Abstract
Selection pressures exerted on Staphylococcus aureus by host factors may lead to the emergence of mutants better adapted to the evolving conditions at the infection site. This study was aimed at identifying the changes that occur in S. aureus exposed to the host defense mechanisms during chronic osteomyelitis and evaluating whether these changes affect the virulence of the organism. Genome assessment of two S. aureus isolates collected 13 months apart (HU-85a and HU-85c) from a host with chronic osteomyelitis was made by whole genome sequencing. Agr functionality was assessed by qRT-PCR. Isolates were tested in a rat model of osteomyelitis and the bacterial load (CFU/tibia) and the morphometric osteomyelitic index (OI) were determined. The ability of the isolates to trigger the release of proinflammatory cytokines was determined on macrophages in culture. Persistence of S. aureus within the host resulted in an agrC frameshift mutation that likely led to the observed phenotype. The capacity to cause bone tissue damage and trigger proinflammatory cytokines by macrophages of the agr-deficient, unencapsulated derivative (HU-85c) was decreased when compared with those of the isogenic CP8-capsulated parental strain (HU-85a). By comparison, no significant differences were found in the bacterial load or the OI from rats challenged with isogenic Reynolds strains [CP5, CP8, and non-typeable (NT)], indicating that lack of CP expression alone was not likely responsible for the reduced capacity to cause tissue damage in HU-85c compared with HU-85a. The production of biofilm was significantly increased in the isogenic derivative HU-85c. Lack of agr-dependent factors makes S. aureus less virulent during chronic osteomyelitis and alteration of the agr functionality seems to permit better adaptation of S. aureus to the chronically infected host.
Highlights
Staphylococcus aureus is an ubiquitous opportunistic pathogen that can infect, replicate and persist in humans making this species a worldwide threat to public health
Once S. aureus is well established at the infected tissue, and the infection becomes refractory to antibiotic treatment, certain regulatory traits may be fixed by spontaneous mutations occurring during chronic infection (Tuchscherr et al, 2010), likely due to selection pressure exerted by a vast number of yet undefined host factors
To test whether HU-85c was an agr-deficient derivative, the expression of RNAIII from the agr locus was assessed by qRT-PCR
Summary
Staphylococcus aureus is an ubiquitous opportunistic pathogen that can infect, replicate and persist in humans making this species a worldwide threat to public health. Once S. aureus is well established at the infected tissue, and the infection becomes refractory to antibiotic treatment, certain regulatory traits may be fixed by spontaneous mutations occurring during chronic infection (Tuchscherr et al, 2010), likely due to selection pressure exerted by a vast number of yet undefined host factors. These variants are more suitable to evade immune defense mechanisms than the parental infecting wild type and are able to generate chronic infection refractory to antibiotic treatment, not necessarily associated to bacterial antibiotic resistance. The present study was designed to investigate the main changes that occurred in S. aureus in a chronically infected patient persisting over a period exceeding 1 year
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