Mechanisms of action of vitamin D as supplemental therapy for Pneumocystis pneumonia [PublishAheadOfPrint]

The combination of trimethoprim and sulfamethoxazole (TMP-SMX) is the most effective regimen for therapy of Pneumocystis pneumonia (PcP). As many patients with PcP are allergic or do not respond to it, efforts have been devoted to develop alternative therapies for PcP. We have found that the combination of vitamin D3 (VitD3; 300 IU/kg/day) and PMQ (5 mg/kg/day) was as effective as TMP-SMX for therapy of PcP. In this study, we investigated the mechanisms by which vitamin D enhances the efficacy of PMQ. C57BL/6 mice were immunosuppressed by CD4⁺ cell depletion, infected with P. murina for eight weeks, and then treated for 9 days with the combination of VitD3 and PMQ (VitD3-PMQ) or with TMP-SMX or PMQ to serve as controls. Results showed that vitamin D supplementation increased the number of CD11c⁺ cells; suppressed the production of pro-inflammatory cytokines (TNF-α, IFN, and IL-6) and iNOS; and enhanced the expression of genes related to anti-oxidation (glutathione reductase and glutamate-cysteine ligase modifier subunit), anti-microbial peptides (cathelicidin), and autophagy (ATG5 and Beclin-1). These results suggest that the main action of vitamin D is enhancing the ability of the host to defend Pneumocystis infection.

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