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Infection and Immunity, October 2009, p. 4256-4264, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00195-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Tricarboxylic Acid Cycle-Dependent Attenuation of Staphylococcus aureus In Vivo Virulence by Selective Inhibition of Amino Acid Transport{triangledown}

Yefei Zhu,1,{dagger} Yan Q. Xiong,2,3,{dagger} Marat R. Sadykov,1 Paul D. Fey,4 Mei G. Lei,5 Chia Y. Lee,5 Arnold S. Bayer,2,3 and Greg A. Somerville1*

Department of Veterinary and Biomedical Sciences, University of Nebraska, Lincoln, Nebraska,1 Department of Medicine, Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California,2 Geffen School of Medicine at UCLA, Los Angeles, California,3 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska,4 Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas5

Received 19 February 2009/ Returned for modification 16 April 2009/ Accepted 28 July 2009

Staphylococci are the leading causes of endovascular infections worldwide. Commonly, these infections involve the formation of biofilms on the surface of biomaterials. Biofilms are a complex aggregation of bacteria commonly encapsulated by an adhesive exopolysaccharide matrix. In staphylococci, this exopolysaccharide matrix is composed of polysaccharide intercellular adhesin (PIA). PIA is synthesized when the tricarboxylic acid (TCA) cycle is repressed. The inverse correlation between PIA synthesis and TCA cycle activity led us to hypothesize that increasing TCA cycle activity would decrease PIA synthesis and biofilm formation and reduce virulence in a rabbit catheter-induced model of biofilm infection. TCA cycle activity can be induced by preventing staphylococci from exogenously acquiring a TCA cycle-derived amino acid necessary for growth. To determine if TCA cycle induction would decrease PIA synthesis in Staphylococcus aureus, the glutamine permease gene (glnP) was inactivated and TCA cycle activity, PIA accumulation, biofilm forming ability, and virulence in an experimental catheter-induced endovascular biofilm (endocarditis) model were determined. Inactivation of this major glutamine transporter increased TCA cycle activity, transiently decreased PIA synthesis, and significantly reduced in vivo virulence in the endocarditis model in terms of achievable bacterial densities in biofilm-associated cardiac vegetations, kidneys, and spleen. These data confirm the close linkage of TCA cycle activity and virulence factor production and establish that this metabolic linkage can be manipulated to alter infectious outcomes.

* Corresponding author. Mailing address: Department of Veterinary and Biomedical Sciences, University of Nebraska, 155 VBS, Fair St. and East Campus Loop, Lincoln, NE 68583-0905. Phone: (402) 472-6063. Fax: (402) 472-9690. E-mail: gsomerville3{at}unl.edu

{triangledown} Published ahead of print on 10 August 2009.

Editor: A. Camilli

{dagger} Equal contributors to the success of this study.

Infection and Immunity, October 2009, p. 4256-4264, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00195-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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