Hypersusceptibility of A/J mice to tuberculosis is in part due to a deficiency of the fifth complement component (C5)

Mycobacterium tuberculosis (MTB) causes tuberculosis in man, which occurs a s an acute, chronic or dormant disease reactivating over several years. The mechanisms of persistence and reactivation are not well understood and the re is a need for animal models. Moderate-dose, aerosol infection killed A/J mice earlier than partially resistant C57Bl/6 mice, whereas a low-dose, ae rosol-induced chronic infection exacerbated earlier in A/J mice. A/J mice l ethally infected with MTB but drug cured of disease underwent reactivation of tuberculosis at least 100 days before similarly infected C57Bl/6 mice. B ecause A/J mice were C5 deficient, congenic B10 mice sufficient and deficie nt for C5 were infected intravenously with MTB to define the role of C5. C5 -deficient mice again showed enhanced growth of MTB in the lungs. MTB-infec ted macrophages from C5-deficient mice showed enhanced growth of MTB coinci ding with a reduced secretion of both cytokines (TNF-alpha, IL-1 beta, IL-6 , IL-12) and chemokines (KC, MIP-2 and MIP-1 alpha) in A/J and TNF-alpha an d chemokines in C5-deficient mice. Because C5-deficient macrophages could b e activated from extraneous C5 and TNF-alpha we suggest that both play a ro le in the macrophage-mediated killing as well as containment mechanisms in tuberculosis.