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Protective role of membrane tumour necrosis factor in the host's resistance to mycobacterial infection.

Allie N, Alexopoulou L, Quesniaux VJ, Fick L, Kranidioti K, Kollias G, Ryffel B, Jacobs M - Immunology (2008)

Bottom Line: Membrane expressed TNF allowed a substantial recruitment of activated T cells and macrophages with granuloma formation and expression of bactericidal inducible nitric oxide synthase (iNOS).Using virulent Mycobacterium tuberculosis infection we confirm that membrane TNF conferred partial protection.Therefore, the data suggest that membrane-expressed TNF plays a critical role in host defence to mycobacterial infection and may partially substitute for soluble TNF.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, South Africa.

ABSTRACT
Tumour necrosis factor-alpha (TNF-alpha) plays a critical role in the recruitment and activation of mononuclear cells in mycobacterial infection. The role of membrane TNF, in host resistance against Mycobacterium bovis bacille Calmette-Guérin (BCG), was tested in knock-in mice in which the endogenous TNF was replaced by a non-cleavable and regulated allele (Delta1-12, TNF(tm/tm)). While 100% of mice with complete TNF deficiency (TNF(-/-)) succumbed to infection, 50% of TNF(tm/tm) mice were able to control M. bovis BCG infection and survived the experimental period. Membrane expressed TNF allowed a substantial recruitment of activated T cells and macrophages with granuloma formation and expression of bactericidal inducible nitric oxide synthase (iNOS). Using virulent Mycobacterium tuberculosis infection we confirm that membrane TNF conferred partial protection. Infection in TNF(tm/tm) double transgenic mice with TNF-R1 or TNF-R2 suggest protection is mediated through TNF-R2 signalling. Therefore, the data suggest that membrane-expressed TNF plays a critical role in host defence to mycobacterial infection and may partially substitute for soluble TNF.

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Comparison of resistance to M. tuberculosis infection in TNFtm/tm and TNFR1−/− or TNFR2−/− × TNFtm/tm double transgenic mice. (a) Survival of mice infected by H37Rv i.n. (10–30 CFU per lung, n = 9–11 mice pooled from two independent experiments). (b) Mycobacterial burden in the lung (CFU) 6 weeks after infection. The results are expressed as the mean ± SD (n = 4–6 mice per group of transgenic mice).
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fig11: Comparison of resistance to M. tuberculosis infection in TNFtm/tm and TNFR1−/− or TNFR2−/− × TNFtm/tm double transgenic mice. (a) Survival of mice infected by H37Rv i.n. (10–30 CFU per lung, n = 9–11 mice pooled from two independent experiments). (b) Mycobacterial burden in the lung (CFU) 6 weeks after infection. The results are expressed as the mean ± SD (n = 4–6 mice per group of transgenic mice).

Mentions: Lastly, we asked whether the protective effect of membrane TNF is signalled through TNFR1 or TNFR2. Therefore, we generated double transgenic mice by crossing TNFtm/tm mice with TNFR1−/− or TNFR2−/− mice. We further assessed the mycobacterial burden in the lung of M. tuberculosis infected mice. In this experiment, TNF−/− mice lost weight rapidly and died within 5 weeks, while TNFtm/tm mice were less sensitive, half surviving up to 45 days. TNFtm/tm × TNFR2 KO mice seemed essentially as sensitive as TNF−/− mice, while TNFtm/tm × TNFR1 KO mice behaved more like TNFtm/tm mice (Fig. 11a). Therefore, signalling of membrane TNF through TNF-R2 likely confers protection. This hypothesis is further corroborated by increased mycobacterial loads in the lung of TNFtm/tm × TNFR2 KO at 6 weeks post-infection, a time point when all TNF−/− had succumbed, essentially doubled as compared to TNFtm/tm or TNFtm/tm × TNFR1 KO mice (Fig. 11b).


