Abstract
Candida albicans is a commensal fungus that can cause disease ranging in severity from moderate to severe mucosal infections to more serious life-threating disseminated infections in severely immunocompromised hosts. Chronic mucocutaneous candidiasis (CMC) occurs in patients with mutations in genes affecting IL-17-mediated immunity, such as STAT3, AIRE, RORC, CARD9, IL12B, and IL12RB1, or gain of function (GOF) mutations in STAT1. New strategies for the treatment of candidiasis are needed because of the increased burden of infections and the emergence of drug-resistant strains. In this study, we investigated an aspect of the role of antibodies in the control of C. albicans infection. We tested in vitro the effects of C. albicans opsonization with commercial human polyvalent intravenous IgG (IV IgG) on NADPH oxidase activity and killing of the fungi by blood leukocytes from 11 healthy donors and found a significant enhancement in both phenomena that was improved by IV IgG opsonization. Then, we hypothesized that the opsonization of Candida in vivo could help its elimination by mucosal phagocytes in human patients with mucocutaneous candidiasis. We tested a novel adjunctive treatment for oral candidiasis in humans based on topical treatment with IV IgG. For this purpose, we choose two pediatric patients with well-characterized primary immunodeficiencies who are susceptible to CMC. Two 8-year-old female patients with an autosomal recessive mutation in the IL12RB1 gene (P1, with oral candidiasis) and a GOF mutation in STAT1 (P2, with severe CMC persistent since the age of 8 months and resistant to pharmacological treatments) were treated with IV IgG administered daily three times a day as a mouthwash over the course of 2 weeks. The treatment with the IV IgG mouthwash reduced C. albicans mouth infection by 98 and 70% in P1 and P2, respectively, after 13 days, and complete fungal clearance was observed after complementary nystatin and caspofungin treatments, respectively. Therefore, treatment of oral candidiasis with human polyvalent IgG administered as a mouthwash helps eliminate mucosal infection in humans, circumventing drug resistance, and opening its potential use in patients with primary or transient immunodeficiency.
Highlights
Candidiasis is a fungal infection caused by yeasts belonging to the genus Candida
Both monocytes and neutrophils gated on FSC vs. SSC graphics showed NADPH oxidase activity in response to the Candida albicans stimulation, we focused our analysis on the neutrophils
The opsonization with HIS increased the NADPH activity by 3.7- and 4.4-fold when serum was used at 3 or 30%, respectively (Figure 2, lower panel) (p < 0.001). These results show that compared with unopsonized C. albicans, the antibody opsonization of C. albicans with polyvalent commercial human IgG or human serum clearly increases the NADPH oxidase activity of blood neutrophils in healthy human volunteers
Summary
Candidiasis is a fungal infection caused by yeasts belonging to the genus Candida. Over 20 species of Candida yeasts can cause infection in humans, and the most common species is Candida albicans, which is a commensal organism that can be isolated from oral mucosa, the intestinal tract, and vaginal mucosa in healthy individuals. The contribution of the adaptive immune response to Candida includes the participation of Th1 and Th17 cells. Distinct evidence obtained from studies involving animal models and humans suggests that the Th17 immune response plays a major role in the control of mucosal Candidal infections [reviewed in [6, 7]]. Th2 cells, which cooperate with B cells in antibody production, are activated in response to Candida infection, and the antibodies produced against Candida can neutralize antigens, including virulence factors, and adhesion molecules, that interfere with cell adherence and colonization and promote fungal opsonization, phagocytosis, killing, and complement activation and participate in antibody-dependent cellular toxicity [8,9,10,11]. The antibodies produced against Candida play an important role in the inhibition of the dissemination of infections [11,12,13] as recently observed in patients with candidemia [14]
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