Iron alters the cell wall composition and intracellular lactate to affect Candida albicans susceptibility to antifungals and host immune response

Abstract

Fungal pathogen <i>Candida albicans</i> has a complex cell wall consisting of an outer layer of mannans and an inner layer of β-glucans and chitin. The fungal cell wall is the primary target for antifungals and is recognized by host immune cells. Environmental conditions such as carbon sources, pH, temperature, and oxygen tension can modulate the fungal cell wall architecture. Cellular signaling pathways, including the mitogen-activated protein kinase (MAPK) pathways, are responsible for sensing environmental cues and mediating cell wall alterations. Although iron has recently been shown to affect β-1,3-glucan exposure on the cell wall, we report here that iron changes the composition of all major <i>C. albicans</i> cell wall components. Specifically, high iron decreased the levels of mannans (including phosphomannans) and chitin; and increased β-1,3-glucan levels. These changes increased the resistance of <i>C. albicans</i> to cell wall-perturbing antifungals. Moreover, high iron cells exhibited adequate mitochondrial functioning; leading to a reduction in accumulation of lactate that signals through the transcription factor Crz1 to induce β-1,3-glucan masking in <i>C. albicans</i> We show here that iron-induced changes in β-1,3-glucan exposure are lactate-dependent; and high iron causes β-1,3-glucan exposure by preventing lactate-induced, Crz1-mediated inhibition of activation of the fungal MAPK Cek1. Furthermore, despite exhibiting enhanced antifungal resistance, high iron <i>C. albicans</i> cells had reduced survival upon phagocytosis by macrophages. Our results underscore the role of iron as an environmental signal in multiple signaling pathways that alter cell wall architecture in <i>C. albicans</i>, thereby affecting its survival upon exposure to antifungals and host immune response.