TY - JOUR
T1 - Apoptosis in Mycobacterium tuberculosis infection in mice exhibiting varied immunopathology
AU - Watson, Virginia E.
AU - Hill, Laurie L.
AU - Owen-Schaub, Laurie B.
AU - Davis, Darren W.
AU - McConkey, David J.
AU - Jagannath, Chinnaswamy
AU - Hunter, Robert L.
AU - Actor, Jeffrey K.
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 2000/2
Y1 - 2000/2
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Bioluminescent RT-PCR
KW - Cytokines
KW - FAS
KW - FAS ligand
KW - Granzyme B
KW - Mycobacteria
KW - Perforin
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=0033965118&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033965118&partnerID=8YFLogxK
U2 - 10.1002/(SICI)1096-9896(200002)190:2<211::AID-PATH530>3.0.CO;2-3
DO - 10.1002/(SICI)1096-9896(200002)190:2<211::AID-PATH530>3.0.CO;2-3
M3 - Article
C2 - 10657021
AN - SCOPUS:0033965118
VL - 190
SP - 211
EP - 220
JO - Journal of Pathology
JF - Journal of Pathology
SN - 0022-3417
IS - 2
ER -