Loss of the Vitamin D Receptor Exacerbates Influenza Severity Through Dysregulated Immunity and Elevated Parathyroid Hormone 2249087

Abstract Introduction Respiratory infections caused by influenza viruses remain a global health burden, with disease severity in part determined by host immune responses. Immune cells have vitamin D receptors (VDR) and vitamin D has been shown to regulate host immunity to infection. Methods Wild-type (WT) and VDR knockout (KO) mice were infected with mouse-adapted influenza A/H1N1 (A/California/04/2009(H1N1pdm09)). Some WT mice also received exogenous PTH. Clinical scores and lung histology assessed disease severity, whereas viral load, immune cell responses, and cytokine levels in the lungs were quantified by viral titration assay, qPCR, ELISA, and flow cytometry. Results WT mice cleared virus efficiently with non-lethal disease, whereas VDR KO mice had 22% mortality, delayed viral clearance, and exacerbated lung pathology. These outcomes were accompanied by heightened type I and II interferon responses, increased infiltration of myeloid cells and CD4+ T cells but less natural killer (NK) cells into the lungs. Vitamin D deficiency and VDR KO result in very high parathyroid hormone (PTH) levels. WT mice were treated with PTH to determine the effects of PTH on host immunity to influenza virus infection. Influenza virus infection in PTH treated WT mice resulted in more severe clinical scores, higher viral burden, and amplified IFN-γ responses compared to WT mice. Conclusion Vitamin D deficiency and high PTH combine to create a hyperinflammatory environment with excessive interferon production, delayed viral clearance, and tissue injury. The work highlights a novel paradigm in which the vitamin D-PTH axis governs host resistance to influenza virus disease by controlling the amount of inflammation and the amount of virus in the lung. The data suggest that a low cost vitamin D supplement would improve vitamin D status, and limit PTH-driven immune dysregulation protecting the lung against influenza virus infection. Funding Source This work was supported by the National Institutes of Health (NIH) grants R01AT005378 to M.T.C., T32GM154124 to M.T and T32DK120509 to N.E.F. And USDA National Institute of Food and Agriculture and Hatch Appropriations Projects #PEN04963 Accession #700657 Topic Categories Viral Immunology (VIR)