Correction of defective host response to Mycobacterium bovis BCG infection in TNF-deficient mice by bone marrow transplantation.
Tumour necrosis factor-alpha (TNF) plays a central role in the recruitment and activation of mononuclear cells in mycobacterial infection. In the absence of type 1 TNF receptor, Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection of mice is not contained, leading to fatal disease. Because type 1 TNF receptor binds both TNF and lymphotoxin-a, we used TNF-deficient mice to determine the specific role of TNF in the host resistance to BCG infection. The bacterial burden of the lungs of TNF-deficient mice was substantially increased and the mice succumbed to pneumonia between 8 and 12 weeks with a defective granuloma response. Atypical granulomas developed by 4 weeks expressing low levels of MHC class II, intracellular adhesion molecule (ICAM-1), CD11b and CD11c. Macrophages showed little signs of activation and had low levels of acid phosphatase activity and inducible nitric oxide synthase (INOS) expression. Despite the defective cellular recruitment, the chemokines, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1alpha), were increased in broncho-alveolar lavage fluid of TNF-deficient mice. The defective host response was corrected by the transplantation of normal bone marrow cells into irradiated TNF-deficient mice. These results demonstrate that TNF derived from hemopoietic cells rather than from mesenchymal origin are essential for a normal host response to BCG infection. Furthermore, TNF dependent expression of adhesion molecules may be essential for the recruitment of mononuclear cells for the formation of bactericidal BCG granulomas.
Jacobs
M
M
Department of Immunology, University of Cape Town, South Africa.
Marino
M W
MW
Brown
N
N
Abel
B
B
Bekker
L G
LG
Quesniaux
V J
VJ
Fick
L
L
Ryffel
B
B
D000135:Acid Phosphatase / Q000032:analysis; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D016026:Bone Marrow Transplantation; D006099:Granuloma / Q000382:microbiology; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007113:Immunity, Innate; D016167:Integrin alphaXbeta2 / Q000032:analysis; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology* / Q000302:isolation & purification; D011014:Pneumonia / Q000382:microbiology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D014376:Tuberculosis / Q000150:complications / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*
D015703:Antigens, CD; D000949:Histocompatibility Antigens Class II; D016167:Integrin alphaXbeta2; D016177:Macrophage-1 Antigen; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D000135:Acid Phosphatase