The Candida glabrata adhesin Epa1p causes adhesion, phagocytosis, and cytokine secretion by innate immune cells.
While Candida albicans is the most significant fungal pathogen for humans, Candida glabrata accounts for an increasing number of infections. Little is known about how C. glabrata interacts with the innate immune system, the first line of defense against such organisms. The C. glabrata adhesin Epa1p was previously shown to bind mammalian epithelial cells. We hypothesized that Epa1p mediates unique, nonopsonic binding to macrophages, leading to induction of immune responses. We found that Epa1p mediated adhesion by both C. glabrata (Cg) and transformed Saccharomyces cerevisiae (Sc(EPA1) ) to human macrophage-like cells, including Thp1 and U937 lines, and donor PBMCs. Adhesion was distinct from described mechanisms such as Dectin-1. Epa1p expression was necessary and sufficient for S. cerevisiae binding and phagocytosis, the latter of which was actin-mediated. Sc(EPA1)  induced inflammatory cytokine production (IL-8 and TNF-α) by human PBMC-derived macrophages. Despite expressing Epa1p and binding to macrophages, Cg avoided phagocytosis and cytokine induction. In contrast to human results, in murine cell models (RAW264.7, J774A.1, and C57BL/6-derived cells), Epa1p-mediated binding was only revealed after blocking the Dectin-1 system. Recognition of Epa1p represents a novel mechanism by which human innate immune cells bind fungi, and for Sc(EPA1)  results in phagocytosis and subsequent cytokine production.
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02139, USA. dukuhn@challiance.org
Duncan M
DM
Kuhn
Valmik K
VK
Vyas
D000818:Animals; D041221:Candida glabrata / Q000276:immunology*; D002448:Cell Adhesion; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005656:Fungal Proteins / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D037102:Lectins / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D010587:Phagocytosis; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000276:immunology; D014170:Transformation, Genetic
D016207:Cytokines; D005656:Fungal Proteins; D037102:Lectins; C120505:epithelial adhesin 1, Candida glabrata