Skin Immunity to Candida albicans

Abstract

Candida albicans is a dimorphic commensal fungus that colonizes healthy human skin, mucosa, and the reproductive tract. C. albicans is also a predominantly opportunistic fungal pathogen, leading to disease manifestations such as disseminated candidiasis and chronic mucocutaneous candidiasis (CMC). The differing host susceptibilities for the sites of C. albicans infection have revealed tissue compartmentalization with tailoring of immune responses based on the site of infection. Furthermore, extensive studies of host genetics in rare cases of CMC have identified conserved genetic pathways involved in immune recognition and the response to the extracellular pathogen. We focus here on human and mouse skin as a site of C. albicans infection, and we review established and newly discovered insights into the cellular pathways that promote cutaneous antifungal immunity.

Figure 1. Innate immunity against C. albicans skin infection

The skin has a layered innate immune system. C. albicans directly activates cutaneous sensory nerves to induce the release of calcitonin gene related peptide (CGRP). CGRP acts on CD301b+ dermal dendritic cells (dDC), which subsequently release IL-23. IL-23 acts on dermal γδ T cells to drive IL-17 production in the skin, leading to anti-C. albicans resistance through the presumed activation of neutrophils and antimicrobial peptides such as β-defensins[14]. In addition, melanocytes in the basal epidermis can also recognize C. albicans via TLR-4 to drive production and release of melanin granules, which are antimicrobial in nature[52]. Finally, Langerhans cells of the epidermis can suppress liver derived CD49a+ NK cells in response to C. albicans through unknown mechanisms[73].

Figure 2. Adaptive immunity against C. albicans skin infection

The skin generates heterogeneous T helper response that provides compartmentalized immunity against C. albicans. In the epidermis, C. albicans exists as yeasts. C. albicans yeasts are recognized by Dectin-1 on Langerhans cells (LCs). Dectin-1 engagement on LCs lead to production of IL-6 in the secondary lymphoid organs that differentiate naïve CD4+ T cells to the Th17 cell lineage. These Th17 cells provide protection against secondary cutaneous infections but not against secondary systemic infections. Conversely, C. albicans invades as filamentous pseudohyphae in the dermis. Recognition of C. albicans filaments by CD103+ dDCs, presumably through TLR-2, lead to Th1 cell differentiation in the secondary lymphoid organs. These Th1 cells provide protection against secondary systemic infections but not secondary skin infection[5,12]. Thus, recognition of distinct morphology of C. albicans via different dendritic cell subsets lead to tailored immune response that provide protect against specific subsequent routes of infections.