A Candida albicans Strain Expressing Mammalian Interleukin-17A Results in Early Control of Fungal Growth during Disseminated Infection

Abstract

dCandida albicans is normally a commensal fungus of the human mucosae and skin, but it causes life-threatening systemic infections in hospital settings in the face of predisposing conditions, such as indwelling catheters, abdominal surgery, or antibiotic use. Immunity to C. albicans involves various immune parameters, but the cytokine interleukin-17A (IL-17A) (also known as IL-17) has emerged as a centrally important mediator of immune defense against both mucosal and systemic candidiasis. Conversely, IL-17A has been suggested to enhance the virulence of C. albicans, indicating that it may exert detrimental effects on pathogenesis. In this study, we hypothesized that a C. albicans strain expressing IL-17A would exhibit reduced virulence in vivo.To that end, we created a Candida-optimized expression cassette encoding murine IL-17A, which was transformed into the DAY286 strain of C. albicans. Candida-derived IL-17A was indistinguishable from murine IL-17A in terms of biological activity and detection in standard enzyme-linked immunosorbent assays (ELISAs). Expression of IL-17A did not negatively impact the growth of these strains in vitro. Moreover, the IL-17A-expressing C. albicans strains showed significantly reduced pathogenicity in a systemic model of Candida infection, mainly evident during the early stages of disease. Collectively, these findings suggest that IL-17A mitigates the virulence of C. albicans. Candida albicans is a commensal fungus of human skin and mucosal surfaces. Although normally nonpathogenic, C. albicans can cause disease in settings of immunodeficiency, abdominal surgery or otherwise disrupted barriers, antibiotic use, or other conditions (1, 2). By far the most serious form of candidiasis is a systemic infection characterized by fungal invasion into target organs, particularly the liver, kidney, and brain (3). Disseminated candidiasis is the 4th most common cause of hospital-acquired infections and has a high mortality rate (averaging 40%) (4).In recent years, accumulating data have implicated the cytokine interleukin-17A (IL-17A) (also known as IL-17) in immunity to Candida and other fungi (5, 6). IL-17A-and IL-17 receptordeficient mice are highly susceptible to candidemia (7-9). Similarly, humans with defects in the IL-17 pathway are especially sensitive to Candida infections; the defects arise from mutations in genes controlling IL-17 signaling (ACT1, IL17RA, IL17RC, and IL17F) or genes that drive Th17 cell differentiation (DECTIN1, CARD9, STAT3, STAT1, IL12B, and IL12RB) or arise in individuals with naturally occurring anti-IL-17 antibodies (occurring in certain thymomas and AIRE deficiency, also known as autoimmune polyglandular syndrome type 1 [APS-1] or autoimmune polyendocrinopathy candidiasis ectodermal dystrophy [APECED]) (10, 11).Although Candida infections can be treated pharmacologically, currently available antifungal medications are limited by significant drug-drug interactions, the emergence of drug resistance, and toxicity (12, 13). To date, there are no vaccines availab...

Vulvovaginal candidiasis: An overview of mycological, clinical, and immunological aspects

“…IL‐17 induces the production of chemokines in the vagina in C. albicans infection, and chemokines may induce neutrophils recruitment. Huppler et al transformed an IL‐17‐expressing cassette into C. albicans and reported that IL‐17 expression did not adversely affect the growth of this species but reduced its pathogenicity in a systemic model of Candida infection 99 . It is noteworthy that susceptibility to Candida infections increases when IL‐17 is not produced, such as in patients with defects in genes involved in differentiation of Th17 cells, autoimmune polyglandular syndrome type 1 (APS1), Job's syndrome, and deficiency of Candida receptors (Dectin‐1 and CARD9) 100 .…”

“…Huppler et al transformed an IL-17-expressing cassette into C. albicans and reported that IL-17 expression did not adversely affect the growth of this species but reduced its pathogenicity in a systemic model of Candida infection. 99 It is noteworthy that susceptibility to Candida infections increases when IL-17 is not produced, such as in patients with defects in genes involved in differentiation of Th17 cells, autoimmune polyglandular syndrome type 1 (APS1), Job's syndrome, and deficiency of Candida receptors (Dectin-1 and CARD9). 100 Nevertheless, the loss of only one functional allele in Dectin-1 has no major effect on susceptibility to RVVC, and complete loss of function in this molecule is associated with a significant risk of infection 96 Dectin-1 abnormalities have not been found in women with idiopathic RVVC.…”

Candida albicans and candidalysin in inflammatory disorders and cancer

“…Of particular interest is the central role of IL-17A in orchestration of antifungal defences. IL-17A and associated effector molecules and cells are potently induced in response to C. albicans infection, [38][39][40][41] with candidalysin accounting for robust induction of early and innate 'natural' Th17 cell-derived IL-17A. 20 Notably, elevated incidence or sensitization to C. albicans is often observed in a specific group of IL-17-mediated pathologies localized at mucosal and epithelial surfaces.…”

“…Of particular interest is the central role of IL‐17A in orchestration of antifungal defences. IL‐17A and associated effector molecules and cells are potently induced in response to C. albicans infection, 38–41 with candidalysin accounting for robust induction of early and innate ‘natural’ Th17 cell‐derived IL‐17A 20 …”