title: Reactivation of M. tuberculosis infection in trans-membrane tumour necrosis factor mice.
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.
authors: Division of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors: Ivy
authors: I
authors: Dambuza
authors: Roanne
authors: R
authors: Keeton
authors: Nasiema
authors: N
authors: Allie
authors: Nai-Jen
authors: NJ
authors: Hsu
authors: Philippa
authors: P
authors: Randall
authors: Boipelo
authors: B
authors: Sebesho
authors: Lizette
authors: L
authors: Fick
authors: Valerie J F
authors: VJ
authors: Quesniaux
authors: Muazzam
authors: M
authors: Jacobs
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006099:Granuloma / Q000150:complications / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D014376:Tuberculosis / Q000150:complications / Q000382:microbiology* / Q000473:pathology* / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II