title: Efficacy of membrane TNF mediated host resistance is dependent on mycobacterial virulence.
abstract: TNF is required for protection against virulent and non-virulent mycobacterial infections. Here we compared the effect of Tm-TNF and sTNF, two different molecular forms of TNF, in virulent and non-virulent murine challenge models. Using non-virulent Mycobacterium bovis BCG intranasal infection we established that immunity is durably compromised in Tm-TNF mice, with augmented bacilli burden, leading to chronic but non-lethal infection. Acute infection by a virulent Mycobacterium tuberculosis low-dose aerosol challenge was controlled in Tm-TNF mice with bacilli burdens equivalent to that in WT mice and pulmonary pathology characterised by the formation of well-defined, bactericidal granulomas. Protective immunity was however compromised in Tm-TNF mice during the chronic phase of M. tuberculosis infection, with increased lung bacterial growth and inflammatory cell activation, dissolution of granulomas associated with dispersed iNOS expression, increased pulmonary IFNgamma and IL-10 expression but decreased IL-12 production, followed by death. In conclusion, membrane TNF is sufficient to control non-virulent, M. bovis BCG infection, and acute but not chronic infection with virulent M. tuberculosis.
authors.affiliation: Division of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa.
authors.forename: I
authors.initials: I
authors.lastname: Dambuza
authors.forename: N
authors.initials: N
authors.lastname: Allie
authors.forename: L
authors.initials: L
authors.lastname: Fick
authors.forename: N
authors.initials: N
authors.lastname: Johnston
authors.forename: C
authors.initials: C
authors.lastname: Fremond
authors.forename: J
authors.initials: J
authors.lastname: Mitchell
authors.forename: V F J
authors.initials: VF
authors.lastname: Quesniaux
authors.forename: B
authors.initials: B
authors.lastname: Ryffel
authors.forename: M
authors.initials: M
authors.lastname: Jacobs
mesh_terms: D000208:Acute Disease; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D004198:Disease Susceptibility; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009163:Mycobacterium bovis / Q000254:growth & development / Q000302:isolation & purification / Q000472:pathogenicity*; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000302:isolation & purification / Q000472:pathogenicity*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D014375:Tuberculoma / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D014774:Virulence
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II