title: Apoptosis in mycobacterium tuberculosis infection in mice exhibiting varied immunopathology.
abstract: This study examined mechanisms contributing to pulmonary immunopathology following acute Mycobacterium tuberculosis (MTB) infection in vivo in a murine model. A/J and C57BL/6 mice were intravenously infected with MTB (Erdman). Pathological differences were found between strains, unrelated to pulmonary load of bacilli. A/J mice developed progressive interstitial pneumonitis, while C57BL/6 mice maintained granuloma formation. The contribution of FAS and FAS ligand-mediated apoptosis was assessed via bioluminescent reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemical staining, and TUNEL assessment of DNA fragmentation. Cytokine messages for pulmonary tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), as well as for the lytic molecules perforin and granzyme B, were quantified. Immunohistochemical staining for CD3 receptor was performed to monitor lymphocytic lung infiltration. Soon after infection, A/J mice exhibited increased pulmonary IFN-gamma message, concurrent with the appearance of CD3+ lymphocytes distributed throughout the lung. C57BL/6 mice exhibited perivascular cuffing, with no accompanying increase in IFN-gamma message. A/J mice also had elevated levels of FAS and FAS ligand message and protein early after infection, while the C57BL/6 mice had no increased expression of these molecules. Both strains exhibited qualitatively similar numbers of TUNEL-positive cells throughout infection, with a marked increase on day 7. Apoptotic cells appeared to co-localize with acid fast bacilli. It is therefore 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, thus further aggravating pulmonary pathology.
authors.affiliation: University of Texas Houston Medical School, Department of Pathology, Houston, TX 77030, USA.
authors.forename: V E
authors.initials: VE
authors.lastname: Watson
authors.forename: L L
authors.initials: LL
authors.lastname: Hill
authors.forename: L B
authors.initials: LB
authors.lastname: Owen-Schaub
authors.forename: D W
authors.initials: DW
authors.lastname: Davis
authors.forename: D J
authors.initials: DJ
authors.lastname: McConkey
authors.forename: C
authors.initials: C
authors.lastname: Jagannath
authors.forename: R L
authors.initials: RL
authors.lastname: Hunter
authors.forename: J K
authors.initials: JK
authors.lastname: Actor
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D017252:CD3 Complex / Q000032:analysis; D053222:Fas Ligand Protein; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D017252:CD3 Complex; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma