Resistance to nitric oxide in Mycobacterium avium complex and its implication in pathogenesis

Susceptibility of three different strains of Mycobacterium avium complex (MAC), i.e., one strain of M. avium (Mino) and two strains of M. intracellulare (31F093T and KUMS 9007), to nitric oxide (NO) generated by rat alveolar macrophages (Mφ) or NO generated chemically by acidification of NO₂^- was examined in vitro. We also investigated the effects of NO on phagocytosis and superoxide anion (O₂^-) generation by Mφ. The intracellular growth of M. avium Mino was significantly suppressed by NO generated by gamma interferon (IFN-γ)-stimulated Mφ, whereas that of two strains of M. intracellulare (31F093T and KUMS 9007) was not. M. avium Mino was also more susceptible to NO generated chemically by acidification of NO₂/^- than the two M. intracellulare strains. In L-arginine (1 mM)- containing medium, NO release from the Mφ assessed by measuring NO₂/^- increased as the concentration of IFN-γ increased. The enhancing potential of IFN-γ for NO release became more pronounced when Mφ were infected with 31F093T, an NO-resistant strain. A large amount of NO generated by IFN-γ- stimulated Mφ suppressed both phagocytosis and O₂^- generation by the Mφ, especially after infection of the Mφ with strain 31F093T. These results indicate that the intracellular growth of MAC is not always inhibited by NO generated by immunologically activated Mφ; rather, NO generation induced by infection with an NO-resistant MAC strain suppresses phagocytosis of the Mφ, which may allow extracellular spreading of such NO-resistant mycobacteria. Therefore, the pathogenic potential of MAC may be partly attributed to its resistance to NO.