title: CovR Regulates Streptococcus mutans Susceptibility To Complement Immunity and Survival in Blood.
abstract: Streptococcus mutans, a major pathogen of dental caries, may promote systemic infections after accessing the bloodstream from oral niches. In this study, we investigate pathways of complement immunity against S. mutans and show that the orphan regulator CovR (CovRSm) modulates susceptibility to complement opsonization and survival in blood. S. mutans blood isolates showed reduced susceptibility to C3b deposition compared to oral isolates. Reduced expression of covRSmin blood strains was associated with increased transcription of CovRSm-repressed genes required for S. mutans interactions with glucans (gbpC, gbpB, and epsC), sucrose-derived exopolysaccharides (EPS). Consistently, blood strains showed an increased capacity to bind glucan in vitro Deletion of covRSmin strain UA159 (UAcov) impaired C3b deposition and binding to serum IgG and C-reactive protein (CRP) as well as phagocytosis through C3b/iC3b receptors and killing by neutrophils. Opposite effects were observed in mutants of gbpC, epsC, or gtfBCD (required for glucan synthesis). C3b deposition on UA159 was abolished in C1q-depleted serum, implying that the classical pathway is essential for complement activation on S. mutans Growth in sucrose-containing medium impaired the binding of C3b and IgG to UA159, UAcov, and blood isolates but had absent or reduced effects on C3b deposition in gtfBCD, gbpC, and epsC mutants. UAcov further showed increased ex vivo survival in human blood in an EPS-dependent way. Consistently, reduced survival was observed for the gbpC and epsC mutants. Finally, UAcov showed an increased ability to cause bacteremia in a rat model. These results reveal that CovRSmmodulates systemic virulence by regulating functions affecting S. mutans susceptibility to complement opsonization.
authors: Department of Oral Diagnosis, Piracicaba Dental School-State University of Campinas, Piracicaba, SP, Brazil.
authors: Lívia A
authors: LA
authors: Alves
authors: Department of Pediatric Dentistry, Osaka University, Graduate School of Dentistry, Osaka, Japan.
authors: Ryota
authors: R
authors: Nomura
authors: Department of Oral Diagnosis, Piracicaba Dental School-State University of Campinas, Piracicaba, SP, Brazil.
authors: Flávia S
authors: FS
authors: Mariano
authors: Department of Oral Diagnosis, Piracicaba Dental School-State University of Campinas, Piracicaba, SP, Brazil.
authors: Erika N
authors: EN
authors: Harth-Chu
authors: Department of Oral Diagnosis, Piracicaba Dental School-State University of Campinas, Piracicaba, SP, Brazil.
authors: Rafael N
authors: RN
authors: Stipp
authors: Department of Pediatric Dentistry, Osaka University, Graduate School of Dentistry, Osaka, Japan.
authors: Kazuhiko
authors: K
authors: Nakano
authors: Department of Oral Diagnosis, Piracicaba Dental School-State University of Campinas, Piracicaba, SP, Brazil rmgraner@fop.unicamp.br.
authors: Renata O
authors: RO
authors: Mattos-Graner
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000502:physiology*; D001769:Blood / Q000382:microbiology; D003179:Complement C3b / Q000378:metabolism; D003165:Complement System Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005936:Glucans / Q000378:metabolism; D006801:Humans; D011135:Polysaccharides, Bacterial / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013295:Streptococcus mutans / Q000472:pathogenicity / Q000502:physiology*; D014158:Transcription, Genetic; D014774:Virulence / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; D005936:Glucans; D011135:Polysaccharides, Bacterial; C098632:exopolysaccharide, Streptococcus; D003179:Complement C3b; D003165:Complement System Proteins