Neutrophil swarming is crucial for limiting oral mucosal infection by Candida albicans.

Oral mucosal colonization by C. albicans (Ca) is benign in healthy people but progresses to deeper infection known as oropharyngeal candidiasis (OPC) that may become disseminated when combined with immunosuppression. Cortisone use and neutropenia are risk factors for invasive mucosal fungal infections, however the mechanisms are poorly understood.

Fungi and bacteria occupy distinct spatial niches within carious dentin.

The role of bacteria in the etiology of dental caries is long established, while the role of fungi has only recently gained more attention. The microbial invasion of dentin in advanced caries especially merits additional research. We evaluated the fungal and bacterial community composition and spatial distribution within carious dentin.

Neutrophil swarms containing myeloid-derived suppressor cells are crucial for limiting oral mucosal infection by C. albicans.

Oral mucosal colonization by (Ca) is benign in healthy people but progresses to deeper infection known as oropharyngeal candidiasis (OPC) that may become disseminated when combined with immunosuppression. Cortisone-induced immunosuppression is a well-known risk factor for OPC, however the mechanism by which it permits infection is poorly understood. Neutrophils are the primary early sentinels preventing invasive fungal growth, and here we identify that neutrophil functional complexes known as swarms are crucial for preventing Ca invasion which are disrupted by cortisone.

Sap6 Initiates Oral Mucosal Inflammation the Protease Activated Receptor PAR2.

Sap6, a secreted aspartyl protease (Sap), contributes to fungal virulence in oral candidiasis. Beside its protease activity, Sap6 contains RGD (RGDRGD) motif required for its binding to host integrins. Sap6 activates immune cells to induce proinflammatory cytokines, although its ability to interact and activate human oral epithelial cells (OECs) remain unknown.

A Novel Role for Histatin 5 in Combination with Zinc to Promote Commensalism in Survivor Cells.

is maintained as a commensal by immune mechanisms at the oral epithelia. Oral antifungal peptide Histatin 5 (Hst 5) may function in innate immunity, but the specific role Hst 5 plays in commensalism is unclear. Since Zn-binding potentiates the candidacidal activity of Hst 5, we hypothesized that Hst 5+Zn would elicit a unique fungal stress response to shape interactions between and oral epithelial cells (OECs).

Bacteria Modify Hypha Formation, Microcolony Properties, and Survival within Macrophages.

Phagocytic cells are crucial components of the innate immune system preventing mucosal infections. and often colonize mucosal sites, along with , and yet interkingdom interactions that might alter the survival and escape of fungi from macrophages are not understood. Murine macrophages were coinfected with or , along with to evaluate changes in fungal survival.

Zinc Binding by Histatin 5 Promotes Fungicidal Membrane Disruption in and .

Histatin 5 (Hst 5) is an antimicrobial peptide produced in human saliva with antifungal activity for opportunistic pathogen . Hst 5 binds to multiple cations including dimerization-inducing zinc (Zn), although the function of this capability is incompletely understood. Hst 5 is taken up by and acts on intracellular targets under metal-free conditions; however, Zn is abundant in saliva and may functionally affect Hst 5.

Sho1p Connects Glycolysis to Ras1-cAMP Signaling and Is Required for Microcolony Formation in Candida albicans.

is an opportunistic, dimorphic fungus that causes candidiasis in immunocompromised people. forms specialized structures called microcolonies that are important for surface adhesion and virulence. Microcolonies form in response to specific environmental conditions and require glycolytic substrates for optimal growth.

biofilm development is governed by cooperative attachment and adhesion maintenance proteins.

The opportunistic fungal pathogen is capable of adhering to the oral mucosa despite forces created by salivary flow. Although many fungal adhesion proteins have been identified, less is known about the temporal development of cell adhesion and biofilm growth in a flow environment. In this study, we use a flow system with real-time imaging of cells as they adhere and grow.

Filamentous Non- Species Adhere to and Benefit From Dual Biofilm Growth.

Non- species (NACS) are often isolated along with in cases of oropharyngeal candidiasis. readily forms biofilms in conjunction with other oral microbiota including both bacteria and yeast. Adhesion between species is important to the establishment of these mixed biofilms, but interactions between and many NACS are not well-characterized.

Aggregate Filamentous Growth Responses in Yeast.

Many fungal species, including pathogens, undergo a morphogenetic response called filamentous growth, where cells differentiate into a specialized cell type to promote nutrient foraging and surface colonization. Despite the fact that filamentous growth is required for virulence in some plant and animal pathogens, certain aspects of this behavior remain poorly understood. By examining filamentous growth in the budding yeast and the opportunistic pathogen , we identify responses where cells undergo filamentous growth in groups of cells or aggregates.

Iron Chelator Deferasirox Reduces Invasion of Oral Epithelial Cells and Infection Levels in Murine Oropharyngeal Candidiasis.

