Candida albicansYeast and Germ Tube Forms Interfere Differently with Human Monocyte Differentiation into Dendritic Cells: a Novel Dimorphism-Dependent Mechanism To Escape the Host's Immune Response

Abstract

The ability of Candida albicans to convert from the yeast (Y) form to mycelial forms through germ tube (GT) formation is considered a key feature of the transition of the organism from commensalism to virulence. We show here that human monocytes cultured with granulocyte-macrophage colony-stimulating factor and interleukin-4 (IL-4) after phagocytosis of Y forms did not differentiate into dendritic cells (DCs); they retained CD14, did not acquire CD1a, and were unable to express the maturation markers CD83 and CCR7. Moreover, they did not produce IL-12p70 but secreted IL-10. In addition, they spontaneously expressed high levels of tumor necrosis factor alpha (TNF-␣), IL-6, and IL-8 mRNA transcripts and were able to induce proliferation of alloreactive memory but not naïve T lymphocytes. Conversely, monocytes that had phagocytosed GT forms differentiated into mature CD83 ؉ and CCR7 ؉ DCs; however, there was no up-regulation of CD40, CD80, and major histocompatibility complex class II, irrespective of lipopolysaccharide (LPS) treatment. In addition, these cells were unable to produce IL-12 even after LPS stimulation, but they were not functionally exhausted, as shown by their capacity to express TNF-␣ and IL-8 mRNA transcripts. These cells were able to prime naïve T cells but not to induce their functional polarization into effector cells. These data indicate that phagocytosis of Y and GT forms has profound and distinct effects on the differentiation pathway of monocytes. Thus, the differentiation of human monocytes into DCs appears to be tunable and exploitable by C. albicans to elude immune surveillance.

Interaction ofCandida albicanswith Adherent Human Peripheral Blood Mononuclear Cells IncreasesC. albicansBiofilm Formation and Results in Differential Expression of Pro- and Anti-Inflammatory Cytokines

“…This response is similar to our findings, in which up-regulated hypha formation associated with mature biofilm formation did not result in any change in IFN-␥ level. Similar results were also reported for interactions between dendritic cells and C. albicans yeast and hyphae (13) and the role of C. albicans in the differentiation of monocytes to dendritic cells (41).…”

Candida albicans Dampens Host Defense by Downregulating IL-17 Production

“…In our present study, we found that when live C. albicans was cultured in direct contact with PBMCs at a dose lower than 10 4 /ml, most live C. albicans could be phagocytosed and killed by monocytic phagocytes. However, when live C. albicans was cultured with a concentration higher than 10 5 /ml, C. albicans could escape monocytic phagocytes (28) and form a big hyphae clumping within the culture well, accompanied by increasing cell death through trypan blue staining. To bypass this hurdle, we have successfully adopted a transwell system to avoid the direct contact between live C. albicans and PBMCs and demonstrated that soluble factors released by C. albicans actively modulated cytokine profiles induced by heat-killed C. albicans in PBMCs within 24 h of coculturing (19).…”

Adaptive immune responses toCandida albicansinfection

“…Monocytes that phagocytose C. albicans yeast cells or germ tubes were unable to differentiate into DCs, and internalisation of germ tubes was reported to render cells incapable of inducing Th polarization. 78 Further, the yeast and hyphal forms of C. albicans exert opposing effects on DCs, skewing Th polarization induced both in vitro and in vivo. 79,80 Such a polarization of the cytokine response may function to subvert Th subset differentiation to those which enable fungal persistence within the host.…”