The cytokine induced high output L-arginine:nitric oxide pathway is an important biochemical component of the cell mediated immune response and acts as the primary defense against facultative and obligate intra- cellular pathogens. The pathway is induced by the combined action of interferon-gamma (IFNgamma) and either tumor necrosis factor-alpha (TNFalpha) or interleukin-1 (IL-1). Lipopolysaccharide (LPS) or lipoprotein on the surface of pathogenic organisms can induce NO synthesis by first inducing synthesis of these other cytokines.
One aim of the current proposal is to establish the effectiveness of mycobacteria and lipoarabinomannan (LAM), a constituent of mycobacterial membranes, in inducing biosynthesis of NO. The inhibition of mycobacterial enzymes by NO will also be examined. Other proposed experiments focus on uptake and release of iron from bacteria exposed to NO. The bacteriocidal properties of iron-nitrosyl complexes likely to be produced in biological systems and the roles of natural iron sequestering proteins, transferrin and lactoferrin, in the bacteriotoxicity of NO will be evaluated. The ability of mycobacteria to reduce nitrogen oxides (NOx) will be determined and enzymes involved will be isolated and characterized. Of particular interest is whether bacteria can utilize nitrogen oxides, which are produced as breakdown products of NO biosynthesis, to produce ammonia, a known mycobacterial product which prevents lysosome-phagosome fusion. Virulent and avirulent strains of mycobacteria will be evaluated for presence of a nitric oxide reductase. Presence of this reductase may enhance the virulence of the infectious agent by neutralizing NO produced by the cell mediated immune response.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL051963-03
Application #
2229024
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S3))
Project Start
1993-09-30
Project End
1997-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Woods 2nd, M L; Mooney, B; Sutton, D et al. (1996) A pseudoepidemic of recent tuberculin test conversions caused by a dosing error. Clin Infect Dis 22:389-90