title: Mutations in the control of virulence sensor gene from Streptococcus pyogenes after infection in mice lead to clonal bacterial variants with altered gene regulatory activity and virulence.
abstract: The cluster of virulence sensor (CovS)/responder (CovR) two-component operon (CovRS) regulates ∼15% of the genes of the Group A Streptococcal pyogenes (GAS) genome. Bacterial clones containing inactivating mutations in the covS gene have been isolated from patients with virulent invasive diseases. We report herein an assessment of the nature and types of covS mutations that can occur in both virulent and nonvirulent GAS strains, and assess whether a nonvirulent GAS can attain enhanced virulence through this mechanism. A group of mice were infected with a globally-disseminated clonal M1T1 GAS (isolate 5448), containing wild-type (WT) CovRS (5448/CovR+S+), or less virulent engineered GAS strains, AP53/CovR+S+ and Manfredo M5/CovR+S+. SpeB negative GAS clones from wound sites and/or from bacteria disseminated to the spleen were isolated and the covS gene was subjected to DNA sequence analysis. Numerous examples of inactivating mutations were found in CovS in all regions of the gene. The mutations found included frame-shift insertions and deletions, and in-frame small and large deletions in the gene. Many of the mutations found resulted in early translation termination of CovS. Thus, the covS gene is a genomic mutagenic target that gives GAS enhanced virulence. In cases wherein CovS- was discovered, these clonal variants exhibited high lethality, further suggesting that randomly mutated covS genes occur during the course of infection, and lead to the development of a more invasive infection.
authors: W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors: Jeffrey A
authors: JA
authors: Mayfield
authors: W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, United States of America; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors: Zhong
authors: Z
authors: Liang
authors: W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, United States of America; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors: Garima
authors: G
authors: Agrahari
authors: W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, United States of America; Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors: Shaun W
authors: SW
authors: Lee
authors: W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors: Deborah L
authors: DL
authors: Donahue
authors: W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, United States of America; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors: Victoria A
authors: VA
authors: Ploplis
authors: W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, United States of America; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors: Francis J
authors: FJ
authors: Castellino
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D003851:Deoxyribonucleases / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D005818:Genetic Engineering; D000071677:Histidine Kinase; D006801:Humans; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D016019:Survival Analysis
chemical_list: D001426:Bacterial Proteins; C432143:CsrR protein, Streptococcus pyogenes; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C534547:CovS protein, Streptococcus pyogenes; D000071677:Histidine Kinase; D003851:Deoxyribonucleases