Dental caries is a polymicrobial disease that affects much of the human population worldwide, where the
harmony of a cooperative eco-organization shifts towards a dysbiotic framework with overrepresentation of
pathogenic microorganisms, particularly by Streptococcus mutans (SM). For planktonic SM, adhesion to tooth
surface and/or dental biofilms is a crucial step in the pathogenesis of dental caries, and SM has evolved (i) SM-
host and (ii) SM-microbial interactions, which are mediated through its surface proteins (adhesins).
SM’s adhesion mediated interactions include: (A) The recent discovery of redundant high affinity binding of
SM’s adhesins to the scavenger receptor cysteine rich domains (SRCR) of the salivary glycoprotein 340 (Gp340),
which promotes caries susceptibility in the SM-host interface; and (B) The revelation of SM’s adhesin required
for the SM-Candida albicans (CA) biofilm formation and acid production, which enhances cariogenicity in early
childhood caries in the SM-microbial interface. Together these have revealed previously unknown interactions
by once thought to be well-known and well-characterized adhesins on SM. Yet the key unanswered question
remains, “how does SM mediate such redundant, but specific binding to host proteins and to other microbes?”
The goal of this application is to determine the specific motif(s) and/or molecular mechanism(s) that drive
SM’s adherence, particularly how they enable binding to multiple ligands. Our structural and functional studies
show that SM’s surface adhesins mediate these attachments primarily via two major structural domains, the V-
and C-fold. We hypothesize that “the V- and C-fold present on the surface adhesins of SM mediate specific
interactions through common binding motif(s) that are crucial for biofilm formation and microbial colonization”.
We will address our hypothesis through three specific aims (SAs) by (a) mapping the adherence motif(s) on the
V-fold (SA1) and (b) C-fold (SA2) of oral streptococcal adhesins, and (c) investigating the role of SM’s adhesins
in the SM-Candida albicans (CA) interface (SA3).
The results from this multi-PD/PI study will (i) Determine the binding-motif(s)/mechanisms globally adopted
by the V- and C-fold among SM’s adhesins; (ii) Determine the presence of distinct and/or overlapping adherence
sites for various ligands; (iii) Provide a comparative analysis of the V- and C-fold of various adhesins from mutans
and viridans streptococci, revealing species-specific differences in their binding-motifs/mechanisms; (iv)
Characterize the role of SM adhesins at the SM-CA interface; and (v) Elucidate alternations in the microbial
ecology modulated by SM’s V- and C-folds, particularly as they relate to dental caries.
Our proposed structural analyses, genetic manipulation of key adhesion motif(s) and animal model studies
will determine the adherence mechanisms and address the knowledge gap on SM’s V- and C-fold, particularly
their crucial role in promoting colonization and virulence. The results will enable future development of selective
combinatorial therapeutics to prevent SM’s adherence to host and microbes.