Identification and treatment of the Staphylococcus aureus reservoir in vivo.
Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is reaching epidemic proportions causing morbidity, mortality, and chronic disease due to relapses, suggesting an intracellular reservoir. Using spinning-disk confocal intravital microscopy to track MRSA-GFP in vivo, we identified that within minutes after intravenous infection MRSA is primarily sequestered and killed by intravascular Kupffer cells (KCs) in the liver. However, a minority of the Staphylococci overcome the KC's antimicrobial defenses. These bacteria survive and proliferate for many days within this intracellular niche, where they remain undetected by recruited neutrophils. Over time, the KCs lyse, releasing bacteria into the circulation, enabling dissemination to other organs such as the kidneys. Vancomycin, the antibiotic of choice to treat MRSA bacteremia, could not penetrate the KCs to eradicate intracellular MRSA. However, based on the intravascular location of these specific macrophages, we designed a liposomal formulation of vancomycin that is efficiently taken up by KCs and diminished the intracellular MRSA. Targeting the source of the reservoir dramatically protected the liver but also dissemination to other organs, and prevented mortality. This vancomycin formulation strategy could help treat patients with Staphylococcal bacteremia without a need for novel antibiotics by targeting the previously inaccessible intracellular reservoir in KCs.
Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada Department of Medical Microbiology, University Medical Centre, 3584 CX Utrecht, the Netherlands.
Bas G J
BG
Surewaard
Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada.
Justin F
JF
Deniset
Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada.
Franz J
FJ
Zemp
Department of Cell Biology and Anatomy, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada.
Matthias
M
Amrein
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Michael
M
Otto
Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada Department of Pathology and Laboratory Medicine, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada Department of Microbiology, Infectious Diseases and Immunology, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada.
John
J
Conly
Department of Chemistry and Biochemistry, Laurentian University, Sudbury ON P3E 2C6, Ontario, Canada.
Abdelwahab
A
Omri
Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada.
Robin M
RM
Yates
Snyder Institute for Chronic Diseases, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada Department of Physiology and Pharmacology, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada.
Paul
P
Kubes
D000818:Animals; D016470:Bacteremia / Q000276:immunology* / Q000473:pathology; D007728:Kupffer Cells / Q000276:immunology* / Q000473:pathology; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D013203:Staphylococcal Infections / Q000276:immunology* / Q000473:pathology