Response of <i>Candida albicans</i> white and opaque cells to phagocytosis by macrophages suggests that opaque cells are “pre-adapted”

<i>Candida albicans</i> is a normal resident of the human gut and mucosal microbiomes and also an opportunistic fungal pathogen. It undergoes several morphological transitions, one of which is white-opaque switching, where <i>C. albicans</i> reversibly alternates between two distinct cell types, namely, "white" and "opaque." Each state, which is maintained by a complex transcriptional feedback loop, is heritable through many cell divisions. To date, most research works on interactions between <i>C. albicans</i> and the innate immune system have utilized white cells. In this paper, we examine the response of opaque cells following phagocytosis by murine macrophage cell lines and compare it to the response of white cells. White cells are known to rapidly form hyphae that can rupture macrophages, but we show here that opaque cells continue to proliferate as yeast-form opaque cells within the macrophage. Before phagocytosis, white and opaque cells differ markedly in the mRNAs they express and therefore enter macrophages as two distinct types of cells. We were surprised to observe that, within macrophages, the transcriptional profiles of white and opaque cells became much more similar to each other. This convergence was driven, in part, by the upregulation, in white cells, of a set of genes that were already expressed in opaque cells prior to macrophage exposure. These observations indicate that opaque cells, compared to white cells, are "pre-adapted" for life within host macrophages.IMPORTANCEThe human fungal pathogen <i>Candida albicans</i> undergoes several morphological transitions, one of which is white-opaque switching. Although most research works on interactions between <i>C. albicans</i> and the innate immune system have focused on white cells, opaque cells have been shown to interact with macrophages differently compared to white cells. In this study, we examine the transcriptional response of opaque cells to phagocytosis and compare it to that of white cells. Despite differences in how the two cell types proliferate following phagocytosis, their transcriptional responses strongly overlap, and fewer genes are differentially expressed between white and opaque cells following phagocytosis than observed in media lacking macrophages. Unexpectedly, the responses of both white and opaque cells favor genes that were already upregulated in opaque cells (relative to white cells) before exposure to macrophages; these observations suggest that opaque cells are "pre-adapted" for life within macrophages.