title: Membrane TNF confers protection to acute mycobacterial infection.
abstract: BACKGROUND
  Tumour necrosis factor (TNF) is crucial for the control of mycobacterial infection as TNF deficient (KO) die rapidly of uncontrolled infection with necrotic pneumonia. Here we investigated the role of membrane TNF for host resistance in knock-in mice with a non-cleavable and regulated allele (mem-TNF).
  
  
  METHODS
  C57BL/6, TNF KO and mem-TNF mice were infected with M. tuberculosis H37Rv (Mtb at 100 CFU by intranasal administration) and the survival, bacterial load, lung pathology and immunological parameters were investigated. Bone marrow and lymphocytes transfers were used to test the role of membrane TNF to confer resistance to TNF KO mice.
  
  
  RESULTS
  While TNF-KO mice succumbed to infection within 4-5 weeks, mem-TNF mice recruited normally T cells and macrophages, developed mature granuloma in the lung and controlled acute Mtb infection. However, during the chronic phase of infection mem-TNF mice succumbed to disseminated infection with necrotic pneumonia at about 150 days. Reconstitution of irradiated TNF-KO mice with mem-TNF derived bone marrow cells, but not with lymphocytes, conferred host resistance to Mtb infection in TNF-KO mice.
  
  
  CONCLUSIONS
  Membrane expressed TNF is sufficient to allow cell-cell signalling and control of acute Mtb infection. Bone marrow cells, but not lymphocytes from mem-TNF mice confer resistance to infection in TNF-KO mice. Long-term infection control with chronic inflammation likely disrupting TNF mediated cell-cell signalling, additionally requires soluble TNF.
authors.affiliation: Molecular Immunology and Embryology, Centre National de la Recherche Scientifique, Orléans, France. fremond@cnrs-orleans.fr
authors.forename: Cecile
authors.initials: C
authors.lastname: Fremond
authors.forename: Nasiema
authors.initials: N
authors.lastname: Allie
authors.forename: Ivy
authors.initials: I
authors.lastname: Dambuza
authors.forename: Sergei I
authors.initials: SI
authors.lastname: Grivennikov
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yeremeev
authors.forename: Valerie F J
authors.initials: VF
authors.lastname: Quesniaux
authors.forename: Muazzam
authors.initials: M
authors.lastname: Jacobs
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
mesh_terms: D000208:Acute Disease; D000818:Animals; D002462:Cell Membrane / Q000276:immunology*; D002478:Cells, Cultured; D019610:Cytoprotection / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency* / Q000276:immunology*
chemical_list: D014409:Tumor Necrosis Factor-alpha