Transient loss of resistance to pulmonary tuberculosis in p47(phox-/-) mice

Abstract

Mycobacterium tuberculosis is an important respiratory pathogen the growth of which is controlled primarily by cytokine-activated macrophages. One of the principal mediators of this control is nitric oxide; however, superoxide has recently been shown to be protective in systemic mycobacterial infections. To determine whether superoxide is important in controlling M. tuberculosis during primary pulmonary infection, mice lacking the cytosolic p47(phox) gene (which is essential for effective superoxide production by the NADPH oxidase) were infected aerogenically. The lack of superoxide during an aerosol infection with M. tuberculosis resulted in a significant increase in bacterial growth over the early period of infection. Once antigen-specific gamma interferon-producing lymphocytes were detected in the draining lymph nodes, however, bacterial growth in the lung stopped. One interesting consequence of the lack of superoxide was an increase in neutrophilic infiltrates within the granuloma. This may be a consequence of increased tissue damage due to more rapid bacterial growth or may reflect a role for superoxide in controlling inflammation.

FIG. 1

Wild-type (closed circles) and p47-KO (open circles) mice were infected with M. tuberculosis via aerosol (n = 4). p47-KO mice were more susceptible to aerogenic infection from days 15 to 30 (P ≤ 0.05). The results show data from one experiment representative of a total of three experiments.

FIG. 2

Thoracic lymph node cells were cultured with M. tuberculosis antigen, and the amount of IFN-γ produced was measured by ELISA. Cells from both wild-type (closed circles) and p47-KO (open circles) thoracic nodes responded to antigen on days 20 and 40. No IFN-γ was detectable in nodes taken from uninfected (day 0) or 10-day-infected mice (n = 4). The results show data from one experiment representative of a total of two experiments.

FIG. 3

Photomicrograph of representative pulmonary lesions. (A) Lung tissue from a wild-type mouse infected 40 days previously, with typical epithelioid macrophage and lymphocyte accumulations (magnification, ×200). (B) Lung tissue from p47-KO mice 40 days after infection, with macrophage and lymphocyte accumulations as well as aggregates of neutrophils (magnification, ×200; insert magnification, ×1,000; stained with hematoxylin and eosin).