Mycobacterium bovis infection of vitamin D-deficient NOS2(-/-) mice

Vitamin D deficiency is associated with an increased risk for tuberculosis infection. Studies using in vitro systems indicate that 1,25-dihydroxyvitamin D-3 [i.e. 1,25(OH)(2)D-3], the most active form of the vitamin, enhances mycobacterial killing by increasing nitric oxide (NO) production. To evaluate concurrently the role of 1,25(OH)(2)D-3 and NO on the host response to tuberculosis infection, mice deficient in NO synthase 2 (NOS2(-/-)) and/or vitamin D were aerosol-challenged with Mycobacterium bovis and subsequently evaluated for mycobacterial colonization and lesion formation. Infected NOS2(-/-) mice developed severe necrotizing pyogranulomatous inflammation of the lungs with heavy M. bovis colonization and systemic dissemination of the bacillus. Colonization and lung lesion area of NOS2(-/-) mice exceeded that of NOS2(+/+) mice. Additionally, disease progression was more rapid in NOS2(-/-) mice than in NOS2(+/+) mice. Lung colonization and lesion area of vitamin D deficient mice exceeded that of vitamin D replete mice, regardless of NOS2 phenotype. However, effects of vitamin D on colonization, but not lesion area, were more pronounced in NOS2(+/+) mice than in NOS2-/- mice. These findings are consistent with the current hypothesis that 1,25(OH)(2)D-3 enhances mycobacterial killing through a NO-dependent mechanism. As responses of NOS2(-/-) mice were affected by 1,25(OH)(2)D-3 deficiency, albeit to a lesser extent than were those of NOS2(+/+) mice, NO-independent actions of 1,25(OH)(2)D-3 also likely exist. Published by Elsevier Ltd.