Apoptosis in Mycobacterium tuberculosis infection in mice exhibiting varied immunopathology

This study examined mechanisms contributing to pulmonary immunopathology fo llowing acute Mycobacterium tuberculosis (MTB) infection in vivo in a murin e model. A/J and C57BL/6 mice were intravenously infected with MTB (Erdman) . Pathological differences were found between strains, unrelated to pulmona ry load of bacilli. A/J mice developed progressive interstitial pneumonitis , while C57BL/6 mice maintained granuloma formation. The contribution of FA S and FAS ligand-mediated apoptosis was assessed via bioluminescent reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemical stai ning, and TUNEL assessment of DNA fragmentation. Cytokine messages for pulm onary tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-ga mma), as well as for the lytic molecules perforin and granzyme B, were quan tified. Immunohistochemical staining for CD3 receptor was performed to moni tor lymphocytic lung infiltration. Soon after infection, A/J mice exhibited increased pulmonary IFN-gamma message, concurrent with the appearance of C D3+ lymphocytes distributed throughout the lung. C57BL/6 mice exhibited per ivascular cuffing, with no accompanying increase in IFN-gamma message. A/J mice also had elevated levels of FAS and FAS ligand message and protein ear ly after infection, while the C57BL/6 mice had no increased expression of t hese molecules. Both strains exhibited qualitatively similar numbers of TUN EL-positive cells throughout infection, with a marked increase on day 7. Ap optotic cells appeared to co-localize with acid fast bacilli. It is therefo re proposed that apoptosis during initial granuloma formation following MTB infection may occur through a FAS/FAS ligand-independent pathway. Moreover , a failure of completion of the FAS/FAS ligand-mediated apoptosis pathway in the A/J mice may contribute to inefficient elimination of lymphocytes, t hus further aggravating pulmonary pathology. Copyright (C) 2000 John Wiley & Sons, Ltd.