VraSR Regulatory System Contributes to the Virulence of Community-Associated Methicillin-Resistant Staphylococcus aureus (CA-MRSA) in a 3D-Skin Model and Skin Infection of Humanized Mouse Model

被引:5
作者
Barua, Nilakshi [1 ]
Yang, Ying [1 ]
Huang, Lin [2 ]
Ip, Margaret [1 ]
机构
[1] Chinese Univ Hong Kong, Prince Wales Hosp, Fac Med, Dept Microbiol,Sha Tin, Hong Kong 999077, Peoples R China
[2] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Surg, Div Plast Reconstruct & Aesthet Surg,Sha Tin, Hong Kong 999077, Peoples R China
关键词
VraSR regulatory system; 3D Skin model; humanized mouse model; Staphylococcus aureus; MRSA; skin and soft-tissue infections; SOFT-TISSUE INFECTIONS; MICE; ACTIVATION;
D O I
10.3390/biomedicines10010035
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The vancomycin-resistance associated sensor/regulator, VraSR two-component regulatory-system (VraSR), regulates virulence and the response of Staphylococcus aureus (SA) to environmental stress. To investigate the role of VraSR in SA skin and soft tissue infections (SSTI), we inactivated the VraSR of a clinical CA-MRSA ST30 strain by insertional mutation in vraR gene using the TargeTron-Gene Knockout System. We constructed an organotypic keratinocyte fibroblast co-culture (3D-skin model) and a humanized mouse as SSTI infection models. In the 3D-skin model, inactivation of VraSR in the strains ST30 and USA300 showed 1-log reduction in adhesion and internalization (p < 0.001) compared to the respective wildtype. The mutant strains of ST30 (p < 0.05) and USA300-LAC (p < 0.001) also exhibited reduced apoptosis. The wildtype ST30 infection in the humanized mouse model demonstrated increased skin lesion size and bacterial burden compared to BALB/c mice (p < 0.01). The response of the humanized mouse towards the MRSA infection exhibited human similarity indicating that the humanized mouse SSTI model is more suitable for evaluating the role of virulence determinants. Inactivation of VraSR in ST30 strain resulted in decreased skin lesion size in the humanized mouse SSTI model (p < 0.05) and reduction in apoptotic index (p < 0.01) when compared with the wildtype. Our results reveal that inactivating the VraSR system may be a potent anti-virulence approach to control MRSA infection.
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页数:15
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共 33 条
[11]   Mouse models for infectious diseases caused by Staphylococcus aureus [J].
Kim, Hwan Keun ;
Missiakas, Dominique ;
Schneewind, Olaf .
JOURNAL OF IMMUNOLOGICAL METHODS, 2014, 410 :88-99
[12]   Staphylococcus aureus Infection in Humanized Mice: A New Model to Study Pathogenicity Associated With Human Immune Response [J].
Knop, Janin ;
Hanses, Frank ;
Leist, Teresa ;
Archin, Nancie M. ;
Buchholz, Stefan ;
Glaesner, Joachim ;
Gessner, Andre ;
Wege, Anja K. .
JOURNAL OF INFECTIOUS DISEASES, 2015, 212 (03) :435-444
[13]   The economic burden of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) [J].
Lee, B. Y. ;
Singh, A. ;
David, M. Z. ;
Bartsch, S. M. ;
Slayton, R. B. ;
Huang, S. S. ;
Zimmer, S. M. ;
Potter, M. A. ;
Macal, C. M. ;
Lauderdale, D. S. ;
Miller, L. G. ;
Daum, R. S. .
CLINICAL MICROBIOLOGY AND INFECTION, 2013, 19 (06) :528-536
[14]   Differential Target Gene Activation by the Staphylococcus aureus Two-Component System saeRS [J].
Mainiero, Markus ;
Goerke, Christiane ;
Geiger, Tobias ;
Gonser, Christoph ;
Herbert, Silvia ;
Wolz, Christiane .
JOURNAL OF BACTERIOLOGY, 2010, 192 (03) :613-623
[15]   Intramembrane-sensing histidine kinases: a new family of cell envelope stress sensors in Firmicutes bacteria [J].
Mascher, Thorsten .
FEMS MICROBIOLOGY LETTERS, 2006, 264 (02) :133-144
[16]   Distinct two-component systems in methicillin-resistant Staphylococcus aureus can change the susceptibility to antimicrobial agents [J].
Matsuo, Miki ;
Kato, Fuminori ;
Oogai, Yuichi ;
Kawai, Toshihisa ;
Sugai, Motoyuki ;
Komatsuzawa, Hitoshi .
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 2010, 65 (07) :1536-1537
[17]   Staphylococcus aureus-associated skin and soft tissue infections in ambulatory care [J].
McCaig, Linda F. ;
McDonald, L. Clifford ;
Mandal, Sanjay ;
Jernigan, Daniel B. .
EMERGING INFECTIOUS DISEASES, 2006, 12 (11) :1715-1723
[18]   Transforming the Untransformable: Application of Direct Transformation To Manipulate Genetically Staphylococcus aureus and Staphylococcus epidermidis [J].
Monk, Ian R. ;
Shah, Ishita M. ;
Xu, Min ;
Tan, Man-Wah ;
Foster, Timothy J. .
MBIO, 2012, 3 (02)
[19]   Yersinia pestis Two-Component Gene Regulatory Systems Promote Survival in Human Neutrophils [J].
O'Loughlin, Jason L. ;
Spinner, Justin L. ;
Minnich, Scott A. ;
Kobayashi, Scott D. .
INFECTION AND IMMUNITY, 2010, 78 (02) :773-782
[20]   Staphylococcus aureus toxins [J].
Otto, Michael .
CURRENT OPINION IN MICROBIOLOGY, 2014, 17 :32-37