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J Bacteriol. 2019 Jul 22. pii: JB.00367-19. doi: 10.1128/JB.00367-19. [Epub ahead of print]

Glutathione Synthesis Contributes to Virulence of Streptococcus agalactiae in a Murine Model of Sepsis.

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Biology Department, Saint Louis University, Saint Louis, Missouri, USA.
Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, USA.
Biology Department, Saint Louis University, Saint Louis, Missouri, USA


Streptococcus agalactiae, a leading cause of sepsis and meningitis in neonates, utilizes multiple virulence factors to survive and thrive within the human host during an infection. Unique among the pathogenic streptococci, S. agalactiae uses a bifunctional enzyme encoded by a single gene (gshAB) to synthesize glutathione (GSH), a major antioxidant in most aerobic organisms. Since S. agalactiae can also import GSH, similar to all other pathogenic streptococcal species, the contribution of GSH synthesis to the pathogenesis of S. agalactiae disease is not known. In the current study, gshAB deletion mutants were generated in strains representing three of the most prevalent clinical serotypes of S. agalactiae and were compared against isogenic wild type and gshAB-knock-in strains. When cultured in vitro in a chemically-defined medium under non-stress conditions, each mutant and its corresponding wild type had comparable growth rates, generation times and growth yields. However, gshAB deletion mutants were found to be more sensitive than wild type or gshAB-knock-in strains to killing and growth inhibition by several different reactive oxygen species. Furthermore, deletion of gshAB in S. agalactiae strain COH1 significantly attenuated virulence as compared to the wild type or gshAB-knock-in strains in a mouse model of sepsis. Taken together, these data establish that GSH is a virulence factor important for resistance to oxidative stress, that de novo GSH synthesis plays a crucial role in S. agalactiae pathogenesis and suggest that inhibition of GSH synthesis may provide an opportunity for development of novel therapies targeting S. agalactiae disease.IMPORTANCE Approximately 10-30% of women are naturally and asymptomatically colonized by S. agalactiae However, transmission of S. agalactiae from mother to newborn during vaginal birth is a leading cause of neonatal meningitis. Although colonized mothers who are at risk for transmission to the newborn are treated with antibiotics prior to delivery, S. agalactiae is becoming increasingly resistant to current antibiotic therapies and new treatments and needed. This research reveals a critical stress resistance pathway, glutathione synthesis, that is utilized by S. agalactiae and contributes to its pathogenesis. Understanding the role of this unique bifunctional glutathione synthesis enzyme in S. agalactiae during sepsis may help elucidate why S. agalactiae produces such an abundance of GSH compared to other bacteria.


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