Apoptosis in Mycobacterium tuberculosis infection in mice exhibiting varied immunopathology

Virginia E. Watson, Laurie L. Hill, Laurie B. Owen-Schaub, Darren W. Davis, David J. McConkey, Chinnaswamy Jagannath, Robert L. Hunter, Jeffrey K. Actor

Research output: Contribution to journalArticle

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-α (TNF-α) and interferon-γ (IFN-γ), 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-γ message, concurrent with the appearance of CD3+ lymphocytes distributed throughout the lung. C57BL/6 mice exhibited perivascular cuffing, with no accompanying increase in IFN-γ 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.

Original languageEnglish (US)
Pages (from-to)211-220
Number of pages10
JournalJournal of Pathology
Volume190
Issue number2
DOIs
StatePublished - Feb 1 2000
Externally publishedYes

Keywords

  • Apoptosis
  • Bioluminescent RT-PCR
  • Cytokines
  • FAS
  • FAS ligand
  • Granzyme B
  • Mycobacteria
  • Perforin
  • Tuberculosis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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