Poster Presentation 20th Lancefield International Symposium on Streptococci and Streptococcal Diseases 2017

RocA is a pseudokinase that enhances the virulence-regulating activity of the CovR/S two-component system in the group A Streptococcus (#193)

Ira Jain 1 , Eric W. Miller 1 , Jessica L. Danger 1 , Kathryn J. Pflughoeft 1 , Paul Sumby 1
  1. University of Nevada, Reno, Reno, NEVADA, United States

Regulating gene expression during infection is critical to the ability of pathogens to circumvent the immune response and cause disease.  This is true for the group A Streptococcus (GAS), a pathogen that causes both invasive and non-invasive diseases.  The control of virulence (CovR/S) two-component system has a major role in regulating GAS virulence factor expression, tailoring it in a disease-specific manner.  We identified that the regulator of cov (RocA) protein functions through CovR/S to dramatically alter gene expression, including enhancing expression of more than a dozen immunomodulatory virulence factors.  The regulatory activity of RocA reduces the virulence of GAS during invasive infection, as evident from Lancefield bactericidal assays and a murine bacteremia model of infection.  While predicted to be a membrane-spanning kinase, we identified that only the membrane-spanning domains of RocA, not the dimerization or HATPase domains, are required for complementation of a rocA mutant strain.  Thus, our data are consistent with RocA being a pseudokinase.  How RocA functions through CovR/S remains to be fully elucidated, but we have determined that RocA enhances the ratio of phosphorylated to non-phosphorylated CovR.  We propose a model in which RocA complexes with CovS and enhances CovS kinase activity.  Consistent with this, Mg2+ and LL-37, which positively and negatively regulate CovS activity respectively, are attenuated in their activity in the absence of RocA.  Thus, we propose that RocA, as a key accessory protein to the CovR/S system, influences the ability of GAS to modulate gene expression in response to host factors.