Membrane TNF confers protection to acute mycobacterial infection.
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.
Fremond
Cecile
C
Molecular Immunology and Embryology, Centre National de la Recherche Scientifique, Orléans, France. fremond@cnrs-orleans.fr
Allie
Nasiema
N
Dambuza
Ivy
I
Grivennikov
Sergei I
SI
Yeremeev
Vladimir
V
Quesniaux
Valerie F J
VF
Jacobs
Muazzam
M
Ryffel
Bernhard
B
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*
D014409:Tumor Necrosis Factor-alpha