Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells

Abstract

Candida albicans is the most common cause of hematogenously disseminated and oropharyngeal candidiasis. Both of these diseases are characterized by fungal invasion of host cells. Previously, we have found that C. albicans hyphae invade endothelial cells and oral epithelial cells in vitro by inducing their own endocytosis. Therefore, we set out to identify the fungal surface protein and host cell receptors that mediate this process. We found that the C. albicans Als3 is required for the organism to be endocytosed by human umbilical vein endothelial cells and two different human oral epithelial lines. Affinity purification experiments with wild-type and an als3Δ/als3Δ mutant strain of C. albicans demonstrated that Als3 was required for C. albicans to bind to multiple host cell surface proteins, including N-cadherin on endothelial cells and E-cadherin on oral epithelial cells. Furthermore, latex beads coated with the recombinant N-terminal portion of Als3 were endocytosed by Chinese hamster ovary cells expressing human N-cadherin or E-cadherin, whereas control beads coated with bovine serum albumin were not. Molecular modeling of the interactions of the N-terminal region of Als3 with the ectodomains of N-cadherin and E-cadherin indicated that the binding parameters of Als3 to either cadherin are similar to those of cadherin–cadherin binding. Therefore, Als3 is a fungal invasin that mimics host cell cadherins and induces endocytosis by binding to N-cadherin on endothelial cells and E-cadherin on oral epithelial cells. These results uncover the first known fungal invasin and provide evidence that C. albicans Als3 is a molecular mimic of human cadherins.

Candida albicansdimorphism as a therapeutic target

“…Induced endocytosis is a host-driven process triggered predominantly by interaction between the C. albicans invasin, Als3, and host E-cadherin. This process results in clathrindependent uptake, similar to the internalin-E-cadherin dependent internalization of Listeria monocytogenes [36,41,42]. Under standard laboratory growth conditions, Als3 is expressed on hyphal, but not yeast cell surfaces [43].…”

“…Under standard laboratory growth conditions, Als3 is expressed on hyphal, but not yeast cell surfaces [43]. Consequently, only hyphal cells were observed to be endocytosed by epithelial and endothelial cells [36,41].…”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…Als3 and Ssa1 on the surface of C. albicans hyphae bind to Ncadherin and other receptors on the surface of endothelial cell, which mediates the endocytosis. [98][99][100] In contrast to the ALS proteins and endocytosis, the interaction between C. albicans PAMPs and PRRs on endothelial cells was rarely investigated. A study revealed that C. albicans triggers proinflammatory gene expression in primary human endothelial cells through TLR3 signaling, NF-kB, and p38 MAPK pathways in response to C. albicans invasion.…”

PI3-kinase activation is critical for host barrier permissiveness to Listeria monocytogenes

“…As an example, Candida albicans may cross the intestinal barrier in an Als3-Ecad-dependent manner, leading to a systemic infection (Phan et al, 2007), but it has not been described to breach the placental barrier. This indicates that targeting of Ecad alone is not sufficient to promote placental invasion, and that C. albicans is likely missing an effector inducing PI3-K signaling at the placental barrier, as does Lm.…”