Patient Susceptibility to Candidiasis-A Potential for Adjunctive Immunotherapy

Abstract

Candida spp. are colonizing fungi of human skin and mucosae of the gastrointestinal and genitourinary tract, present in 30-50% of healthy individuals in a population at any given moment. The host defense mechanisms prevent this commensal fungus from invading and causing disease. Loss of skin or mucosal barrier function, microbiome imbalances, or defects of immune defense mechanisms can lead to an increased susceptibility to severe mucocutaneous or invasive candidiasis. A comprehensive understanding of the immune defense against Candida is essential for developing adjunctive immunotherapy. The important role of underlying genetic susceptibility to Candida infections has become apparent over the years. In most patients, the cause of increased susceptibility to fungal infections is complex, based on a combination of immune regulation gene polymorphisms together with other non-genetic predisposing factors. Identification of patients with an underlying genetic predisposition could help determine which patients could benefit from prophylactic antifungal treatment or adjunctive immunotherapy. This review will provide an overview of patient susceptibility to mucocutaneous and invasive candidiasis and the potential for adjunctive immunotherapy.

Keywords: candidemia; chronic mucocutaneous candidiasis (CMC); genetic predisposition; hyper IgE syndrome; immune defense; immunotherapy; invasive candidiasis; mucocutaneous candidiasis; patient susceptibility.

Figure 1

Recognition of Candida species by innate immune cells. Ligand binding to extracellular Toll-like receptors (TLRs), such as TLR2 and TLR4, leads to the production of pro-inflammatory cytokines during Candida infections. The intracellular TLRs that recognize nucleic acids—namely, TLR3 and TLR9—might also have a role in anti-Candida host responses. Chitin from C. albicans has been proposed to induce the production of interleukin-10 (IL-10) via a nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-dependent mechanism and in this way may contribute to dampening pro-inflammatory host responses during fungal infection. The pattern recognition receptors (PRRs) dectin 1, dectin 2 and dectin 3, and Fc receptors for IgG (FcγRs), induce responses in a spleen tyrosine kinase (SYK)-dependent manner, whereas the signalling pathways engaged by the mannose receptor remain unknown. Dectin 1 can interact with TLR2 and can induce intracellular signalling via SYK- and RAF proto-oncogene serine/threonine-protein kinase (RAF1)-dependent pathways. Complement receptor 3 (CR3) is important for the recognition of unopsonized Candida, whereas FcγRs are important for recognition of opsonized Candida by neutrophils. Dendritic cell (DC)-specific -ICAM3-grabbing non-integrin (DC-SIGN) recognizes N-linked mannans of Candida and has a role in inducing T helper (TH) cell responses. There is no known Candida-derived ligand that triggers the macrophage-inducible C-type lectin receptor (MINCLE), whereas β-mannans from Candida are recognized by galectin 3. Although a role for melanoma differentiation-associated protein 5 (MDA5) in anti-Candida host responses has been described, it remains to be determined what ligand induces MDA5 activation. Together, these signalling pathways induce the secretion of cytokines and chemokines and initiate phagocytosis to clear Candida infections. CARD9, caspase activation and recruitment domain-containing 9; C. glabrata, Candida glabrata; NF-κB, nuclear factor-κB; PAMP, pathogen-associated molecular pattern; PKCδ, protein kinase Cδ; ROS, reactive oxygen species.