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C. albicans interactions with S. mutans modulate cariogenic biofilm formation and virulence

Award Number: R01DE034383
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/10/2025
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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C. albicans interactions with S. mutans modulate cariogenic biofilm formation and virulence - Clinical microbiome studies show that C. albicans, along with elevated levels of S. mutans, in plaque (biofilm) is strongly associated with severe early-childhood caries (S-ECC). Previously, we demonstrated that C. albicans interacts with S. mutans and enhances the accumulation and virulence of plaque-biofilms, amplifying the disease severity in vivo. We found that the presence of C. albicans activates S. mutans Gtf exoenzymes production and promotes extracellular glucan synthesis, cross-feeding/co-metabolism, and acid production, leading to rampant and extensive carious lesions (similar to those found in S-ECC) in a rodent caries model. However, a key question remains unanswered. How C. albicans interacts with S. mutans to initiate the pathogenic process? Recently, we discovered that C. albicans forms highly structured assemblages with S. mutans that are uniquely found in the saliva of S-ECC patients. The C. albicans (Ca)-S. mutans (Sm) assemblage binds avidly to apatite surface through hyphae acting as anchoring points. The attached assemblage displays a new type of cell-group mobility that is mediated by the fungal hyphal formation and elongation in saliva, which promotes rapid surface spreading with enhanced growth and acidogenesis causing more extensive and severe enamel decay than either species alone. Conversely, inactivation of fungal growth or filamentation prevents surface mobility/spreading and cariogenic activity. In this proposal, we will investigate how C. albicans mediates this interkingdom assemblage formation and its emergent properties to initiate pathogenic biofilms. Understanding the early events of Ca-Sm interactions that coordinates effective colonization and rapid biofilm formation will provide new mechanistic insights about the rampant nature and severity of S-ECC carious lesions, which remains poorly understood. Fungal transcription factors (TF) and protein kinase (PK) networks play key roles in Ca filamentation but are highly influenced by the niche environment. Preliminary data show that Ca hyphal morphogenesis in saliva is distinct from previously studied conditions. Thus, we hypothesize that interkingdom assemblage and surface mobility in the unique dental niche depend on novel C. albicans TF and PK networks that respond to saliva and presence of S. mutans, enhancing surface colonization, biofilm spreading and virulence. In Aim 1, we will identify C. albicans TFs and PKs and their target genes that regulate hyphal morphogenesis in saliva with S. mutans mediating interkingdom assemblage formation, colonization, and mobility. In Aim 2, we will investigate how TF and PK networks modulate biofilm initiation/spreading and enamel demineralization. Then, in Aim 3, we will examine the role of TF and PK in biofilm virulence and their impact on oral microbiome and caries severity in vivo. A comprehensive program from laboratory studies to in vivo investigations is offered to understand the underlying mechanisms governing this highly virulent interkingdom interaction and its implications in S-ECC, an unresolved public health problem.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $445,260 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Oral Diseases and Disorders Research	001	2	4/15/2026	NON-COMPETING CONTINUATION	$44,526
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Oral Diseases and Disorders Research	000	2	1/29/2026	NON-COMPETING CONTINUATION	$400,734
														Subtotal = $445,260

Issue Date FY: 2025 ( Subtotal = $460,885 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Oral Diseases and Disorders Research	000	1	3/10/2025	NEW	$460,885
														Subtotal = $460,885

Grand Total All Awards = $906,145

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C. albicans interactions with S. mutans modulate cariogenic biofilm formation and virulence

Award Number: R01DE034383

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/10/2025

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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