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Updated: May 27, 2026
A 3D Human Lung Tissue Model for Functional Studies on Mycobacterium tuberculosis Infection
Published on: October 5, 2015
Reactivation of M. tuberculosis infection in trans-membrane tumour necrosis factor mice
Ivy Dambuza1, Roanne Keeton, Nasiema Allie
1Division of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Abstract:
Of those individuals who are infected with M. tuberculosis, 90% do not develop active disease and represents a large reservoir of M. tuberculosis with the potential for reactivation of infection. Sustained TNF expression is required for containment of persistent infection and TNF neutralization leads to tuberculosis reactivation. In this study, we investigated the contribution of soluble TNF (solTNF) and transmembrane TNF (Tm-TNF) in immune responses generated against reactivating tuberculosis. In a chemotherapy induced tuberculosis reactivation model, mice were challenged by aerosol inhalation infection with low dose M. tuberculosis for three weeks to establish infection followed chemotherapeutic treatment for six weeks, after which therapy was terminated and tuberculosis reactivation investigated. We demonstrate that complete absence of TNF results in host susceptibility to M. tuberculosis reactivation in the presence of established mycobacteria-specific adaptive immunity with mice displaying unrestricted bacilli growth and diffused granuloma structures compared to WT control mice. Interestingly, bacterial re-emergence is contained in Tm-TNF mice during the initial phases of tuberculosis reactivation, indicating that Tm-TNF sustains immune pressure as in WT mice. However, Tm-TNF mice show susceptibility to long term M. tuberculosis reactivation associated with uncontrolled influx of leukocytes in the lungs and reduced IL-12p70, IFNγ and IL-10, enlarged granuloma structures, and failure to contain mycobacterial replication relative to WT mice. In conclusion, we demonstrate that both solTNF and Tm-TNF are required for maintaining immune pressure to contain reactivating M. tuberculosis bacilli even after mycobacteria-specific immunity has been established.
Insights
Tumor necrosis factor (TNF) is crucial for controlling tuberculosis reactivation. Both soluble TNF (solTNF) and transmembrane TNF (Tm-TNF) are essential for sustained immune pressure against M. tuberculosis, even after adaptive immunity is established.
Area of Science:
- Immunology
- Infectious Diseases
- Microbiology
Background:
- 90% of Mycobacterium tuberculosis infections remain latent, forming a reservoir for potential reactivation.
- Sustained Tumor Necrosis Factor (TNF) expression is vital for containing persistent tuberculosis infection; TNF neutralization triggers reactivation.
- The distinct roles of soluble TNF (solTNF) and transmembrane TNF (Tm-TNF) in tuberculosis reactivation immunity require further investigation.
Purpose of the Study:
- To investigate the specific contributions of solTNF and Tm-TNF to immune responses during tuberculosis reactivation.
- To elucidate the mechanisms by which TNF variants influence host defense against M. tuberculosis reactivation.
Main Methods:
- A murine model of chemotherapy-induced tuberculosis reactivation was established using aerosol M. tuberculosis infection.
- Mice lacking TNF, or specifically Tm-TNF, were compared to wild-type (WT) controls following infection and treatment cessation.
- Analysis included bacillary load, granuloma structure, leukocyte infiltration, and cytokine profiles (IL-12p70, IFNγ, IL-10).
Main Results:
- Complete TNF deficiency led to susceptibility to M. tuberculosis reactivation, characterized by uncontrolled bacterial growth and diffuse granulomas.
- Tm-TNF-deficient mice initially contained bacterial re-emergence but later exhibited susceptibility to long-term reactivation.
- Tm-TNF deficiency was associated with lung inflammation, reduced key cytokines, and impaired control of mycobacterial replication compared to WT mice.
Conclusions:
- Both solTNF and Tm-TNF are indispensable for maintaining immune control over reactivating M. tuberculosis.
- Tm-TNF plays a role in initial containment, while both forms are required for sustained host defense against tuberculosis reactivation.
- These findings highlight the dual requirement of TNF forms for effective long-term control of latent M. tuberculosis infections.
