DEFECTS IN CELL-MEDIATED-IMMUNITY AFFECT CHRONIC, BUT NOT INNATE, RESISTANCE OF MICE TO MYCOBACTERIUM-AVIUM INFECTION

To investigate the role of cell-mediated immunity in the control of My cobacterium avium infection, we studied the effects of targeted gene d isruptions in components of the T lymphocyte-dependent, macrophage-med iated response on resistance of mice to this pathogen. Normal mice dev eloped a chronic, asymptomatic infection, with rapid induction of mRNA s for IFN-gamma, IL-12, and TNF-alpha in spleen, liver, and lung. Bact erial loads in gene knockout, scid, and wild-type mice were indistingu ishable for the first 4 wk of infection. However, by 8 wk postinfectio n, scid mice as well as animals with a targeted disruption of the IFN- gamma gene showed enhanced bacterial growth compared with wild-type co ntrols. In contrast, knockout mice lacking the genes for the TNF-alpha p55/p75 receptors or inducible nitric oxide synthase not only develop ed comparable bacterial loads to wild-type animals they also failed to display the splenomegaly and profound suppression of mitogen-induced lymphocyte proliferative responses evident in infected wild-type contr ols. Thus, M. avium is clearly distinct from other intracellular patho gens (e.g., Leishmania monocytogenes. Toxoplasma gondii, and Mycobacte rium tuberculosis) whose initial replication in the host is tightly co ntrolled by Th1-dependent effector mechanisms. Instead, the major effe ct of host cell-mediated immunity is to limit bacterial growth during the chronic phase of infection. Surprisingly, inducible nitric oxide a ppears to be more important for the immunopathology than for the host resistance induced by this bacterial pathogen.