Inhibition of Inducible Nitric Oxide Synthase Reactivates Growth of Dormant Mycobacterium Tuberculosis within Infected Macrophages - Abstract
Tuberculosis is one of the top ten causes of human death. The generation of reactive nitrogen intermediates within the macrophages and to some extent in Mycobacterium tuberculosis cells as well is well documented. Release of NO from lung macrophage cells after challenge with M. tuberculosis bacilli is reported. However, the link between these reactive nitrogen intermediates and M. tuberculosis survival inside macrophage is still far from resolved. In this study, we have shown that supplementation of medium with nitrite (10mM) transformed the actively growing intracellular M. tuberculosis cells into dormant form. This is confirmed from colony forming units, acid fast staining and drug resistance studies. However, exposure of infected macrophage cells with iNOS inhibitor (1400 W) at 5?M concentration resulted in two-fold increase of intracellular growth of mycobacterial cells within 8 days of infection. Similar trend is also observed on nitrite exposed intracellular M. tuberculosis cells. Whereas 1400W does not have any significant effect on extracellular survival of either active or dormant
M. tuberculosis cells. Therefore, this report suggests that both host NO and mycobacterial NO together play important role to achieve and maintain dormancy during intracellular stage. In addition, the inhibition of host derived nitric oxide could help to redesign the tuberculosis combination therapy..