, the causative agent of mucosal infections, including oropharyngeal candidiasis (OPC), as well as bloodstream infections, is becoming increasingly resistant to existing treatment options. In the absence of novel drug candidates, drug repurposing aimed at using existing drugs to treat off-label diseases is a promising strategy. requires environmental iron for survival and virulence, while host nutritional immunity deploys iron-binding proteins to sequester iron and reduce fungal growth.

Real-time Imaging and Quantification of Fungal Biofilm Development Using a Two-Phase Recirculating Flow System.

In oropharyngeal candidiasis, members of the genus Candida must adhere to and grow on the oral mucosal surface while under the effects of salivary flow. While models for the growth under flow have been developed, many of these systems are expensive, or do not allow imaging while the cells are under flow. We have developed a novel apparatus that allows us to image the growth and development of Candida albicans cells under flow and in real-time.

Candida albicans Sfl1/Sfl2 regulatory network drives the formation of pathogenic microcolonies.

Candida albicans is an opportunistic fungal pathogen that can infect oral mucosal surfaces while being under continuous flow from saliva. Under specific conditions, C. albicans will form microcolonies that more closely resemble the biofilms formed in vivo than standard in vitro biofilm models.

Candida albicans Ras1 Inactivation Increases Resistance to Phagosomal Killing by Human Neutrophils.

Host phagocytic cells are crucial players in initial defense against infection. utilizes MAP kinases and Ras1 stress response signaling pathways to protect itself from killing by immune cells. In this study, we tested the importance of these pathways in phagocytosis by neutrophils and subsequent phagosomal survival.

Methodologies for and evaluation of efficacy of antifungal and antibiofilm agents and surface coatings against fungal biofilms.

Unlike superficial fungal infections of the skin and nails, which are the most common fungal diseases in humans, invasive fungal infections carry high morbidity and mortality, particularly those associated with biofilm formation on indwelling medical devices. Therapeutic management of these complex diseases is often complicated by the rise in resistance to the commonly used antifungal agents. Therefore, the availability of accurate susceptibility testing methods for determining antifungal resistance, as well as discovery of novel antifungal and antibiofilm agents, are key priorities in medical mycology research.

Salivary metals, age, and gender correlate with cultivable oral carriage levels.

: Little is known about the normal range of metal levels in unstimulated saliva, nor whether these might impact carriage in healthy individuals. Both are important in determining which populations are at risk for candidiasis, as the availability of metal ions can influence the growth and pathogenesis of . : We quantified salivary metals of healthy individuals to determine the correlation with oral colonization.

Real-Time Approach to Flow Cell Imaging of Candida albicans Biofilm Development.

The ability of to form biofilms is a virulence factor that allows tissue attachment and subsequent infection of host tissues. Fungal biofilms have been particularly well studied, however the vast majority of these studies have been conducted under static conditions. Oral biofilms form in the presence of salivary flow, therefore we developed a novel flow system used for real-time imaging of fungal biofilm development.

Fluconazole-Resistant Candida auris Is Susceptible to Salivary Histatin 5 Killing and to Intrinsic Host Defenses.

is a newly identified species causing invasive candidemia and candidiasis. It has broad multidrug resistance (MDR) not observed for other pathogenic species. Histatin 5 (Hst 5) is a well-studied salivary cationic peptide with significant antifungal activity against and is an attractive candidate for treating MDR fungi, since antimicrobial peptides induce minimal drug resistance.

An acquired mechanism of antifungal drug resistance simultaneously enables Candida albicans to escape from intrinsic host defenses.

The opportunistic fungal pathogen Candida albicans frequently produces genetically altered variants to adapt to environmental changes and new host niches in the course of its life-long association with the human host. Gain-of-function mutations in zinc cluster transcription factors, which result in the constitutive upregulation of their target genes, are a common cause of acquired resistance to the widely used antifungal drug fluconazole, especially during long-term therapy of oropharyngeal candidiasis. In this study, we investigated if C.

Candida albicans Sap6 amyloid regions function in cellular aggregation and zinc binding, and contribute to zinc acquisition.

Candida albicans is an opportunistic fungal pathogen colonizing the oral cavity. C. albicans secreted aspartic protease Sap6 is important for virulence during oral candidiasis since it degrades host tissues to release nutrients and essential transition metals.

Structural Characterization of Histatin 5-Spermidine Conjugates: A Combined Experimental and Theoretical Study.

Histatin 5 (Hst5) is a naturally occurring antimicrobial peptide that acts as the first line of defense against oral candidiasis. It has been shown that conjugation of the active Hst5 fragment, Hst5, and the polyamine spermidine (Spd) improves the candidacidal effect. Knowledge about the structure of these conjugates is, however, very limited.

Human Salivary Protein Histatin 5 Has Potent Bactericidal Activity against ESKAPE Pathogens.

ESKAPE (, , , , , and species) pathogens have characteristic multiple-drug resistance and cause an increasing number of nosocomial infections worldwide. Peptide-based therapeutics to treat ESKAPE infections might be an alternative to conventional antibiotics. Histatin 5 (Hst 5) is a salivary cationic histidine-rich peptide produced only in humans and higher primates.