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Regulatory rewiring confers serotype‐specific hyper‐virulence in the human pathogen group A S treptococcus
Author(s) -
Miller Eric W.,
Danger Jessica L.,
Ramalinga Anupama B.,
Horstmann Nicola,
Shelburne Samuel A.,
Sumby Paul
Publication year - 2015
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.13136
Subject(s) - biology , virulence , microbiology and biotechnology , pathogen , serotype , mutant , streptococcus pyogenes , phenotype , virulence factor , genetics , virology , gene , bacteria , staphylococcus aureus
Summary Phenotypic heterogeneity is commonly observed between isolates of a given pathogen. Epidemiological analyses have identified that some serotypes of the group A S treptococcus ( GAS ) are non‐randomly associated with particular disease manifestations. Here, we present evidence that a contributing factor to the association of serotype M 3 GAS isolates with severe invasive infections is the presence of a null mutant allele for the orphan kinase RocA . Through use of RNA seq analysis, we identified that the natural roc A 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 M 3 GAS isolate survived human phagocytic killing at a level 13‐fold higher than a roc A 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 cov R or cov S mutation. Our data are consistent with RocA interfacing with the CovR / S two‐component system, and that the absence of this activity in M 3 GAS potentiates the severity of invasive infections caused by isolates of this serotype.