Bimodal Influence Of Vitamin D In Host Response To Systemic Candida Infection-Vitamin D Dose Matters

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 D-3 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)(2)D-3 had reduced fungal burden and better survival relative to untreated mice. Conversely, higher 1,25(OH)(2)D-3 doses led to poor outcomes. Mechanistically, low-dose 1,25(OH)(2)D-3 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 gamma. These beneficial effects were negated with higher vitamin D3 doses. While the antiinflammatory effects of vitamin D-3 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.