Staphylococcus aureusagrandsarAFunctions Are Required for Invasive Infection but Not Inflammatory Responses in the Lung

Abstract

Staphylococcus aureus strains lacking agr-and sarA-dependent gene products or specific MSCRAMM (microbial surface components recognizing adhesive matrix molecules) adhesins were compared for the ability to activate inflammatory responses in the lung. The mutants were evaluated for virulence in a mouse model of pneumonia and by quantifying their ability to stimulate interleukin-8 (IL-8) and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in respiratory epithelial cells. In a neonatal mouse, only strains with intact agr and sarA loci were consistently associated with invasive, fatal pulmonary infection (P < 0.001) and sarA was specifically required to cause bacteremia (P < 0.001). The agr and/or sarA mutants were, nonetheless, fully capable of producing pneumonia and were as proficient as the wild-type strain in stimulating epithelial IL-8 expression, a polymorphonuclear leukocyte chemokine, in airway cells. In contrast, agr and especially sarA mutants induced less epithelial GM-CSF expression, and MSCRAMM mutants lacking fibronectin binding proteins or clumping factor A, a ligand for fibrinogen, were unable to stimulate epithelial GM-CSF production. The ability to induce IL-8 expression was independent of the adherence properties of intact bacteria, indicating that shed and/or secreted bacterial components activate epithelial responses. While conserved staphylococcal components such as peptidoglycan are sufficient to evoke inflammation and cause pneumonia, the agr and sarA loci of S. aureus are critical for the coordination of invasive infection of the lungs.

Fibrinogen Depletion Attenuates Staphyloccocus aureus Infection by Preventing Density-Dependent Virulence Gene Up-Regulation

“…Under conditions of high autoinducer concentration, i.e., high bacterial density, RNAIII down-regulates gene expression encoding for surface adhesins while up-regulating those encoding for capsule production, secreted toxins, and proteases (24, 27, 29 -31). This conversion from a tissue-adhering to a tissue-damaging and phagocyte-evading phenotype is thought to be important for in vivo pathogenesis and the development of invasive infection (10,24,27,32). In this work we show for the first time that fibrinogen-mediated bacterial clumping significantly potentiates density-dependent virulence gene expression and the resultant bacterial infection.…”

Quorum sensing in bacterial virulence

“…Many studies have found that agr is required for virulence in models of septic arthritis, osteomyelitis, endophthalmitis and pulmonary infections (Abdelnour et al, 1993;Booth et al, 1997;Gillaspy et al, 1995;Heyer et al, 2002). However, other evidence seems to question the role of the agr system in virulence in other models (Cheung et al, 1994;Kielian et al, 2001).…”

Neutrophil Depletion Causes a Fatal Defect in Murine Pulmonary Staphylococcus aureus clearance

“…Additionally, intranasal inoculation of 4-8 × 10 8 (but not 8 × 10 7 ) CFU of S. aureus Newman, a human clinical isolate, causes a rapidly fatal model of pneumonia in immunocompetent C57Bl/6 mice with evidence of bacterial growth in vivo associated with production of sortase A (11). Intranasal injection of 2 × 10 8 CFUs S. aureus also causes early pneumonia in neonatal mice, which is dependent on the agr and sar A loci, but survival in this model beyond 24 hours has not been described (12).…”