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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

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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 4

S.aureus infects the kidney initially on the capsule and then infiltrates into the interstitium.

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S.aureus infects the kidney initially on the capsule and then infiltrat...
(A) Representative 2-photon stitched image from kidney around 150 μm deep where approximately 20 glomeruli can be seen (left). Vasculature including glomeruli appear in grey (AF680-albumin), tubules appear in dark yellow autofluorescence, and S. aureus is in bright green GFP (not visible). The right panel shows 3 enlarged glomeruli. (B) Two-photon IVM images from a glomerulus (Supplemental Video 5) during the first 10 minutes of i.v. infection with 5 × 107 S. aureus Newman. Vasculature (glomerulus) is shown in blue (Qtracker 655), tubules are autofluorescent in all channels and appear in brown around the glomerulus, neutrophils are labelled in red (Ly6G-PE), and GFP S. aureus appears in yellow inside a neutrophil (white arrow). (C) Representative stitched images from kidney surfaces at indicated time points after infection. Scale bar: 500 μm. S. aureus (bright green) is circled in white and an enlarged view of bacteria on the surface at 48 hours is shown. (D) 3D representation FOV of a kidney 48 hours after infection with GFP S. aureus (bright green) on the capsule (purple collagen/second harmonic generation [SHG]) and the vasculature in grey (AF680-albumin). (E) Representative FOV of a kidney 72 hours after infection, view from the bottom of the Z-stack. Tubules appear autofluorescent in brown, GFP S. aureus is bright green and indicated with white arrows. (F) Analysis of location of bacteria as determined using 2-photon IVM of the kidney. Six FOV per mouse were analyzed (n = 3–4 per time point).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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