title: Regulatory rewiring confers serotype-specific hyper-virulence in the human pathogen group A Streptococcus.
abstract: 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.
authors.affiliation: Department of Microbiology & Immunology, School of Medicine, University of Nevada, Reno, Nevada, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Miller
authors.affiliation: Department of Microbiology & Immunology, School of Medicine, University of Nevada, Reno, Nevada, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Danger
authors.affiliation: Department of Microbiology & Immunology, School of Medicine, University of Nevada, Reno, Nevada, USA.
authors.forename: Anupama B
authors.initials: AB
authors.lastname: Ramalinga
authors.affiliation: Department of Infectious Diseases, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Horstmann
authors.affiliation: Department of Infectious Diseases, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Shelburne
authors.affiliation: Department of Microbiology & Immunology, School of Medicine, University of Nevada, Reno, Nevada, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Sumby
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism; D016470:Bacteremia / Q000382:microbiology; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D008969:Molecular Sequence Data; D009154:Mutation; D065288:Serogroup; D013290:Streptococcal Infections / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000145:classification / Q000235:genetics* / Q000472:pathogenicity*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; C474644:RocA protein, Streptococcus pyogenes; D015534:Trans-Activators; D037521:Virulence Factors; C014689:streptococcal M protein