Genetic susceptibility to Candida infections

Abstract

Candida spp. are medically important fungi causing severe mucosal and life-threatening invasive infections, especially in immunocompromised hosts. However, not all individuals at risk develop Candida infections, and it is believed that genetic variation plays an important role in host susceptibility. On the one hand, severe fungal infections are associated with monogenic primary immunodeficiencies such as defects in STAT1, STAT3 or CARD9, recently discovered as novel clinical entities. On the other hand, more common polymorphisms in genes of the immune system have also been associated with fungal infections such as recurrent vulvovaginal candidiasis and candidemia. The discovery of the genetic susceptibility to Candida infections can lead to a better understanding of the pathogenesis of the disease, as well as to the design of novel immunotherapeutic strategies. This review is part of the review series on host-pathogen interactions. See more reviews from this series.

Figure 1. Schematic overview of the anti-Candida albicans immune response

When Candida is recognized by Toll-like receptors (TLRs) and C-type lectin receptors, the production of cytokines is initiated through activation of transcription factors like NF-κB. IL-1β and IL-18 first need to be cleaved by the NLRP3 inflammasome before they can be secreted. IL-2 is involved in the differentiation of all effector T-cells. The IL-2 receptor is highly expressed on regulatory T-cells (T_reg). IL-12 and IL-18 promote the differentiation of T helper 1 (Th1) cells, with IFN-γ being their main product. IL-4 and IL-10 promote the differentiation of Th2 cells, while IL-10 can also suppress Th1 cells. IL-1β, IL-6 and IL-23 drive the development of Th17 cells. DOCK8 is involved in the maintenance of Th17 cells. IL-17 promotes the recruitment of neutrophils, which have tissue protective effects by the production of beta-defensins. Cytokines are recognized by cytokine receptors, which use several adaptor molecules like STAT1, STAT3 and TYK2. PTPN22 is involved in B- and T-cell receptor signaling. Components with mutations and/or genetic variation known to be associated with Candida infection are shown in color. APC: antigen presenting cell, BCR: B-cell receptor, CARD9: caspase recruitment domain 9, DC-SIGN: dendritic cell-specific ICAM-grapping non-integrin, MBL: mannose binding lectin, MMR: macrophage mannose receptor, NLRP3: NACHT, LRR and PYD domains-containing protein 3, TCR: T-cell receptor, TLR: Toll-like receptor.