A Novel LysR-Type Global Regulator RpvA Controls Persister Formation and Virulence inStaphylococcus aureus

Abstract

9Staphylococcus aureus is the leading cause of wound and nosocomial infections. 0Persister formation and virulence factors play crucial roles during S. aureus infection. 1However, the mechanisms of persister formation and its relationship to virulence in S.3 2 aureus are poorly understood. In this study, we screened a transposon mutant library 3 3 and identified a LysR-type global transcriptional regulator NWMN_0037, which we 3 4 called RpvA, for regulator of persistence and virulence, whose mutation leads to 3 5 higher susceptibility to antibiotics ampicillin and norfloxacin and various stresses 3 6including oxidative stress, heat, and starvation in late exponential and early stationary 3 7 phase. Interestingly, the rpvA mutant was highly attenuated for virulence compared 3 8with the parent S. aureus Newman strain as shown by a much higher lethal dose, 3 9 reduced ability to survive in macrophages and to form abscess in the mouse model. 4 0 Transcriptional profiling and metabolomic analysis revealed that RpvA could repress 4 1 multiple genes including gapR, gapA, tpi, pgm, eno, glpD, and acs expression and 4 2 enhance production of numerous intermediate metabolites including 4 3 dihydroxyacetone phosphate, 2-phosphoglycerate, acetyl-CoA, glycerol 3-phosphate, 4 4 L-glutamate in the cells. The differentially expressed genes and altered production of 4 5 metabolites are distributed in global metabolism including carbohydrate metabolism, 4 6 amino acid metabolism, energy metabolism and metabolism of cofactors and vitamins. 4 7These metabolic adjustments could cause the cell to go into dormancy, thus promoting 4 8 S. aureus to convert to persisters. In addition, RpvA could upregulate the expression 4 9 of virulence genes including hla, hlgA, hlgB, hlgC, lukF, lukS, lukD, sea and coa, and 5 0

PurN Is Involved in Antibiotic Tolerance and Virulence in Staphylococcus aureus

“…Our findings further suggest that there is a close relationship between persister formation and bacterial virulence. In addition to the reported multiple persistence-related genes, such as argJ , lysR , phoU , and msaABCR , which are involved in bacterial virulence [ 26 , 33 , 38 , 39 ], the PurN of S. aureus is another multifunctional factor that not only participates in persister formation but also participates in virulence regulation.…”

“…This indicates that there may be differences in the mechanisms of persister formation at different growth phases. Furthermore, multiple persistence-related genes such as argJ , lysR , phoU , and msaABCR [ 26 , 33 , 38 , 39 ] are involved in regulating S. aureus virulence, indicating that the persister formation mechanism is associated with virulence.…”