Protective role of membrane tumour necrosis factor in the host's resistance to mycobacterial infection.

Allie N, Alexopoulou L, Quesniaux VJ, Fick L, Kranidioti K, Kollias G, Ryffel B, Jacobs M - Immunology (2008)

Comparison of resistance to M. tuberculosis infection in TNFtm/tm and TNFR1−/− or TNFR2−/− × TNFtm/tm double transgenic mice. (a) Survival of mice infected by H37Rv i.n. (10–30 CFU per lung, n = 9–11 mice pooled from two independent experiments). (b) Mycobacterial burden in the lung (CFU) 6 weeks after infection. The results are expressed as the mean ± SD (n = 4–6 mice per group of transgenic mice).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2612548&req=5

fig11: Comparison of resistance to M. tuberculosis infection in TNFtm/tm and TNFR1−/− or TNFR2−/− × TNFtm/tm double transgenic mice. (a) Survival of mice infected by H37Rv i.n. (10–30 CFU per lung, n = 9–11 mice pooled from two independent experiments). (b) Mycobacterial burden in the lung (CFU) 6 weeks after infection. The results are expressed as the mean ± SD (n = 4–6 mice per group of transgenic mice).
Mentions: Lastly, we asked whether the protective effect of membrane TNF is signalled through TNFR1 or TNFR2. Therefore, we generated double transgenic mice by crossing TNFtm/tm mice with TNFR1−/− or TNFR2−/− mice. We further assessed the mycobacterial burden in the lung of M. tuberculosis infected mice. In this experiment, TNF−/− mice lost weight rapidly and died within 5 weeks, while TNFtm/tm mice were less sensitive, half surviving up to 45 days. TNFtm/tm × TNFR2 KO mice seemed essentially as sensitive as TNF−/− mice, while TNFtm/tm × TNFR1 KO mice behaved more like TNFtm/tm mice (Fig. 11a). Therefore, signalling of membrane TNF through TNF-R2 likely confers protection. This hypothesis is further corroborated by increased mycobacterial loads in the lung of TNFtm/tm × TNFR2 KO at 6 weeks post-infection, a time point when all TNF−/− had succumbed, essentially doubled as compared to TNFtm/tm or TNFtm/tm × TNFR1 KO mice (Fig. 11b).

Bottom Line: Membrane expressed TNF allowed a substantial recruitment of activated T cells and macrophages with granuloma formation and expression of bactericidal inducible nitric oxide synthase (iNOS).Using virulent Mycobacterium tuberculosis infection we confirm that membrane TNF conferred partial protection.Therefore, the data suggest that membrane-expressed TNF plays a critical role in host defence to mycobacterial infection and may partially substitute for soluble TNF.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, South Africa.

ABSTRACT
Tumour necrosis factor-alpha (TNF-alpha) plays a critical role in the recruitment and activation of mononuclear cells in mycobacterial infection. The role of membrane TNF, in host resistance against Mycobacterium bovis bacille Calmette-Guérin (BCG), was tested in knock-in mice in which the endogenous TNF was replaced by a non-cleavable and regulated allele (Delta1-12, TNF(tm/tm)). While 100% of mice with complete TNF deficiency (TNF(-/-)) succumbed to infection, 50% of TNF(tm/tm) mice were able to control M. bovis BCG infection and survived the experimental period. Membrane expressed TNF allowed a substantial recruitment of activated T cells and macrophages with granuloma formation and expression of bactericidal inducible nitric oxide synthase (iNOS). Using virulent Mycobacterium tuberculosis infection we confirm that membrane TNF conferred partial protection. Infection in TNF(tm/tm) double transgenic mice with TNF-R1 or TNF-R2 suggest protection is mediated through TNF-R2 signalling. Therefore, the data suggest that membrane-expressed TNF plays a critical role in host defence to mycobacterial infection and may partially substitute for soluble TNF.

Show MeSH
Related in: MedlinePlus