Host-derived protease promotes aggregation of Staphylococcus aureus by cleaving the surface protein SasG.

Autor:	Crosby HA; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA., Keim K; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA., Kwiecinski JM; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.; Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland., Langouët-Astrié CJ; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA., Oshima K; Division of Pulmonary Sciences and Critical Care, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., LaRivière WB; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA., Schmidt EP; Division of Pulmonary Sciences and Critical Care, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Horswill AR; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.; Department of Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado, USA.
Jazyk:	angličtina
Zdroj:	MBio [mBio] 2024 Apr 10; Vol. 15 (4), pp. e0348323. Date of Electronic Publication: 2024 Mar 21.
DOI:	10.1128/mbio.03483-23
Abstrakt:	Staphylococcus aureus is one of the leading causes of hospital-acquired infections, many of which begin following attachment and accumulation on indwelling medical devices or diseased tissue. These infections are often linked to the establishment of biofilms, but another often overlooked key characteristic allowing S. aureus to establish persistent infection is the formation of planktonic aggregates. Such aggregates are physiologically similar to biofilms and protect pathogens from innate immune clearance and increase antibiotic tolerance. The cell-wall-associated protein SasG has been implicated in biofilm formation via mechanisms of intercellular aggregation but the mechanism in the context of disease is largely unknown. We have previously shown that the expression of cell-wall-anchored proteins involved in biofilm formation is controlled by the ArlRS-MgrA regulatory cascade. In this work, we demonstrate that the ArlRS two-component system controls aggregation, by repressing the expression of sasG by activation of the global regulator MgrA. We also demonstrate that SasG must be proteolytically processed by a non-staphylococcal protease to induce aggregation and that strains expressing functional full-length sasG aggregate significantly upon proteolysis by a mucosal-derived host protease found in human saliva. We used fractionation and N-terminal sequencing to demonstrate that human trypsin within saliva cleaves within the A domain of SasG to expose the B domain and induce aggregation. Finally, we demonstrated that SasG is involved in virulence during mouse lung infection. Together, our data point to SasG, its processing by host proteases, and SasG-driven aggregation as important elements of S. aureus adaptation to the host environment.IMPORTANCEHere, we demonstrate that the Staphylococcus aureus surface protein SasG is important for cell-cell aggregation in the presence of host proteases. We show that the ArlRS two-component regulatory system controls SasG levels through the cytoplasmic regulator MgrA. We identified human trypsin as the dominant protease triggering SasG-dependent aggregation and demonstrated that SasG is important for S. aureus lung infection. The discovery that host proteases can induce S. aureus aggregation contributes to our understanding of how this pathogen establishes persistent infections. The observations in this study demonstrate the need to strengthen our knowledge of S. aureus surface adhesin function and processing, regulation of adhesin expression, and the mechanisms that promote biofilm formation to develop strategies for preventing chronic infections. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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