Mycobacterium bovis infection of vitamin D-deficient NOS2 −/− mice

• Published in: Microbial pathogenesis Vol. 36; no. 1; pp. 11 - 17
• Main Authors: Waters, W.R, Palmer, M.V, Nonnecke, B.J, Whipple, D.L, Horst, R.L
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier India Pvt Ltd 2004; Elsevier
• Subjects: 1,25-Dihydroxyvitamin D 3; Animals; Biological and medical sciences; Calcitriol - metabolism; Fundamental and applied biological sciences. Psychology; Liver - microbiology; Lung - microbiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiology; Mouse; Mycobacterium bovis; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase - deficiency; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type II; NOS2; Spleen - microbiology; Tuberculosis - etiology; Tuberculosis - metabolism; Tuberculosis - microbiology; Vitamin D Deficiency - complications; 1,25-Dihydroxyvitamin D 3; Mycobacterium bovis; NOS2; Mouse; Nitric oxide; Microbiology; Rodentia; Mycobacterial infection; Infection; Vertebrata; Mammalia; Vitamin D; Mycobacteriales; Bacteriosis; Mycobacteriaceae; Bacteria; Actinomycetes
• ISSN: 0882-4010; 1096-1208
• DOI: 10.1016/j.micpath.2003.08.008

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) 2D 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) 2D 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) 2D 3 enhances mycobacterial killing through a NO-dependent mechanism. As responses of NOS2 −/− mice were affected by 1,25(OH) 2D 3 deficiency, albeit to a lesser extent than were those of NOS2 +/+ mice, NO-independent actions of 1,25(OH) 2D 3 also likely exist.