title: Bimodal Influence of Vitamin D in Host Response to Systemic Candida Infection-Vitamin D Dose Matters.
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.
authors.affiliation: Division of Infectious Diseases.
authors.forename: Joan Hui Juan
authors.initials: JH
authors.lastname: Lim
authors.affiliation: Division of Infectious Diseases.
authors.forename: Sharada
authors.initials: S
authors.lastname: Ravikumar
authors.affiliation: Institute of Molecular and Cell Biology.
authors.forename: Yan-Ming
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Department of Pathology.
authors.forename: Thomas Paulraj
authors.initials: TP
authors.lastname: Thamboo
authors.affiliation: Department of Laboratory Medicine.
authors.forename: Lizhen
authors.initials: L
authors.lastname: Ong
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology, and Research.
authors.forename: Jinmiao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Division of Infectious Diseases.
authors.forename: Jessamine Geraldine
authors.initials: JG
authors.lastname: Goh
authors.affiliation: Division of Rheumatology.
authors.forename: Sen Hee
authors.initials: SH
authors.lastname: Tay
authors.affiliation: Cancer Science Institute.
authors.forename: Lufei
authors.initials: L
authors.lastname: Chengchen
authors.affiliation: Division of Infectious Diseases Cancer Science Institute.
authors.forename: Mar Soe
authors.initials: MS
authors.lastname: Win
authors.affiliation: Division of Infectious Diseases.
authors.forename: Winnie
authors.initials: W
authors.lastname: Leong
authors.affiliation: Division of Nephrology, University Medicine Cluster.
authors.forename: Titus
authors.initials: T
authors.lastname: Lau
authors.affiliation: Cardiovascular Research Institute.
authors.forename: Roger
authors.initials: R
authors.lastname: Foo
authors.affiliation: Department of Microbiology.
authors.forename: Haris
authors.initials: H
authors.lastname: Mirza
authors.affiliation: Department of Microbiology.
authors.forename: Kevin Shyong Wei
authors.initials: KS
authors.lastname: Tan
authors.affiliation: Department of Laboratory Medicine.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sethi
authors.affiliation: Pharmacy and Therapeutic Office, Group Corporate Development, National Healthcare Group, Singapore.
authors.forename: Ai Leng
authors.initials: AL
authors.lastname: Khoo
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System Cancer Science Institute Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore.
authors.forename: Wee Joo
authors.initials: WJ
authors.lastname: Chng
authors.affiliation: Cancer Science Institute.
authors.forename: Motomi
authors.initials: M
authors.lastname: Osato
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Institute of Molecular and Cell Biology.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Infectious Diseases.
authors.forename: Louis Yi Ann
authors.initials: LY
authors.lastname: Chai
mesh_terms: D000818:Animals; D002177:Candidiasis / Q000188:drug therapy* / Q000276:immunology; D002762:Cholecalciferol / Q000008:administration & dosage / Q000494:pharmacology*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014807:Vitamin D / Q000097:blood*
chemical_list: D012333:RNA, Messenger; D050791:STAT Transcription Factors; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014807:Vitamin D; D002762:Cholecalciferol; D007371:Interferon-gamma
keywords: 1,25(OH)2D3; cytokine; interferon gamma; suppressor of cytokine signaling (SOCS)