ABSTRACT
Vitamin D level is linked to susceptibility to infections, but its relevance in candidemia is unknown. We aimed to investigate the in vivo sequelae of vitamin D3 supplementation in systemic Candida infection. Implicating the role of vitamin D in Candida infections, we showed that candidemic patients had significantly lower 25-OHD concentrations. Candida-infected mice treated with low-dose 1,25(OH)2D3 had reduced fungal burden and better survival relative to untreated mice. Conversely, higher 1,25(OH)2D3 doses led to poor outcomes. Mechanistically, low-dose 1,25(OH)2D3 induced proinflammatory immune responses. This was mediated through suppression of SOCS3 and induction of vitamin D receptor binding with the vitamin D-response elements in the promoter of the gene encoding interferon γ. These beneficial effects were negated with higher vitamin D3 doses. While the antiinflammatory effects of vitamin D3 are well described, we found that, conversely, lower doses conferred proinflammatory benefits in Candida infection. Our study highlights caution against extreme deviations of vitamin D levels during infections.
Subject(s)
Candidiasis/drug therapy , Cholecalciferol/pharmacology , Vitamin D/blood , Animals , Candidiasis/immunology , Cholecalciferol/administration & dosage , Cohort Studies , Dose-Response Relationship, Drug , Gene Expression Regulation/drug effects , Humans , Inflammation/immunology , Inflammation/metabolism , Interferon-gamma/metabolism , Leukocytes, Mononuclear , Mice , Mice, Inbred BALB C , Promoter Regions, Genetic , RNA, Messenger/genetics , RNA, Messenger/metabolism , STAT Transcription Factors/genetics , STAT Transcription Factors/metabolism , Suppressor of Cytokine Signaling 3 Protein , Suppressor of Cytokine Signaling Proteins/genetics , Suppressor of Cytokine Signaling Proteins/metabolismABSTRACT
Candida tropicalis is one of the more common Candida causing human disease in tropical countries; the frequency of invasive disease varies by geography causing 3--66% of candidaemia. C. tropicalis is taxonomically close to C. albicans and shares many pathogenic traits. C. tropicalis is particularly virulent in neutropenic hosts commonly with hematogenous seeding to peripheral organs. For candidaemia and invasive candidiasis amphotericin B or an echinocandin are recommended as first-line treatment, with extended-spectrum triazoles acceptable alternatives. Primary fluconazole resistance is uncommon but may be induced on exposure. Physicians in regions where C. tropicalis is common need to be mindful of this lesser-described pathogen.