Abstract
Bacterial brain abscesses (BAs) are difficult to treat with conventional antibiotics. Thus, the development of alternative therapeutic strategies for BAs is of high priority. Identifying the virulence determinants that contribute to BA formation induced by Staphylococcus aureus would improve the effectiveness of interventions for this disease. In this study, RT-qPCR was performed to compare the expression levels of 42 putative virulence determinants of S. aureus strains Newman and XQ during murine BA formation, ear colonization, and bacteremia. The alterations in the expression levels of 23 genes were further confirmed through specific TaqMan RT-qPCR. Eleven S. aureus genes that persistently upregulated expression levels during BA infection were identified, and their functions in BA formation were confirmed through isogenic mutant experiments. Bacterial loads and BA volumes in mice infected with isdA, isdC, lgt, hla, or spa deletion mutants and the hla/spa double mutant strain were lower than those in mice infected with the wild-type Newman strain. The therapeutic application of monoclonal antibodies against Hla and SpA decreased bacterial loads and BA volume in mice infected with Newman. This study provides insights into the virulence determinants that contribute to staphylococcal BA formation and a paradigm for antivirulence factor therapy against S. aureus infections.
Highlights
Brain abscesses (BAs) are severe sequelae of central nervous system infections, and their prevention and treatment remains a major challenge in the medical field (Brouwer et al, 2014b)
We found that the therapeutic application of monoclonal antibodies against Hla and SpA inhibited brain abscesses (BAs) formation in mice infected with the wild-type S. aureus Newman strain
The clinical course developed by C57BL/6 mice after intracranial injection with S. aureus-encapsulated agarose beads was similar to that developed by previously reported BA models (Baldwin and Kielian, 2004; Bloch et al, 2005)
Summary
Brain abscesses (BAs) are severe sequelae of central nervous system infections, and their prevention and treatment remains a major challenge in the medical field (Brouwer et al, 2014b). The treatment of BAs necessitates multiple approaches, including medical and surgical therapies. Patients with BAs should receive prompt empiric antibiotic therapy, and the surgical drainage of purulent material is necessary in most cases of BA (Brouwer et al, 2014b; Patel and Clifford, 2014). The most effective antimicrobial therapy for BAs, can be defined only after the infecting pathogen has been isolated (Brouwer et al, 2014b). The development of alternative therapeutic strategies for BAs is urgently needed
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