title: Staphylococcus aureus hyaluronidase is a CodY-regulated virulence factor.
abstract: Staphylococcus aureus is a Gram-positive pathogen that causes a diverse range of bacterial infections. Invasive S. aureus strains secrete an extensive arsenal of hemolysins, immunomodulators, and exoenzymes to cause disease. Our studies have focused on the secreted enzyme hyaluronidase (HysA), which cleaves the hyaluronic acid polymer at the β-1,4 glycosidic bond. In the study described in this report, we have investigated the regulation and contribution of this enzyme to S. aureus pathogenesis. Using the Nebraska Transposon Mutant Library (NTML), we identified eight insertions that modulate extracellular levels of HysA activity. Insertions in the sigB operon, as well as in genes encoding the global regulators SarA and CodY, significantly increased HysA protein levels and activity. By altering the availability of branched-chain amino acids, we further demonstrated CodY-dependent repression of HysA activity. Additionally, through mutation of the CodY binding box upstream of hysA, the repression of HysA production was lost, suggesting that CodY is a direct repressor of hysA expression. To determine whether HysA is a virulence factor, a ΔhysA mutant of a community-associated methicillin-resistant S. aureus (CA-MRSA) USA300 strain was constructed and found to be attenuated in a neutropenic, murine model of pulmonary infection. Mice infected with this mutant strain exhibited a 4-log-unit reduction in bacterial burden in their lungs, as well as reduced lung pathology and increased levels of pulmonary hyaluronic acid, compared to mice infected with the wild-type, parent strain. Taken together, these results indicate that S. aureus hyaluronidase is a CodY-regulated virulence factor.
authors: Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors: Carolyn B
authors: CB
authors: Ibberson
authors: Department of Wound Infections, Walter Reed Army Institute of Research (WRAIR), Silver Spring, Maryland, USA.
authors: Crystal L
authors: CL
authors: Jones
authors: Department of Wound Infections, Walter Reed Army Institute of Research (WRAIR), Silver Spring, Maryland, USA.
authors: Shweta
authors: S
authors: Singh
authors: Department of Wound Infections, Walter Reed Army Institute of Research (WRAIR), Silver Spring, Maryland, USA.
authors: Matthew C
authors: MC
authors: Wise
authors: Division of Microbiology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas, USA.
authors: Mark E
authors: ME
authors: Hart
authors: Department of Wound Infections, Walter Reed Army Institute of Research (WRAIR), Silver Spring, Maryland, USA.
authors: Daniel V
authors: DV
authors: Zurawski
authors: Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA alex-horswill@uiowa.edu.
authors: Alexander R
authors: AR
authors: Horswill
mesh_terms: D000818:Animals; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D006651:Histocytochemistry; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011023:Pneumonia, Staphylococcal / Q000382:microbiology / Q000473:pathology; D011133:Polysaccharide-Lyases / Q000096:biosynthesis*; D012097:Repressor Proteins / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000235:genetics* / Q000472:pathogenicity*; D014774:Virulence; D037521:Virulence Factors / Q000096:biosynthesis*
chemical_list: D001426:Bacterial Proteins; C540555:CodY protein, Staphylococcus aureus; D012097:Repressor Proteins; D037521:Virulence Factors; D011133:Polysaccharide-Lyases; C100002:hyaluronate lyase