Identification of surface proteins of Streptococcus mutans involved in the scape to opsonization by the complement system

• Grant number: 15/07237-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2015
• End date: November 30, 2017
• Field of knowledge: Health Sciences - Dentistry
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Renata de Oliveira Mattos Graner
• Grantee: Lívia Araújo Alves
• Host Institution: Faculdade de Odontologia de Piracicaba (FOP). Universidade Estadual de Campinas (UNICAMP). Piracicaba , SP, Brazil
• Associated scholarship(s): 16/17216-4 - Analysis of the functions of pepO protein in systemic virulence of Streptococcus mutans, BE.EP.DR

Abstract

Streptococcus mutans (SM) is a common bacterial species of the oral cavity of humans involved in the pathogenesis of dental caries, which can promote bacterial endocarditis after gaining access to the bloodstream (Nomura et al., 2006). Little is known about the virulence factors involved in the ability of this species to survive in the bloodstream to cause systemic infections (Nomura et al., 2004; Negrini et al., 2012; Alves, 2014). During the process of colonization and/or infection of the host, SM undergoes several changes in its transcriptome in response to environmental stimuli, which are in part, controlled by transcriptional regulatory systems of two-components (TCS). SM UA159 has 14 TCSs, which are typically composed by a sensor histidine kinase membrane protein (K) and an intracellular transcription factor (response regulator; R). These include the TCS VicRK and the orphan CovR, a R protein without its cognate K protein. VicRK and CovR are involved in the regulation of virulence genes associated with the formation of cariogenic biofilms and evasion of phagocytosis by PMN of human blood. Recently, we found that the inactivation of genes encoding VicK (vicK) and CovR (covR) in strain UA159 significantly reduces deposition of C3b/iC3b of the complement system, a major opsonizing blood factor (Alves, 2014; Proc 2012/04222-5 masters). Because VicRK and CovR regulate genes encoding surface proteins, it is likely that some of these genes directly or indirectly influence on deposition of C3b/iC3b on the bacterial surface. Genes directly regulated by VicRK and/or CovR include wapE, lysM, 2146c, smaA and epsC. In addition, other genes in genomic loci apparently regulated by VicRK and CovR, encode proteins with homology to C3-proteases [smu.399 and pepO (smu.2036)] and proteins which potentially influence on deposition of C3b (smu.1247 and smu.360). The aim of this project is to identify surface proteins of SM directly or indirectly regulated by the TCS VicRK and/or CovR, which affects deposition of C3b/iC3b the human complement system. To this end, intensities of C3b/iC3b deposition on bacterial surface and phagocytosis of opsonized strains by PMN will be determined in knockout mutants of genes wapE, lysM, 2146c, smaA, epsC, smu.399 and pepO and compared with the parental strain UA159. The capacities to adsorb soluble blood components (fibronectin, plasminogen and fibrinogen), which influence on the deposition of C3b/iC3b, will be also compared between the same strains. Moreover, the expression of VicRK/CovR-regulated genes in response to SM exposure to human serum will be determined. The identification of SM surface components which influence on opsonization by the complement system may contribute to the development of therapies to control bacteremia and systemic infections by this bacterial species. (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ALVES, LIVIA A.; HARTH-CHU, ERIKA N.; PALMA, THAIS H.; STIPP, RAFAEL N.; MARIANO, FLAVIA S.; HOEFLING, JOSE F.; ABRANCHES, JACQUELINE; MATTOS-GRANER, RENATA O.. The two-component system VicRK regulates functions associated with Streptococcus mutans resistance to complement immunity. Molecular Oral Microbiology, v. 32, n. 5, p. 419-431, OCT 2017. (15/12940-3, 12/04222-5, 09/50547-0, 12/50966-6, 15/07237-1)

ALVES, LIVIA A.; DE CARLI, THAIS R.; HARTH-CHU, ERIKA N.; MARIANO, FLAVIA S.; HOFLING, JOSE F.; STIPP, RAFAEL N.; MATTOS-GRANER, RENATA O.. Oral streptococci show diversity in resistance to complement immunity. Journal of Medical Microbiology, v. 68, n. 4, p. 600-608, APR 2019. (18/02054-4, 13/07098-6, 15/12940-3, 09/50547-0, 12/04222-5, 12/50966-6, 15/07237-1, 17/19899-4)

CAMARGO, TARSILA M.; STIPP, RAFAEL N.; ALVES, LIVIA A.; HARTH-CHU, ERIKA N.; HOFLING, JOSE F.; MATTOS-GRANER, RENATA O.. Novel Two-Component System of Streptococcus sanguinis Affecting Functions Associated with Viability in Saliva and Biofilm Formation. Infection and Immunity, v. 86, n. 4, APR 2018. (15/12940-3, 09/50547-0, 15/07237-1, 12/51832-3, 12/04222-5)

ALVES, LIVIA ARAUJO; GANGULY, TRIDIB; MATTOS-GRANER, RENATA O.; KAJFASZ, JESSICA; HARTH-CHU, ERIKA N.; LEMOS, JOSE A.; ABRANCHES, JACQUELINE. CovR and VicRKX Regulate Transcription of the Collagen Binding Protein Cnm of Streptococcus mutans. Journal of Bacteriology, v. 200, n. 23, DEC 2018. (15/12940-3, 16/17216-4, 15/07237-1)

HARTH-CHU, ERIKA N.; ALVES, LIVIA A.; THEOBALDO, JESSICA D.; SALOMAO, MARIANA F.; HOFLING, JOSE F.; KING, WILLIAM F.; SMITH, DANIEL J.; MATTOS-GRANER, RENATA O.. PcsB Expression Diversity Influences on Streptococcus mitis Phenotypes Associated With Host Persistence and Virulence. FRONTIERS IN MICROBIOLOGY, v. 10, NOV 12 2019. (17/19899-4, 15/12940-3, 12/04222-5, 18/02054-4, 15/07237-1, 09/50547-0, 12/50966-6)

ALVES, LIVIA A.; NOMURA, RYOTA; MARIANO, FLVIA S.; HARTH-CHU, ERIKA N.; STIPP, RAFAEL N.; NAKANO, KAZUHIKO; MATTOS-GRANER, RENATA O.. CovR Regulates Streptococcus mutans Susceptibility To Complement Immunity and Survival in Blood. Infection and Immunity, v. 84, n. 11, p. 3206-3219, NOV 2016. (15/12940-3, 12/04222-5, 09/50547-0, 15/07237-1)

MATTOS-GRANER, RENATA O.; KLEIN, MARLISE I.; ALVES, LIVIA ARAUJO. The complement system as a key modulator of the oral microbiome in health and disease. CRITICAL REVIEWS IN MICROBIOLOGY, v. N/A, p. 30-pg., 2023-01-05. (12/04222-5, 21/13074-9, 15/12940-3, 16/17216-4, 12/50966-6, 12/51832-3, 17/19899-4, 21/06801-1, 18/02054-4, 15/07237-1)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

ALVES, Lívia Araújo. Analysis of factors regulated by CovR and VicRK involved in the susceptibility to opsonization by the complement system and systemic virulence in Streptococcus mutans. 2017. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Faculdade de Odontologia de Piracicaba Piracicaba, SP.