N-cadherin mediates endocytosis of Candida albicans by endothelial cells

University of California, Los Angeles, Los Ángeles, California, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2005; 280(11):10455-61. DOI: 10.1074/jbc.M412592200
Source: PubMed


Candida albicans is the most common cause of fungal bloodstream infections. To invade the deep tissues, blood-borne organisms must cross the endothelial cell lining of the vasculature. We have found previously that C. albicans hyphae, but not blastospores, invade endothelial cells in vitro by inducing their own endocytosis. Therefore, we set out to identify the endothelial cell receptor that mediates the endocytosis of C. albicans. We determined that endocytosis of C. albicans was not mediated by bridging molecules in the serum and that it was partially dependent on the presence of extracellular calcium. Using an affinity purification procedure, we discovered that endothelial cell N-cadherin bound to C. albicans hyphae but not blastospores. N-cadherin also co-localized with C. albicans hyphae that were being endocytosed by endothelial cells. Chinese hamster ovary (CHO) cells expressing human N-cadherin endocytosed significantly more C. albicans hyphae than did CHO cells expressing either human VE-cadherin or no human cadherins. The expression of N-cadherin by the CHO cells resulted in enhanced endocytosis of hyphae, but not blastospores, indicating the selectivity of the N-cadherin-mediated endocytosis. Down-regulation of endothelial cell N-cadherin expression with small interfering RNA significantly inhibited the endocytosis of C. albicans hyphae. Therefore, a novel function of N-cadherin is that it serves as an endothelial cell receptor, which mediates the endocytosis of C. albicans.

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    • "Collectively, these results demonstrate the key role of PDGFRB signaling in the endocytosis of C. albicans. E-cadherin and N-cadherin function as host cell receptors for C. albicans and are required for efficient endocytosis by host cells into epithelial and endothelial cells, respectively (Phan et al. 2005, 2007). We tested whether the decrease in endocytosis that we observe by knockdown of PDGFRB or NEDD9 could be simply the result of reduced expression of the cadherins. "
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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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    • "Such interactions may also inhibit the interaction between invasins and host cell receptors required to induce endocytosis. Thus, in agreement with the study of Phan et al. (2005), which demonstrated inhibition of endocytosis by serum, it would appear unlikely that serum components act as bridging molecules during interactions with epithelial cells [30]. However, we only observed reduced invasiveness upon treatment with human serum, indicating that invasion-inhibitory factors are host specific and not found in bovine serum. "
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    ABSTRACT: Candida albicans frequently causes superficial infections by invading and damaging epithelial cells, but may also cause systemic infections by penetrating through epithelial barriers. C. albicans is a remarkable pathogen because it can invade epithelial cells via two distinct mechanisms: induced endocytosis, analogous to facultative intracellular enteropathogenic bacteria, and active penetration, similar to plant pathogenic fungi. Here we investigated the contributions of the two invasion routes of C. albicans to epithelial invasion. Using selective cellular inhibition approaches and differential fluorescence microscopy, we demonstrate that induced endocytosis contributes considerably to the early time points of invasion, while active penetration represents the dominant epithelial invasion route. Although induced endocytosis depends mainly on Als3-E-cadherin interactions, we observed E-cadherin independent induced endocytosis. Finally, we provide evidence of a protective role for serum factors in oral infection: human serum strongly inhibited C. albicans adhesion to, invasion and damage of oral epithelial cells.
    PLoS ONE 05/2012; 7(5):e36952. DOI:10.1371/journal.pone.0036952 · 3.23 Impact Factor
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    • "At present it is obvious that Toll-like receptors 2 and 4 and other receptors present on the surface of human immune cells, such as monocytes, macrophages and dendritic cells, are involved in these interactions. Probably some proteins present on the surface of epithelial or endothelial cells, for example N-cadherin, are important for binding of different morphological forms of C. albicans cells, followed by their endocytosis (Phan et al., 2005; Filler, 2006). Due to the ability to bind and invade human endothelial cells C. albicans can traverse the human blood-brain barrier and cause life-threatening meningitis (Jong et al., 2001). "
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    ABSTRACT: The frequency of severe systemic fungal diseases has increased in the last few decades. The clinical use of antibacterial drugs, immunosuppressive agents after organ transplantation, cancer chemotherapy, and advances in surgery are associated with increasing risk of fungal infections. Opportunistic pathogens from the genera Candida and Aspergillus as well as pathogenic fungi from the genus Cryptococcus can invade human organism and may lead to mucosal and skin infections or to deep-seated mycoses of almost all inner organs, especially in immunocompromised patients. Nowadays, there are some effective antifungal agents, but, unfortunately, some of the pathogenic species show increasing resistance. The identification of fungal virulence factors and recognition of mechanisms of pathogenesis may lead to development of new efficient antifungal therapies. This review is focused on major virulence factors of the most common fungal pathogens of humans: Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans. The adherence to host cells and tissues, secretion of hydrolytic enzymes, phenotypic switching and morphological dimorphism contribute to C. albicans virulence. The ability to grow at 37 degrees C, capsule synthesis and melanin formation are important virulence factors of C. neoformans. The putative virulence factors of A. fumigatus include production of pigments, adhesion molecules present on the cell surface and secretion of hydrolytic enzymes and toxins.
    Acta biochimica Polonica 07/2009; 56(2):211-24. · 1.15 Impact Factor
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