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 5

Intraperitoneal liposomal vancomycin (vancosomes) targets tissue resident macrophages to eradicate infections and sustain survival.

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Intraperitoneal liposomal vancomycin (vancosomes) targets tissue residen...
Mice were infected i.v. with 5 × 107 S. aureus Newman and treated 2 (24 hours plus 48 hours, A–C) or 3 times (24 hours plus 48 hours plus 72 hours, D) with either vancomycin i.v (red), vancosomes i.p. (blue), a combination of vancomycin i.v. plus i.p. (orange), or vancomycin i.v. plus vancosomes i.p. (green). (A) Seventy-two hours after infection, organs were harvested, peritoneal lavage was performed, and CFU were determined (n = 6–11 from 3 independent experiments). Data are presented as the geometric mean; Kruskal-Wallis with Dunn’s post test; *P < 0.05 and **P < 0.01. (B) Representative 2-photon IVM images of kidneys 72 hours after infection with or without treatment 2 times. Dead tubular cells are stained with Sytox Orange (red), tubules appear in dark green autofluorescence. Scale bar: 75 μm. (C) Analysis of B. Number of Sytox Orange+ (dead) cells from 8 FOV per mouse, data represent the mean ± SEM (n = 3, 1-way ANOVA with Bonferroni’s multiple comparisons test). *P < 0.05, ***P < 0.001, and ****P < 0.0001. (D) Survival curve of S. aureus-infected and treated mice (n = 4 mice per group from 2 independent experiments). Log-rank test compared with vancomycin i.v., *P < 0.05 and **P < 0.01.