Bimodal Influence of Vitamin D in Host Response to Systemic Candida Infection—Vitamin D Dose Matters

• Published in: The Journal of infectious diseases Vol. 212; no. 4; pp. 635 - 644
• Main Authors: Lim, Joan Hui Juan, Ravikumar, Sharada, Wang, Yan-Ming, Thamboo, Thomas Paulraj, Ong, Lizhen, Chen, Jinmiao, Goh, Jessamine Geraldine, Tay, Sen, Chengchen, Lufei, Win, Mar Soe, Leong, Winnie, Lau, Titus, Foo, Roger, Mirza, Haris, Tan, Kevin Shyong Wei, Sethi, Sunil, Khoo, Ai Leng, Chng, Wee Joo, Osato, Motomi, Netea, Mihai G., Wang, Yue, Chai, Louis Yi Ann
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 15.08.2015
• Subjects: Animals; Candidiasis - drug therapy; Candidiasis - immunology; Cholecalciferol - administration & dosage; Cholecalciferol - pharmacology; Cohort Studies; Dose-Response Relationship, Drug; FUNGI; 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 - metabolism; Vitamin D - blood; cytokine; 1,25(OH)2D3; interferon gamma; suppressor of cytokine signaling (SOCS)
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiv033

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.