title: Limited role for lymphotoxin α in the host immune response to Mycobacterium tuberculosis.
abstract: The contribution of lymphotoxin (LT)α in the host immune response to virulent Mycobacterium tuberculosis and Mycobacterium bovis bacillus Calmette-Guérin infections was investigated. Despite their ability to induce Th1 cytokine, IFN-γ, and IL-12 pulmonary response, "conventional" LTα(-/-) mice succumb rapidly to virulent M. tuberculosis aerosol infection, with uncontrolled bacilli growth, defective granuloma formation, necrosis, and reduced pulmonary inducible NO synthase expression, similar to TNF(-/-) mice. Contributions from developmental lymphoid abnormalities in LTα(-/-) mice were excluded because hematopoietic reconstitution with conventional LTα(-/-) bone marrow conferred enhanced susceptibility to wild-type mice, comparable to conventional LTα(-/-) control mice. However, conventional LTα(-/-) mice produced reduced levels of TNF after M. bovis bacillus Calmette-Guérin infection, and their lack of control of mycobacterial infection could be due to a defective contribution of either LTα or TNF, or both, to the host immune response. To address this point, the response of "neo-free" LTα(-/-) mice with unperturbed intrinsic TNF expression to M. tuberculosis infection was investigated in a direct comparative study with conventional LTα(-/-) mice. Strikingly, although conventional LTα(-/-) mice were highly sensitive, similar to TNF(-/-) mice, neo-free LTα(-/-) mice controlled acute M. tuberculosis infection essentially as wild-type mice. Pulmonary bacterial burden and inflammation was, however, slightly increased in neo-free LTα(-/-) mice 4-5 mo postinfection, but importantly, they did not succumb to infection. Our findings revise the notion that LTα might have a critical role in host defense to acute mycobacterial infection, independent of TNF, but suggest a contribution of LTα in the control of chronic M. tuberculosis infection.
authors.affiliation: Division of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Nasiema
authors.initials: N
authors.lastname: Allie
authors.forename: Roanne
authors.initials: R
authors.lastname: Keeton
authors.forename: Nathalie
authors.initials: N
authors.lastname: Court
authors.forename: Brian
authors.initials: B
authors.lastname: Abel
authors.forename: Lizette
authors.initials: L
authors.lastname: Fick
authors.forename: Virginie
authors.initials: V
authors.lastname: Vasseur
authors.forename: Rachel
authors.initials: R
authors.lastname: Vacher
authors.forename: Maria L
authors.initials: ML
authors.lastname: Olleros
authors.forename: Marina S
authors.initials: MS
authors.lastname: Drutskaya
authors.forename: Reto
authors.initials: R
authors.lastname: Guler
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
authors.forename: Irene
authors.initials: I
authors.lastname: Garcia
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Valerie F J
authors.initials: VF
authors.lastname: Quesniaux
authors.forename: Muazzam
authors.initials: M
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D008233:Lymphotoxin-alpha / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D016207:Cytokines; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II