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Tumour necrosis factor-alpha (TNF-alpha) in the host resistance to mycobacteria of distinct virulence
R Appelberg1, A Sarmento, A G Castro
1Centro de Citologia Experimental, University of Porto, Portugal.
Abstract:
The relative virulence of different isolates of Mycobacterium avium has been linked to their capacity to trigger the secretion of TNF from the macrophages they infect. Smooth opaque (SmOp) variants of Myco. avium have been shown to trigger higher expression of TNF-alpha by macrophages in vitro than the smooth transparent (SmTr) variants. To analyse the role of TNF in resistance to infection by Myco. avium, we studied the infection by two different morphotypes of strain 2.151 of Myco. avium both in vitro and in vivo in the presence or absence of neutralizing antibodies to TNF. No effects were found in vitro regarding the growth of either isolate of Myco. avium. In vivo, only the virulent SmTr morphotype showed enhanced growth in the presence of the neutralizing antibodies. This enhancement occurred relatively late when priming for TNF secretion in vivo was evident. Among four isolates of Myco. avium, three virulent ones induced a marked priming for TNF release and one avirulent strain did not. Mycobacterium tuberculosis H37Ra, which is very active in inducing TNF release due to its lipoarabinomannan moiety, was used to compare with the previous results. The growth of H37Ra in macrophages was increased in vitro by the neutralization of TNF and neutralization of either TNF and/or interferon-gamma (IFN-gamma) enhanced the in vivo proliferation of this microbe in the spleen and liver of infected animals, whereas only the combination of both anti-TNF and anti-IFN-gamma enhanced bacterial proliferation in the lung. We conclude that resistance to the avirulent strains of Myco. avium did not involve TNF, but rather antimicrobial mechanisms expressed constitutively in the mononuclear phagocytes. In contrast, TNF plays an important role in the control of Myco. tuberculosis H37Ra infection.
Insights
Tumor necrosis factor (TNF) influences Mycobacterium avium virulence, with its neutralization enhancing virulent strains in vivo. Resistance to avirulent strains relies on innate immunity, not TNF.
Area of Science:
- Immunology
- Microbiology
- Infectious Diseases
Background:
- Virulence of Mycobacterium avium strains correlates with their ability to induce tumor necrosis factor (TNF) secretion from infected macrophages.
- Smooth opaque (SmOp) variants of M. avium induce higher TNF-alpha expression in vitro compared to smooth transparent (SmTr) variants.
Purpose of the Study:
- To investigate the role of TNF in resistance to Mycobacterium avium infection.
- To analyze the impact of TNF neutralization on M. avium morphotype growth in vitro and in vivo.
- To compare the TNF response to M. avium with that of Mycobacterium tuberculosis H37Ra.
Main Methods:
- Studied M. avium strain 2.151 morphotypes (SmOp and SmTr) in vitro and in vivo.
- Utilized neutralizing antibodies against TNF to assess its role in infection.
- Compared M. avium results with Mycobacterium tuberculosis H37Ra, using TNF and interferon-gamma (IFN-gamma) neutralization.
Main Results:
- In vitro, TNF neutralization did not affect M. avium growth.
- In vivo, virulent SmTr morphotype M. avium showed increased growth with TNF neutralization, particularly late in infection.
- Virulent M. avium isolates primed for TNF release, unlike one avirulent strain.
- TNF neutralization enhanced Mycobacterium tuberculosis H37Ra growth in vitro; combined TNF and IFN-gamma neutralization boosted its proliferation in vivo.
Conclusions:
- Resistance to avirulent M. avium strains involves constitutive antimicrobial mechanisms in mononuclear phagocytes, independent of TNF.
- TNF plays a significant role in controlling Mycobacterium tuberculosis H37Ra infection.