Mycobacterial Antigens Exacerbate Disease Manifestations inMycobacterium tuberculosis-Infected Mice

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Abstract
To control tuberculosis worldwide, the burden of adult pulmonary disease must be reduced. Although widely used,Mycobacterium bovisBCG vaccination given at birth does not protect against adult pulmonary disease. Therefore, postexposure vaccination of adults with mycobacterial antigens is being considered. We examined the effect of various mycobacterial antigens on mice with priorM. tuberculosisinfection. Subcutaneous administration of live or heat-treated BCG with or without lipid adjuvants to infected mice induced increased antigen-specific T-cell proliferation but did not reduce the bacterial load in the lungs and caused larger lung granulomas. Similarly, additional mycobacterial antigen delivered directly to the lungs by aerosol infection with viableM. tuberculosismixed with heat-killedMycobacterium tuberculosis(1:1) also did not reduce the bacillary load but caused increased expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), which was associated with larger granulomas in the lungs. WhenM. tuberculosis-infected mice were treated with recombinant BCG that secreted cytokines shown to reduce disease in a preinfection vaccine model, the BCG secreting TNF-α, and to a lesser extent, IL-2 and gamma interferon (IFN-γ), caused a significant increase in granuloma size in the lungs. Moreover, treatment ofM. tuberculosis-infected mice with recombinant murine TNF-α resulted in increased inflammation in the lungs and accelerated mortality without affecting the bacillary load. Taken together, these studies suggest that administration of mycobacterial antigens to mice with priorM. tuberculosisinfection leads to immune activation that may exacerbate lung pathology via TNF-α-induced inflammation without reducing the bacillary load.