Background: Salivary histatin 5 (Hst 5) kills the fungal pathogen Candida albicans upon its internalization. Results: Hst 5 requires C. albicans polyamine transporters Dur3 and Dur31 for its uptake and toxicity. Conclusion: C. albicans Dur polyamine transporters recognize and internalize cationic peptides competitively with spermidine. Significance: Modification of Hsts based upon polyamine structure may improve targeting and fungicidal activity.
Candida albicans, a commensal fungus of the oral microbiome, causes oral candidiasis in humans with localized or systemic immune deficiencies. Secreted aspartic proteinases (Saps) are a family of 10 related proteases and are virulence factors due to their proteolytic activity, as well as their roles in adherence and colonization of host tissues. We found that mice infected sublingually with C. albicans cells overexpressing Sap6 (SAP6 OE and a ⌬sap8 strain) had thicker fungal plaques and more severe oral infection, while infection with the ⌬sap6 strain was attenuated. These hypervirulent strains had highly aggregative colony structure in vitro and higher secreted proteinase activity; however, the levels of proteinase activity of C. albicans Saps did not uniformly match their abilities to damage cultured oral epithelial cells (SCC-15 cells). Hyphal induction in cells overexpressing Sap6 (SAP6 OE and ⌬sap8 cells) resulted in formation of large cell-cell aggregates. These aggregates could be produced in germinated wild-type cells by addition of native or heat-inactivated Sap6. Sap6 bound only to germinated cells and increased C. albicans adhesion to oral epithelial cells. The adhesion properties of Sap6 were lost upon deletion of its integrin-binding motif (RGD) and could be inhibited by addition of RGD peptide or anti-integrin antibodies. Thus, Sap6 (but not Sap5) has an alternative novel function in cell-cell aggregation, independent of its proteinase activity, to promote infection and virulence in oral candidiasis. Candida albicans is a commensal fungus that is often part of the oral microflora of healthy people. Loss of host immunity, HIV infection, corticosteroid use, or alteration of the oral microflora following antibiotic therapies permits a pathogenic transition of C. albicans to cause oropharyngeal candidiasis (OPC) (1, 2). Acute pseudomembranous candidiasis is one of the most common forms of OPC, in which C. albicans forms white patches on the surface of the buccal mucosa, tongue, or soft palate. These superficial fungal plaques can be lifted from underlying tissues for purposes of clinical diagnosis and analysis (3).C. albicans expresses specific sets of virulence factors that promote hypha formation and adhesion and invasion of host tissues (4). Secreted aspartyl proteinases (Saps) are recognized virulence factors because they degrade host proteins to provide nitrogen for fungal cell metabolism, contribute to adherence, facilitate fungal epithelial and endothelial penetration, and are immunogenic during infection (5-7). Microbial proteinases are classified as serine, cysteine, metallo-, or aspartyl proteinases according to the site of catalytic hydrolysis of substrate peptide bonds; however, C. albicans produces only aspartyl proteinases (5, 6).C. albicans expresses a family of 10 SAP genes that are clustered into groups SAP1 to SAP3, SAP4 to SAP6, SAP7, SAP8, and SAP9 and SAP10 based upon their sequence homologies and pH activities (8, 9). Sap1 through Sap8 are processed and transported via the secreto...
SUMMARY Human oligodendrocyte progenitor cells (hOPCs) persist into adulthood as an abundant precursor population capable of division and differentiation. The transcriptional mechanisms that regulate hOPC homeostasis remain poorly defined. Herein, we identify paired related homeobox protein 1 (PRRX1) in primary PDGFαR+ hOPCs. We show that enforced PRRX1 expression results in reversible G1/0 arrest. While both PRRX1 splice variants reduce hOPC proliferation, only PRRX1a abrogates migration. hOPC engraftment into hypomyelinated shiverer/rag2 mouse brain is severely impaired by PRRX1a, characterized by reduced cell proliferation and migration. PRRX1 induces a gene expression signature characteristic of stem cell quiescence. Both IFN-γ and BMP signaling upregulate PRRX1 and induce quiescence. PRRX1 knockdown modulates IFN-γ-induced quiescence. In mouse brain, PRRX1 mRNA was detected in non-dividing OPCs and is upregulated in OPCs following demyelination. Together, these data identify PRRX1 as a regulator of quiescence in hOPCs and as a potential regulator of pathological quiescence.
Summary Temperature is a potent inducer of fungal dimorphism. Multiple signalling pathways control the response to growth at high temperature, but the sensors that regulate these pathways are poorly defined. We show here that the signalling mucin Msb2 is a global regulator of temperature stress in the fungal pathogen Candida albicans. Msb2 was required for survival and hyphae formation at 42°C. The cytoplasmic signalling domain of Msb2 regulated temperature-dependent activation of the CEK mitogen activated proteins kinase (MAPK) pathway. The extracellular glycosylated domain of Msb2 (100–900 amino acid residues) had a new and unexpected role in regulating the protein kinase C (PKC) pathway. Msb2 also regulated temperature-dependent induction of genes encoding regulators and targets of the unfolded protein response (UPR), which is a protein quality control (QC) pathway in the endoplasmic reticulum that controls protein folding/degradation in response to high temperature and other stresses. The heat shock protein and cell wall component Ssa1 was also required for hyphae formation and survival at 42° C and regulated the CEK and PKC pathways.
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. We found that zinc specifically increased C. albicans autoaggregation induced by Sap6; and that Sap6 itself bound zinc ions. In silico analysis of Sap6 predicted four amyloidogenic regions that were synthesized as peptides (P1–P4). All peptides, as well as full length Sap6, demonstrated amyloid properties, and addition of zinc further increased amyloid formation. Disruption of amyloid regions by Congo red significantly reduced auotoaggregation. Deletion of C. albicans genes that control zinc acquisition in the ZAP1 regulon, including zinc transporters (Pra1 and Zrt1) and other zinc-regulated surface proteins, resulted in lower autoaggregation and reduction of surface binding of Sap6. Cells with high expression of PRA1 and ZRT1 also showed increased Sap6-mediated autoaggregation. C. albicans ∆sap6 deletion mutants failed to accumulate intracellular zinc comparable to ∆zap1, ∆zrt1, and ∆pra1 cells. Thus Sap6 is a multi-functional molecule containing amyloid regions that promotes autoaggregation and zinc uptake, and may serve as an additional system for the community acquisition of zinc.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.