CovR Regulates Streptococcus mutans Susceptibility To Complement Immunity and Survival in Blood

• Published in: Infection and immunity 2016-11, Vol.84 (11), p.3206-3219
• Main Authors: Alves, Lívia A, Nomura, Ryota, Mariano, Flávia S, Harth-Chu, Erika N, Stipp, Rafael N, Nakano, Kazuhiko, Mattos-Graner, Renata O
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Proteins - physiology; Blood - microbiology; Complement C3b - metabolism; Complement System Proteins - genetics; Complement System Proteins - immunology; Complement System Proteins - metabolism; Disease Models, Animal; Glucans - metabolism; Humans; Molecular Pathogenesis; Polysaccharides, Bacterial - metabolism; Rats; Rats, Sprague-Dawley; Streptococcus mutans; Streptococcus mutans - pathogenicity; Streptococcus mutans - physiology; Transcription, Genetic; Virulence - physiology
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/iai.00406-16

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 (CovR ) 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 covR in blood strains was associated with increased transcription of CovR -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 covR in 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 CovR modulates systemic virulence by regulating functions affecting S. mutans susceptibility to complement opsonization.