Mycobacteria lacking the RD1 region do not induce necrosis in the lungs of mice lacking interferon-γ

Ana Paula Junqueira-Kipnis, Randall J. Basaraba, Veronica Gruppo, Gopinath Palanisamy, Oliver C. Turner, Tsungda Hsu, William R. Jacobs, Scott A. Fulton, Scott M. Reba, W. Henry Boom, Ian M. Orme

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The genetic region of difference 1 (RD1) in Mycobacterium tuberculosis has recently been hypothesized to encode for proteins that are cytotoxic to the host cell in nature. We demonstrate here that while M. tuberculosis grew progressively in the lungs of gene disrupted mice (GKO) unable to produce interferon-γ (IFN-γ), similar mice infected instead with M. bovis bacillus Calmette-Guérin (BCG) reproducibly exhibited an obvious slowing of the disease after about 20 days. Closer examination of BCG-infected GKO mice showed a florid granulomatous inflammation in the lungs, whereas similar mice infected with M. tuberculosis exhibited wholesale progressive necrosis. In the BCG-infected GKO mice large numbers of activated effector T cells, some strongly positive for the cytokine tumour necrosis factor, as well as activated natural killer cells accumulated in the lungs. To further test the hypothesis that the differences observed were directly associated with the loss of the RD1 region, it was then shown that a mutant of M. tuberculosis lacking RD1 grew progressively in both normal and GKO mice but failed to induce any degree of necrosis in either animal despite reaching similar levels in the lungs. However, when mice were infected with this mutant, in which the RD1 region had been restored by complementation, wholesale necrosis of the lungs again occurred. These data support the hypothesis that proteins encoded in the RD1 region are a major cause of necrosis and contribute significantly to the pathogenesis of the disease.

Original languageEnglish (US)
Pages (from-to)224-231
Number of pages8
JournalImmunology
Volume119
Issue number2
DOIs
StatePublished - Oct 1 2006

Fingerprint

Mycobacterium
Interferons
Necrosis
Lung
Mycobacterium tuberculosis
Bacillus
Natural Killer Cells
Pneumonia
Proteins
Tumor Necrosis Factor-alpha
Cytokines
T-Lymphocytes
Genes

Keywords

  • IFN-γ knockout mice
  • Lung
  • RD1 gene region
  • Tuberculosis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Junqueira-Kipnis, A. P., Basaraba, R. J., Gruppo, V., Palanisamy, G., Turner, O. C., Hsu, T., ... Orme, I. M. (2006). Mycobacteria lacking the RD1 region do not induce necrosis in the lungs of mice lacking interferon-γ. Immunology, 119(2), 224-231. https://doi.org/10.1111/j.1365-2567.2006.02427.x

Mycobacteria lacking the RD1 region do not induce necrosis in the lungs of mice lacking interferon-γ. / Junqueira-Kipnis, Ana Paula; Basaraba, Randall J.; Gruppo, Veronica; Palanisamy, Gopinath; Turner, Oliver C.; Hsu, Tsungda; Jacobs, William R.; Fulton, Scott A.; Reba, Scott M.; Boom, W. Henry; Orme, Ian M.

In: Immunology, Vol. 119, No. 2, 01.10.2006, p. 224-231.

Research output: Contribution to journalArticle

Junqueira-Kipnis, AP, Basaraba, RJ, Gruppo, V, Palanisamy, G, Turner, OC, Hsu, T, Jacobs, WR, Fulton, SA, Reba, SM, Boom, WH & Orme, IM 2006, 'Mycobacteria lacking the RD1 region do not induce necrosis in the lungs of mice lacking interferon-γ', Immunology, vol. 119, no. 2, pp. 224-231. https://doi.org/10.1111/j.1365-2567.2006.02427.x
Junqueira-Kipnis AP, Basaraba RJ, Gruppo V, Palanisamy G, Turner OC, Hsu T et al. Mycobacteria lacking the RD1 region do not induce necrosis in the lungs of mice lacking interferon-γ. Immunology. 2006 Oct 1;119(2):224-231. https://doi.org/10.1111/j.1365-2567.2006.02427.x
Junqueira-Kipnis, Ana Paula ; Basaraba, Randall J. ; Gruppo, Veronica ; Palanisamy, Gopinath ; Turner, Oliver C. ; Hsu, Tsungda ; Jacobs, William R. ; Fulton, Scott A. ; Reba, Scott M. ; Boom, W. Henry ; Orme, Ian M. / Mycobacteria lacking the RD1 region do not induce necrosis in the lungs of mice lacking interferon-γ. In: Immunology. 2006 ; Vol. 119, No. 2. pp. 224-231.
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abstract = "The genetic region of difference 1 (RD1) in Mycobacterium tuberculosis has recently been hypothesized to encode for proteins that are cytotoxic to the host cell in nature. We demonstrate here that while M. tuberculosis grew progressively in the lungs of gene disrupted mice (GKO) unable to produce interferon-γ (IFN-γ), similar mice infected instead with M. bovis bacillus Calmette-Gu{\'e}rin (BCG) reproducibly exhibited an obvious slowing of the disease after about 20 days. Closer examination of BCG-infected GKO mice showed a florid granulomatous inflammation in the lungs, whereas similar mice infected with M. tuberculosis exhibited wholesale progressive necrosis. In the BCG-infected GKO mice large numbers of activated effector T cells, some strongly positive for the cytokine tumour necrosis factor, as well as activated natural killer cells accumulated in the lungs. To further test the hypothesis that the differences observed were directly associated with the loss of the RD1 region, it was then shown that a mutant of M. tuberculosis lacking RD1 grew progressively in both normal and GKO mice but failed to induce any degree of necrosis in either animal despite reaching similar levels in the lungs. However, when mice were infected with this mutant, in which the RD1 region had been restored by complementation, wholesale necrosis of the lungs again occurred. These data support the hypothesis that proteins encoded in the RD1 region are a major cause of necrosis and contribute significantly to the pathogenesis of the disease.",
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