Liang Li1, Genzhu Wang1, Ambrose Cheung2, Wessam Abdelhady1, Kati Seidl3, Yan Q Xiong1,4. 1. Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance. 2. Dartmouth Medical School, Hanover, New Hampshire. 3. University Hospital of Zurich, Switzerland. 4. David Geffen School of Medicine at UCLA, Los Angeles, California.
Abstract
BACKGROUND: MgrA is an important global virulence gene regulator in Staphylococcus aureus. In the present study, the role of mgrA in host-pathogen interactions related to virulence was explored in both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) strains. METHODS: In vitro susceptibilities to human defense peptides (HDPs), adherence to fibronectin (Fn) and endothelial cells (ECs), EC damage, α-toxin production, expression of global regulator (eg, agr RNAIII) and its downstream effectors (eg, α-toxin [hla] and Fn binding protein A [fnbA]), MgrA binding to fnbA promoter, and the effect on HDP-induced mprF and dltA expression were analyzed. The impact of mgrA on virulence was evaluated using a mouse bacteremia model. RESULTS: mgrA mutants displayed significantly higher susceptibility to HDPs, which might be related to the decreased HDP-induced mprF and dltA expression but decreased Fn and EC adherence, EC damage, α-toxin production, agr RNAIII, hla and fnbA expression, and attenuated virulence in the bacteremia model as compared to their respective parental and mgrA-complemented strains. Importantly, direct binding of MgrA to the fnbA promoter was observed. CONCLUSIONS: These results suggest that mgrA mediates host-pathogen interactions and virulence and may provide a novel therapeutic target for invasive S. aureus infections.
BACKGROUND:MgrA is an important global virulence gene regulator in Staphylococcus aureus. In the present study, the role of mgrA in host-pathogen interactions related to virulence was explored in both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) strains. METHODS: In vitro susceptibilities to human defense peptides (HDPs), adherence to fibronectin (Fn) and endothelial cells (ECs), EC damage, α-toxin production, expression of global regulator (eg, agr RNAIII) and its downstream effectors (eg, α-toxin [hla] and Fn binding protein A [fnbA]), MgrA binding to fnbA promoter, and the effect on HDP-induced mprF and dltA expression were analyzed. The impact of mgrA on virulence was evaluated using a mousebacteremia model. RESULTS:mgrA mutants displayed significantly higher susceptibility to HDPs, which might be related to the decreased HDP-induced mprF and dltA expression but decreased Fn and EC adherence, EC damage, α-toxin production, agr RNAIII, hla and fnbA expression, and attenuated virulence in the bacteremia model as compared to their respective parental and mgrA-complemented strains. Importantly, direct binding of MgrA to the fnbA promoter was observed. CONCLUSIONS: These results suggest that mgrA mediates host-pathogen interactions and virulence and may provide a novel therapeutic target for invasive S. aureus infections.
Authors: R Allyn Forsyth; Robert J Haselbeck; Kari L Ohlsen; Robert T Yamamoto; Howard Xu; John D Trawick; Daniel Wall; Liangsu Wang; Vickie Brown-Driver; Jamie M Froelich; Kedar G C; Paula King; Melissa McCarthy; Cheryl Malone; Brian Misiner; David Robbins; Zehui Tan; Zhan-yang Zhu Zy; Grant Carr; Deborah A Mosca; Carlos Zamudio; J Gordon Foulkes; Judith W Zyskind Journal: Mol Microbiol Date: 2002-03 Impact factor: 3.501
Authors: A Peschel; R W Jack; M Otto; L V Collins; P Staubitz; G Nicholson; H Kalbacher; W F Nieuwenhuizen; G Jung; A Tarkowski; K P van Kessel; J A van Strijp Journal: J Exp Med Date: 2001-05-07 Impact factor: 14.307
Authors: Jakub M Kwiecinski; Rachel M Kratofil; Corey P Parlet; Bas G J Surewaard; Paul Kubes; Alexander R Horswill Journal: Cell Rep Date: 2021-07-27 Impact factor: 9.423