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

TY - JOUR

T1 - Peritoneal GATA6+ macrophages function as a portal for Staphylococcus aureus dissemination

AU - Jorch, Selina K

AU - Surewaard, Bas Gj

AU - Hossain, Mokarram

AU - Peiseler, Moritz

AU - Deppermann, Carsten

AU - Deng, Jennifer

AU - Bogoslowski, Ania

AU - van der Wal, Fardau

AU - Omri, Abdelwahab

AU - Hickey, Michael J

AU - Kubes, Paul

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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.

AB - 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.

U2 - 10.1172/JCI127286

DO - 10.1172/JCI127286

M3 - SCORING: Journal article

C2 - 31545300

VL - 129

SP - 4643

EP - 4656

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 11

ER -