TY - JOUR
T1 - Regulatory rewiring confers serotype-specific hyper-virulence in the human pathogen group A Streptococcus
AU - Miller, Eric W.
AU - Danger, Jessica L.
AU - Ramalinga, Anupama B.
AU - Horstmann, Nicola
AU - Shelburne, Samuel A.
AU - Sumby, Paul
N1 - Publisher Copyright:
© 2015 John Wiley & Sons Ltd.
PY - 2015/10
Y1 - 2015/10
N2 - Phenotypic heterogeneity is commonly observed between isolates of a given pathogen. Epidemiological analyses have identified that some serotypes of the group A Streptococcus (GAS) are non-randomly associated with particular disease manifestations. Here, we present evidence that a contributing factor to the association of serotype M3 GAS isolates with severe invasive infections is the presence of a null mutant allele for the orphan kinase RocA. Through use of RNAseq analysis, we identified that the natural rocA mutation present within M3 isolates leads to the enhanced expression of more than a dozen immunomodulatory virulence factors, enhancing phenotypes such as hemolysis and NAD+ hydrolysis. Consequently, an M3 GAS isolate survived human phagocytic killing at a level 13-fold higher than a rocA complemented derivative, and was significantly more virulent in a murine bacteremia model of infection. Finally, we identified that RocA functions through the CovR/S two-component system as levels of phosphorylated CovR increase in the presence of functional RocA, and RocA has no regulatory activity following covR or covS mutation. Our data are consistent with RocA interfacing with the CovR/S two-component system, and that the absence of this activity in M3 GAS potentiates the severity of invasive infections caused by isolates of this serotype.
AB - Phenotypic heterogeneity is commonly observed between isolates of a given pathogen. Epidemiological analyses have identified that some serotypes of the group A Streptococcus (GAS) are non-randomly associated with particular disease manifestations. Here, we present evidence that a contributing factor to the association of serotype M3 GAS isolates with severe invasive infections is the presence of a null mutant allele for the orphan kinase RocA. Through use of RNAseq analysis, we identified that the natural rocA mutation present within M3 isolates leads to the enhanced expression of more than a dozen immunomodulatory virulence factors, enhancing phenotypes such as hemolysis and NAD+ hydrolysis. Consequently, an M3 GAS isolate survived human phagocytic killing at a level 13-fold higher than a rocA complemented derivative, and was significantly more virulent in a murine bacteremia model of infection. Finally, we identified that RocA functions through the CovR/S two-component system as levels of phosphorylated CovR increase in the presence of functional RocA, and RocA has no regulatory activity following covR or covS mutation. Our data are consistent with RocA interfacing with the CovR/S two-component system, and that the absence of this activity in M3 GAS potentiates the severity of invasive infections caused by isolates of this serotype.
UR - http://www.scopus.com/inward/record.url?scp=84945454881&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84945454881&partnerID=8YFLogxK
U2 - 10.1111/mmi.13136
DO - 10.1111/mmi.13136
M3 - Article
C2 - 26192205
AN - SCOPUS:84945454881
SN - 0950-382X
VL - 98
SP - 473
EP - 489
JO - Molecular Microbiology
JF - Molecular Microbiology
IS - 3
ER -