iNOS in Tuberculosis

Inducible Nitric Oxide Synthase in the Tuberculous Human Lung
The NOS2 isoform, often called iNOS, is a leading candidate to account for the incompletely successful bactericidal activity of macrophages toward M. tuberculosis. The designation "i" denotes that production of nitric oxide by iNOS is independent of elevated intracellular Ca2+ ,a biochemically distinctive and biologically important feature that explains how the enzyme can produce nitric oxide for days after its transcription is induced by immunologic and inflammatory stimuli.
Nitric oxide is the only molecule known to be produced by mammalian cells that can kill tubercle bacilli in vitro with a molar potency comparable to that of chemotherapy. That the primary product of iNOS is mycobactericidal provides one type of evidence consistent with a role for iNOS in controlling tuberculosis. There are four more lines of evidence: immunologically activated, iNOS-expressing mouse macrophages can kill M. tuberculosis in vitro, but not if the macrophages are treated with iNOS inhibitors or bear disrupted NOS2 alleles, iNOS is expressed in infected mouse tissues in which the growth of M. tuberculosis is restrained, but iNOS is scant or absent when immunosuppressive drugs or genetic interventions impair host resistance healthy mice that harbor tubercle bacilli succumb abruptly to tuberculosis after ingestion of specific iNOS inhibitors and mice with disrupted NOS2 alleles die with fulminant tuberculosis in a few weeks, whereas wild-type mice survive the infection for about 9 months.
It is difficult to determine how much of this is relevant to human tuberculosis. No one has knowingly administered iNOS inhibitors to people infected with tubercle bacilli, and no primary genetic deficiency of iNOS has been identified in humans. Thus, only two experimental avenues have been open: the impact of iNOS inhibitors on the mycobactericidal activity of human macrophages in vitro, and a search for iNOS at sites of tuberculosis. Studies of human macrophages in vitro have been more frustrating than informative, because the macrophages tested to date have rarely exerted a bactericidal effect against M. tuberculosis, precluding a determination as to the contribution of iNOS to killing. Both mouse and human macrophages that lack iNOS can exert a bacteriostatic effect against M. tuberculosis by an unknown mechanism, but with respect to iNOS these cells do not model human macrophages at sites of infection or inflammation, which are often intensely iNOS-positive. Thus, one of the major unfulfilled goals for research in the immunology of tuberculosis is to learn how to obtain or culture human macrophages that are as iNOS-positive in vitro as they are in vivo and to test whether they kill M. tuberculosis and use iNOS to do so.