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Candida albicans internalization by host cells is mediated by a clathrin-dependent mechanism.

ABSTRACT: Candida albicans is a major cause of oropharyngeal, vulvovaginal and haematogenously disseminated candidiasis. Endocytosis of C. albicans hyphae by host cells is a prerequisite for tissue invasion. This internalization involves interactions between the fungal invasin Als3 and host E- or N-cadherin. Als3 shares some structural similarity with InlA, a major invasion protein of the bacterium Listeria monocytogenes. InlA mediates entry of L. monocytogenes into host cells through binding to E-cadherin. A role in internalization, for a non-classical stimulation of the clathrin-dependent endocytosis machinery, was recently highlighted. Based on the similarities between the C. albicans and L. monocytogenes invasion proteins, we studied the role of clathrin in the internalization of C. albicans. Using live-cell imaging and indirect immunofluorescence of epithelial cells infected with C. albicans, we observed that host E-cadherin, clathrin, dynamin and cortactin accumulated at sites of C. albicans internalization. Similarly, in endothelial cells, host N-cadherin, clathrin and cortactin accumulated at sites of fungal endocytosis. Furthermore, clathrin, dynamin or cortactin depletion strongly inhibited C. albicans internalization by epithelial cells. Finally, beads coated with Als3 were internalized in a clathrin-dependent manner. These data indicate that C. albicans, like L. monocytogenes, hijacks the clathrin-dependent endocytic machinery to invade host cells.

SUBMITTER: Moreno-Ruiz E

PROVIDER: S-EPMC4098847 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Candida albicans internalization by host cells is mediated by a clathrin-dependent mechanism.

Moreno-Ruiz Emilia E Galán-Díez Marta M Zhu Weidong W Fernández-Ruiz Elena E d'Enfert Christophe C Filler Scott G SG Cossart Pascale P Veiga Esteban E

Cellular microbiology 20090331 8

Candida albicans is a major cause of oropharyngeal, vulvovaginal and haematogenously disseminated candidiasis. Endocytosis of C. albicans hyphae by host cells is a prerequisite for tissue invasion. This internalization involves interactions between the fungal invasin Als3 and host E- or N-cadherin. Als3 shares some structural similarity with InlA, a major invasion protein of the bacterium Listeria monocytogenes. InlA mediates entry of L. monocytogenes into host cells through binding to E-cadheri ...[more]

PMID: 19416270

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Project description:UnlabelledClathrin-mediated endocytosis (CME) is conserved among eukaryotes and has been extensively analyzed at a molecular level. Here, we present an analysis of CME in the human fungal pathogen Candida albicans that shows the same modular structure as those in other fungi and mammalian cells. Intriguingly, C. albicans is perfectly viable in the absence of Arp2/3, an essential component of CME in other systems. In C. albicans, Arp2/3 function remains essential for CME as all 15 proteins tested that participate in CME, including clathrin, lose their characteristic dynamics observed in wild-type (WT) cells. However, since arp2/3 cells are still able to endocytose lipids and fluid-phase markers, but not the Ste2 and Mup1 plasma membrane proteins, there must be an alternate clathrin-independent pathway we term Arp2/3-independent endocytosis (AIE). Characterization of AIE shows that endocytosis in arp2 mutants relies on actin cables and other Arp2/3-independent actin structures, as inhibition of actin functions prevented cargo uptake in arp2/3 mutants. Transmission electron microscopy (TEM) showed that arp2/3 mutants still formed invaginating tubules, cell structures whose proper functions are believed to heavily rely on Arp2/3. Finally, Prk1 and Sjl2, two proteins involved in patch disassembly during CME, were not correctly localized to sites of endocytosis in arp2 mutants, implying a role of Arp2/3 in CME patch disassembly. Overall, C. albicans contains an alternative endocytic pathway (AIE) that relies on actin cable function to permit clathrin-independent endocytosis (CIE) and provides a system to further explore alternate endocytic routes that likely exist in fungal species.ImportanceThere is a well-established process of endocytosis that is generally used by eukaryotic cells termed clathrin-mediated endocytosis (CME). Although the details are somewhat different between lower and higher eukaryotes, CME appears to be the dominant endocytic process in all eukaryotes. While fungi such as Saccharomyces cerevisiae have proven excellent models for dissecting the molecular details of endocytosis, loss of CME is so detrimental that it has been difficult to study alternate pathways functioning in its absence. Although the fungal pathogen Candida albicans has a CME pathway that functions similarly to that of S. cerevisiae, inactivation of this pathway does not compromise growth of yeast-form C. albicans. In these cells, lipids and fluid-phase molecules are still endocytosed in an actin-dependent manner, but membrane proteins are not. Thus, C. albicans provides a powerful model for the analysis of CME-independent endocytosis in lower eukaryotes.

Project description:UnlabelledTo understand differences in host-Candida albicans interactions that occur during colonization of healthy or compromised hosts, production of phenotypic variants and colonization of healthy or immunodeficient mice by C. albicans were studied. We showed that activity of the transcription factor Efg1p exhibited cell-to-cell variability and identified Efg1p as a major regulator of colonization. In C. albicans populations colonizing the murine gastrointestinal tract, average expression of EFG1 differed depending on the immune status of the host. We propose that cellular heterogeneity in Efg1p activity allows the C. albicans colonizing population to differ depending on the immune status of the host, because selective pressure from a healthy host alters the composition of the population. These data are the first demonstration that differences in host immune status are associated with differences in gene expression in colonizing C. albicans cells. Altered gene expression in organisms colonizing immunocompromised hosts may begin the transition of C. albicans from a commensal to a pathogen.ImportanceIn healthy people, the fungus Candida albicans colonizes the gastrointestinal tract and other sites without producing obvious pathology. In an immunocompromised patient, the organism can cause serious disease. The demonstration that the expression and activity of the C. albicans transcription factor Efg1p differs during colonization of healthy or immunocompromised mice shows that the organism adjusts its physiology when colonizing different hosts. Further, the effects of a healthy host on a heterogeneous C. albicans population containing cells with different levels of Efg1p activity show that selective pressure in the host can change the makeup of the population, allowing the population to respond to host immune status. The ability to sense host status may be key to the ability of C. albicans to colonize as a harmless commensal in some hosts but become a deadly pathogen in others.

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Candida albicans internalization by host cells is mediated by a clathrin-dependent mechanism.

Publications

Candida albicans internalization by host cells is mediated by a clathrin-dependent mechanism.

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