title: Impact of agr dysfunction on virulence profiles and infections associated with a novel methicillin-resistant Staphylococcus aureus (MRSA) variant of the lineage ST1-SCCmec IV.
abstract: BACKGROUND
  A novel variant of the ST1-SCCmecIV methicillin-resistant Staphylococcus aureus (MRSA) lineage, mostly associated with nosocomial bloodstream infections (BSI), has emerged in Rio de Janeiro. Bacterial biofilm has been considered a major virulence factor in central venous catheter-associated BSI. The mechanisms involved in biofilm formation/accumulation are multifactorial and complex. Studies have suggested that biofilm production was affected in vitro and vivo for agr-null mutants of S. aureus.
  
  
  RESULTS
  The impact of naturally occurring inhibition of agr signaling on virulence profiles and infections associated with the ST1 variant was investigated. agr dysfunction was detected in a significant percentage (13%) of the isolates with concomitant increase in biofilm accumulation in vitro and in vivo, and enhanced ability to adhere to and invade airway cells. The biofilm formed by these ST1 isolates was ica-independent and proteinaceous in nature. In fact, the improved colonization properties were paralleled by an increased expression of the biofilm-associated genes fnbA, spa and sasG. The transcription of sarA, a positive regulator of agr, was two-times reduced for the agr-dysfunctional MRSA. Remarkably, the agr inhibition was genetically stable. Indeed, agr-dysfunctional isolates succeed to colonize and cause both acute and chronic infections in hospitalized patients, and also to effectively accumulate biofilm in a mouse subcutaneous catheter implant model.
  
  
  CONCLUSIONS
  The ability of agr-dysfunctional isolates to cause infections in humans and to form biofilm in the animal model suggests that therapeutic approaches based on agr-inactivation strategies are unlikely to be effective in controlling human-device infections caused by ST1 isolates. The increased biofilm accumulation associated with the acquisition of multiple antimicrobial resistant traits might have influenced (at least in part) the expansion of this USA400 related clone in our hospitals.
authors.affiliation: Departamento de Microbiologia Médica, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Fabienne Antunes
authors.initials: FA
authors.lastname: Ferreira
authors.forename: Raquel Rodrigues
authors.initials: RR
authors.lastname: Souza
authors.forename: Bruno
authors.initials: B
authors.lastname: de Sousa Moraes
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: de Amorim Ferreira
authors.forename: Marco Antônio
authors.initials: MA
authors.lastname: Américo
authors.forename: Sérgio Eduardo Longo
authors.initials: SE
authors.lastname: Fracalanzza
authors.forename: José Nelson
authors.initials: JN
authors.lastname: Dos Santos Silva Couceiro
authors.forename: Agnes Marie
authors.initials: AM
authors.lastname: Sá Figueiredo
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D001426:Bacterial Proteins; D018441:Biofilms / Q000254:growth & development*; D001938:Brazil; D055499:Catheter-Related Infections / Q000382:microbiology*; D004195:Disease Models, Animal; D004705:Endocytosis; D005838:Genotype; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000145:classification / Q000302:isolation & purification / Q000472:pathogenicity* / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D058889:Molecular Typing; D013203:Staphylococcal Infections / Q000382:microbiology*; D015534:Trans-Activators / Q000172:deficiency*; D014774:Virulence
chemical_list: C095698:Agr protein, Staphylococcus aureus; D001426:Bacterial Proteins; D015534:Trans-Activators