Nasal carriage as a source of agr-defective Staphylococcus aureus bacteremia

Abstract

Inactivating mutations in the Staphylococcus aureus virulence regulator agr are associated with worse outcomes in bacteremic patients. However, whether agr dysfunction is primarily a cause or a consequence of early bacteremia is unknown. Analysis of 158 paired S. aureus clones from blood and nasal carriage sites in individual patients revealed that recovery of an agr-defective mutant from blood was usually predicted by the agr functionality of carriage isolates. Many agr-positive blood isolates produced low levels of hemolytic toxins, but levels were similar to those of colonizing strains within patients, suggesting that introduction into the blood did not select for mutations with minor functional effects. Evidently, the transition from commensalism to opportunism in S. aureus does not require full virulence in hospitalized patients. Furthermore, agr-defective mutants were found in uninfected nasal carriers in the same proportion as in carriers who develop bacteremia, suggesting low correlation between virulence and infectivity.

Figure 1.

A representative subset of clonal complex 30 strains showing various levels of agr activity. A, Cross-streaking alongside the β-hemolysin producing strain RN4220; differentiation of the various hemolytic activities in Staphylococcus aureus can be scored on sheep blood agar by virtue of their synergism with β-hemolysin. Strain 277, strain 105, and weakly agr-positive reference strain MRSA252 have identical agr sequences, including an AgrC G55R amino acid change that attenuates agr function (Table 2) [23]. Strain 85 has the same G55R amino acid change but is agr defective, likely owing to an additional mutation in agrA (Table 1 and Table 2). B, Exoprotein profiles prepared from culture supernatants analyzed by sodium dodecyl sulfate–polyacrylamide gel electrophoresis. M, protein ladder; MW2 and MW2 Δagr, control strains. C, Relative quantitation of RNAIII by quantitative nucleic acid sequence–based amplification analysis and the time-to-positivity (TTP) ratio (TTP_gyrB/TTP_RNAIII). Data are representative of 3 separate experiments. Dotted line, TTP ratio of 1.10, indicating the cutoff for agr functionality; MW2 and MW2 Δagr, control strains.