Host Cell Invasion and Virulence Mediated by Candida albicans Ssa1

University of Massachusetts Medical School, United States of America
PLoS Pathogens (Impact Factor: 7.56). 11/2010; 6(11):e1001181. DOI: 10.1371/journal.ppat.1001181
Source: PubMed


Candida albicans Ssa1 and Ssa2 are members of the HSP70 family of heat shock proteins that are expressed on the cell surface and function as receptors for antimicrobial peptides such as histatins. We investigated the role of Ssa1 and Ssa2 in mediating pathogenic host cell interactions and virulence. A C. albicans ssa1Δ/Δ mutant had attenuated virulence in murine models of disseminated and oropharyngeal candidiasis, whereas an ssa2Δ/Δ mutant did not. In vitro studies revealed that the ssa1Δ/Δ mutant caused markedly less damage to endothelial cells and oral epithelial cell lines. Also, the ssa1Δ/Δ mutant had defective binding to endothelial cell N-cadherin and epithelial cell E-cadherin, receptors that mediate host cell endocytosis of C. albicans. As a result, this mutant had impaired capacity to induce its own endocytosis by endothelial cells and oral epithelial cells. Latex beads coated with recombinant Ssa1 were avidly endocytosed by both endothelial cells and oral epithelial cells, demonstrating that Ssa1 is sufficient to induce host cell endocytosis. These results indicate that Ssa1 is a novel invasin that binds to host cell cadherins, induces host cell endocytosis, and is critical for C. albicans to cause maximal damage to host cells and induce disseminated and oropharyngeal disease.

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    • "The observation that invasion-defective C. albicans mutants display attenuated virulence in murine models of OPC and HDC is evidence of the critical importance of invasion to virulence (Phan et al. 2000; Sanchez et al. 2004; Park et al. 2005; Chiang et al. 2007). Invasion into both cell types occurs in part by endocytosis, which is induced when the C. albicans invasins Als3p and Ssa1p interact with receptors expressed on the surface of endothelial and epithelial cells (Phan et al. 2007; Sun et al. 2010). These receptors include N-and E-cadherin, HSP90B1, the epidermal growth factor receptor (EGFR), and ERBB2 (also known as HER2) (Phan et al. 2005, 2007; Liu et al. 2011; Zhu et al. 2012). "
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    ABSTRACT: Candida albicans, the major invasive fungal pathogen of humans, can cause both debilitating mucosal infections and fatal invasive infections. Understanding the complex nature of the host-pathogen interaction in each of these contexts is essential to developing desperately needed therapies to treat fungal infections. RNA-seq enables a systems-level understanding of infection by facilitating comprehensive analysis of transcriptomes from multiple species (e.g., host and pathogen) simultaneously. We used RNA-seq to characterize the transcriptomes of both C. albicans and human endothelial cells or oral epithelial cells during in vitro infection. Network analysis of the differentially expressed genes identified the activation of several signaling pathways that have not previously been associated with the host response to fungal pathogens. Using an siRNA knockdown approach, we demonstrate that two of these pathways-platelet-derived growth factor BB (PDGF BB) and neural precursor-cell-expressed developmentally down-regulated protein 9 (NEDD9)-govern the host-pathogen interaction by regulating the uptake of C. albicans by host cells. Using RNA-seq analysis of a mouse model of hematogenously disseminated candidiasis (HDC) and episodes of vulvovaginal candidiasis (VVC) in humans, we found evidence that many of the same signaling pathways are activated during mucosal (VVC) and/or disseminated (HDC) infections in vivo. Our analyses have uncovered several signaling pathways at the interface between C. albicans and host cells in various contexts of infection, and suggest that PDGF BB and NEDD9 play important roles in this interaction. In addition, these data provide a valuable community resource for better understanding host-fungal pathogen interactions.
    Genome Research 05/2015; 25(5). DOI:10.1101/gr.187427.114 · 14.63 Impact Factor
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    • "C. albicans uses several surface proteins to contact human endothelial cells. In addition to Gpm1 candida also uses Als3 and Ssa1 for interaction with human endothelial cells [47], [48], [49]. Thus candida apparently uses a combination of fungal adhesions proteins that aid in attachment, and in combination with acquired and endogenous proteases aid in destruction of endothelial barriers [50], [51], [52]. "
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    PLoS ONE 03/2014; 9(3):e90796. DOI:10.1371/journal.pone.0090796 · 3.23 Impact Factor
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    • "The virulence of the various strains was analyzed in the mouse model of hematogenously disseminated candidiasis as described previously (Sanchez et al., 2004; Sun et al., 2010). Briefly, eight male ICR mice (Taconic Farms) per strain were injected with 7.5 3 10 5 organisms via the lateral tail vein. "
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