Table 1.

Evidence for the Role of Nitric Oxide (NO) in Tuberculosis Immunology

Study Type, Results	Selected Reference(s)
M. tuberculosis in vitro studies
Mycobacteria are susceptible to NO and other reactive nitrogen species in vitro	[16]
M. tuberculosis isolates differ in their susceptibility to reactive nitrogen intermediates: less susceptible isolates are more virulent in guinea pigs, and less susceptible isolates from human cases are less susceptible to antituberculosis drugs	[16, 17]
M. tuberculosis immune-evasion strategies include the induction of arginase expression (thereby decreasing NO availability) in macrophages	[18]
Mouse macrophage studies
Arginine-derived reactive nitrogen intermediates in mouse macrophages effectively kill M. tuberculosis	[4]
M. tuberculosis lacking genetic resistance to reactive nitrogen intermediates cannot grow in mouse macrophages, in contrast with wild-type M. tuberculosis	[19]
Human macrophage studies
Alveolar macrophages from healthy humans infected ex vivo with M. tuberculosis produce NO, and NO production correlates with intracellular growth inhibition of M. tuberculosis	[10]
Blood mononuclear cells from healthy donors infected ex vivo with M. tuberculosis and from people with preexisting tuberculosis produce NO	[7]
Pulmonary macrophages kill mycobacteria only if they express NOS2; killing is prevented with a NOS inhibitor	[9]
In vivo mouse studies
NOS2 is expressed at sites of disease in immunocompetent mice but is deficient in immunocompromised mice with progressive tuberculosis	[20]
M. tuberculosis infection is poorly contained in mice treated with NOS inhibitors	[4]
Fulminant M. tuberculosis infection develops in NOS2 knockout mice (NOS2−/−) in contrast with controls	[20]
NO ameliorates inflammatory tissue damage in pulmonary tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1β	[11]
In vivo human studies
In lung resection studies, NOS2 and nitrotyrosine (a tissue marker of NO metabolism) are expressed in macrophages within granulomata and areas of tuberculosis pneumonitis	[6]
NOS2 expression is increased in peripheral blood monocytes from people with tuberculosis, compared with healthy controls	[8]
NOS2 is expressed in macrophages from lungs of patients with tuberculosis	[21]

Abbreviations: IL-1β, interleukin 1β; M. tuberculosis, Mycobacterium tuberculosis; NOS2, nitric oxide synthase.