PNAG exopolysaccharide eradication gives neutrophils access to Staphylococcus aureus biofilm infections
PNAG exopolysaccharide eradication gives neutrophils access to Staphylococcus aureus biofilm infections
Abstract Staphylococcus aureus (S. aureus) can form biofilms on biotic or abiotic surfaces making biofilm infections a relevant clinical problem. Biofilms can evade immunity and resist antimicrobial treatment, and as such an understanding of biofilm infection in vivo is necessary to inform new therapeutics. Using a mouse model of S. aureus foreign-body skin infection and intravital microscopy, we imaged the interactions between neutrophils and S. aureus biofilm. We observed that neutrophils were separated from bacteria by a biofilm matrix composed of the polysaccharide intercellular adhesin (PIA), an exopolysaccharide chemically designated as poly-N-acetylglucosamine (PNAG) that is produced by enzymatic machinery encoded by the icaADBC operon. Infection with icaADBC-deficient S. aureus strains led to increased neutrophil infiltration and access to bacteria and resulted in full clearance of infection by 7 days. Moreover, enzymatic treatment with PgaB, which hydrolyzes partially deacetylated PNAG, was shown to disaggregate the biofilm giving neutrophils access into the infection site to improve clearance. Taken together, our results show that PNAG shelters S. aureus biofilms from innate host defense, and that targeting the biofilm matrix with glycoside hydrolases is a promising therapeutic avenue to treat S. aureus biofilm infections. Author SummaryStaphylococcus aureus is a major cause of biofilm-associated infections, which pose a major threat to human health. A biofilm is difficult to treat since bacteria are protected from antimicrobials within an extracellular matrix. This study is the first to show that the PgaB enzyme, a glycoside hydrolase, can disrupt the S. aureus biofilm matrix in vivo. Disrupting the biofilm matrix with PgaB gives neutrophils access to bacteria for elimination.
Kratofil Rachel M.、Raju Deepa、Vargas Mario、Sejuty Rehnuma、Morck Douglas W.、Pier Gerald B.、Kubes Paul、Chisholm Jessica、Hommes Josefien W.、Howell P. Lynne、Harrison Joe J.、Randall Trevor E.
Department of Physiology and Pharmacology, University of Calgary||Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of CalgaryProgram in Molecular Medicine, The Hospital for Sick ChildrenProgram in Molecular Medicine, The Hospital for Sick ChildrenDepartment of Biological Sciences, University of CalgaryDepartment of Biological Sciences, University of Calgary||Department of Comparative Biology and Experimental Medicine, University of CalgaryDivision of Infectious Diseases, Department of Medicine, Brigham and Women?ˉs Hospital/Harvard Medical SchoolDepartment of Physiology and Pharmacology, University of Calgary||Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of CalgaryDepartment of Biological Sciences, University of Calgary||Department of Comparative Biology and Experimental Medicine, University of CalgaryDepartment of Physiology and Pharmacology, University of Calgary||Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of CalgaryProgram in Molecular Medicine, The Hospital for Sick Children||Department of Biochemistry, University of TorontoDepartment of Biological Sciences, University of CalgaryDepartment of Biological Sciences, University of Calgary
微生物学基础医学医学研究方法
Kratofil Rachel M.,Raju Deepa,Vargas Mario,Sejuty Rehnuma,Morck Douglas W.,Pier Gerald B.,Kubes Paul,Chisholm Jessica,Hommes Josefien W.,Howell P. Lynne,Harrison Joe J.,Randall Trevor E..PNAG exopolysaccharide eradication gives neutrophils access to Staphylococcus aureus biofilm infections[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2023.01.23.525131.点此复制
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