title: The two-component system VicRK regulates functions associated with Streptococcus mutans resistance to complement immunity.
abstract: Streptococcus mutans, a dental caries pathogen, can promote systemic infections upon reaching the bloodstream. The two-component system (TCS) VicRKSmof S. mutans regulates the synthesis of and interaction with sucrose-derived exopolysaccharides (EPS), processes associated with oral and systemic virulence. In this study, we investigated the mechanisms by which VicRKSmaffects S. mutans susceptibility to blood-mediated immunity. Compared with parent strain UA159, the vicKSmisogenic mutant (UAvic) showed reduced susceptibility to deposition of C3b of complement, low binding to serum immunoglobulin G (IgG), and low frequency of C3b/IgG-mediated opsonophagocytosis by polymorphonuclear cells in a sucrose-independent way (P<.05). Reverse transcriptase quantitative polymerase chain reaction analysis comparing gene expression in UA159 and UAvic revealed that genes encoding putative peptidases of the complement (pepO and smu.399) were upregulated in UAvic in the presence of serum, although genes encoding murein hydrolases (SmaA and Smu.2146c) or metabolic/surface proteins involved in bacterial interactions with host components (enolase, GAPDH) were mostly affected in a serum-independent way. Among vicKSm-downstream genes (smaA, smu.2146c, lysM, atlA, pepO, smu.399), only pepO and smu.399 were associated with UAvic phenotypes; deletion of both genes in UA159 significantly enhanced levels of C3b deposition and opsonophagocytosis (P<.05). Moreover, consistent with the fibronectin-binding function of PepO orthologues, UAvic showed increased binding to fibronectin. Reduced susceptibility to opsonophagocytosis was insufficient to enhance ex vivo persistence of UAvic in blood, which was associated with growth defects of this mutant under limited nutrient conditions. Our findings revealed that S. mutans employs mechanisms of complement evasion through peptidases, which are controlled by VicRKSm.
authors.affiliation: Department of Oral Diagnosis, Piracicaba Dental School - State University of Campinas, Piracicaba, SP, Brazil.
authors.forename: Livia A
authors.initials: LA
authors.lastname: Alves
authors.affiliation: Department of Oral Diagnosis, Piracicaba Dental School - State University of Campinas, Piracicaba, SP, Brazil.
authors.forename: Erika N
authors.initials: EN
authors.lastname: Harth-Chu
authors.affiliation: Department of Oral Diagnosis, Piracicaba Dental School - State University of Campinas, Piracicaba, SP, Brazil.
authors.forename: Thais H
authors.initials: TH
authors.lastname: Palma
authors.affiliation: Department of Oral Diagnosis, Piracicaba Dental School - State University of Campinas, Piracicaba, SP, Brazil.
authors.forename: Rafael N
authors.initials: RN
authors.lastname: Stipp
authors.affiliation: Department of Oral Diagnosis, Piracicaba Dental School - State University of Campinas, Piracicaba, SP, Brazil.
authors.forename: Flávia S
authors.initials: FS
authors.lastname: Mariano
authors.affiliation: Department of Oral Diagnosis, Piracicaba Dental School - State University of Campinas, Piracicaba, SP, Brazil.
authors.forename: José F
authors.initials: JF
authors.lastname: Höfling
authors.affiliation: Department of Oral Biology, College of Dentistry - University of Florida, Gainesville, FL, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Abranches
authors.affiliation: Department of Oral Diagnosis, Piracicaba Dental School - State University of Campinas, Piracicaba, SP, Brazil.
authors.forename: Renata O
authors.identifier: 0000-0001-8309-8135
authors.initials: RO
authors.lastname: Mattos-Graner
mesh_terms: D016470:Bacteremia; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D018441:Biofilms / Q000254:growth & development; D003179:Complement C3b / Q000276:immunology*; D003731:Dental Caries / Q000382:microbiology; D015870:Gene Expression; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D057131:Immune Evasion; D007074:Immunoglobulin G / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D011485:Protein Binding; D013295:Streptococcus mutans / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D013395:Sucrose / Q000378:metabolism; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D007074:Immunoglobulin G; D008565:Membrane Proteins; C119939:YycF protein, Bacteria; D013395:Sucrose; D003179:Complement C3b
keywords: Streptococcus mutans; bacteremia; complement system; two-component system