Die Wechselwirkung von Immunzellen und Staphylococcus aureus bei Niereninfektionen
Immunologie
Zusammenfassung der Projektergebnisse
Staphylococcus aureus (S. aureus) is a common Gram-positive bacterium, which colonizes the skin and nares of around 30% of healthy people and up to 70% of hospitalized people, yet few problems arise. However, systemic S. aureus infection is one of the most serious and frequent bacteraemias worldwide. A high number of these cases are due to vascular access devices such as catheters or rupture of skin abscesses. Once S. aureus has entered the blood stream, it disseminates to other organs and causes organ dysfunction. Essentially all S. aureus that gain access to the circulation are first plucked out of the bloodstream by the intravascular macrophages of the liver, the Kupffer cells. This project revealed that about 40% of these Kupffer cells are unable to eradicate the bacteria and S. aureus grew inside Kupffer cells and escaped across the mesothelium into the peritoneal cavity. In this compartment, the bacteria immediately infected Gata6+ large peritoneal macrophages (LPMs). These LPMs provided a haven for S. aureus delaying by 48 h the neutrophilic response into the peritoneal cavity. LPMs were, in contrast to neutrophils, not able to eradicate S. aureus and got overgrown like some of the Kupffer cells. This allowed dissemination to various peritoneal organs including the kidneys, which got mainly infected from the capsule side and not to the interstitium or glomeruli. In mice deficient in LPMs, neutrophils infiltrated more robustly and reduced S. aureus dissemination. Intravenously-administered antibiotics did not prevent dissemination into the peritoneum and to the kidneys, while peritoneal administration of vancomycin and particularly, liposomal vancomycin with optimized intracellular penetrance capacity, reduced kidney infection and mortality even when given 24 h post-infection. Overall, this project shows that GATA6+ macrophages within the peritoneal cavity are a conduit of dissemination for intravenous S. aureus and changing the route of antibiotic delivery could provide a more effective treatment for patients with peritonitis associated bacterial sepsis.
Projektbezogene Publikationen (Auswahl)
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(2018) α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis. Cell Host & Microbe 24, 271-284 e273
B.G.J. Surewaard, A. Thanabalasuriar, Z. Zheng, C. Tkaczyk, T.S. Cohen, B.W. Bardoel, S.K. Jorch, C. Deppermann, J. Bubeck Wardenburg, R.P. Davis, C.N. Jenne, K.C. Stover, B.R. Sellman, P. Kubes
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(2019) Gata6(+) Pericardial Cavity Macrophages Relocate to the Injured Heart and Prevent Cardiac Fibrosis. Immunity. 2019;51(1):131-40 e5
J.F. Deniset, D. Belke, W.Y. Lee, S.K. Jorch, C. Deppermann, A.F. Hassanabad, J.D. Turnbull, G. Teng, I. Rozich, K. Hudspeth, Y. Kanno, S.R. Brooks, A.-K. Hadjantonakis, J.J.O´Shea, G.F. Weber, P.W.M. Fedak and P. Kubes
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Peritoneal GATA6+ macrophages function as a portal for Staphylococcus aureus dissemination. The Journal of Clinical Investigation 129: 4643-4656
S.K. Jorch, B.G.J. Surewaard, M. Hossain, M. Peiseler, C. Deppermann, J. Deng, A. Bogoslowski, F. Van Der Wal, A. Omri, M.J. Hickey And P. Kubes
