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 as an acute, chronic or dormant disease reactivating over several years. The mechanisms of persistence and reactivation are not well understood and there 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, aerosol-induced chronic infection exacerbated earlier in A/J mice. A/J mice lethally infected with MTB but drug cured of disease underwent reactivation of tuberculosis at least 100 days before similarly infected C57Bl/6 mice. Because A/J mice were C5 deficient, congenic B10 mice sufficient and deficient 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-infected macrophages from C5-deficient mice showed enhanced growth of MTB coinciding with a reduced secretion of both cytokines (TNF-alpha, IL-1beta, IL-6, IL-12) and chemokines (KC, MIP-2 and MIP-1alpha) in A/J and TNF-alpha and chemokines in C5-deficient mice. Because C5-deficient macrophages could be activated from extraneous C5 and TNF-alpha we suggest that both play a role in the macrophage-mediated killing as well as containment mechanisms in tuberculosis.
Jagannath
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Department of Pathology and Laboratory Medicine, UTHSC, Institute of Molecular Medicine and Prevention of Human Diseases, University of Texas, Houston, TX 77030, USA.
Hoffmann
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Sepulveda
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Actor
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Wetsel
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Hunter
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D000818:Animals; D018925:Chemokines / Q000096:biosynthesis; D003182:Complement C5 / Q000172:deficiency*; D016207:Cytokines / Q000096:biosynthesis; D004198:Disease Susceptibility; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000382:microbiology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000254:growth & development; D009569:Nitric Oxide / Q000096:biosynthesis; D014376:Tuberculosis / Q000276:immunology*
D018925:Chemokines; D003182:Complement C5; D016207:Cytokines; D009569:Nitric Oxide; D006861:Hydrogen Peroxide