results in more neutrophil recruitment ...
GATA6-KOmye mice or littermate controls were infected i.v. (A–H) or i.p. (I and J) for indicated time points with 5 × 107 S. aureus Newman strain. (A–E and J) Organs were collected and the CFU determined; the geometric mean is shown. n = 5–10 from at least 2 independent experiments, Mann-Whitney test, *P < 0.05. (F) S. aureus cell localization inside the peritoneal cavity determined by flow cytometry, mean percentage. n = 5 (WT) or 6 (GATA6-KOmye). (G and I) Neutrophil numbers in the peritoneal cavity assessed by flow cytometry. n = 5–6, mean ± SEM, unpaired t test, **P < 0.01. (H) Body weight loss, n = 6–9 from 3 independent experiments, mean ± SEM, unpaired t test, *P < 0.05.