title: Adhesin competence repressor (AdcR) from Streptococcus pyogenes controls adaptive responses to zinc limitation and contributes to virulence.
abstract: Altering zinc bioavailability to bacterial pathogens is a key component of host innate immunity. Thus, the ability to sense and adapt to the alterations in zinc concentrations is critical for bacterial survival and pathogenesis. To understand the adaptive responses of group A Streptococcus (GAS) to zinc limitation and its regulation by AdcR, we characterized gene regulation by AdcR. AdcR regulates the expression of 70 genes involved in zinc acquisition and virulence. Zinc-bound AdcR interacts with operator sequences in the negatively regulated promoters and mediates differential regulation of target genes in response to zinc deficiency. Genes involved in zinc mobilization and conservation are derepressed during mild zinc deficiency, whereas the energy-dependent zinc importers are upregulated during severe zinc deficiency. Further, we demonstrated that transcription activation by AdcR occurs by direct binding to the promoter. However, the repression and activation by AdcR is mediated by its interactions with two distinct operator sequences. Finally, mutational analysis of the metal ligands of AdcR caused impaired DNA binding and attenuated virulence, indicating that zinc sensing by AdcR is critical for GAS pathogenesis. Together, we demonstrate that AdcR regulates GAS adaptive responses to zinc limitation and identify molecular components required for GAS survival during zinc deficiency.
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, The Methodist Hospital Research Institute, Department of Pathology and Genomic Medicine, The Methodist Hospital System, Houston, TX, USA Escuela de Biotecnología y Alimentos, Escuela de Medicina y Ciencias de la Salud, Tecnologico de Monterrey, Monterrey, NL, Mexico.
authors.forename: Misu
authors.initials: M
authors.lastname: Sanson
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, The Methodist Hospital Research Institute, Department of Pathology and Genomic Medicine, The Methodist Hospital System, Houston, TX, USA.
authors.forename: Nishanth
authors.initials: N
authors.lastname: Makthal
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, The Methodist Hospital Research Institute, Department of Pathology and Genomic Medicine, The Methodist Hospital System, Houston, TX, USA Section of Infectious Diseases, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Flores
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, The Methodist Hospital Research Institute, Department of Pathology and Genomic Medicine, The Methodist Hospital System, Houston, TX, USA.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Olsen
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, The Methodist Hospital Research Institute, Department of Pathology and Genomic Medicine, The Methodist Hospital System, Houston, TX, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, The Methodist Hospital Research Institute, Department of Pathology and Genomic Medicine, The Methodist Hospital System, Houston, TX, USA mkumaraswami@houstonmethodist.org.
authors.forename: Muthiah
authors.initials: M
authors.lastname: Kumaraswami
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D001665:Binding Sites; D015964:Gene Expression Regulation, Bacterial; D051379:Mice; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D013290:Streptococcal Infections / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014774:Virulence; D015032:Zinc / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D015032:Zinc