Contribution of transmembrane tumor necrosis factor to host defense against Mycobacterium bovis bacillus Calmette-guerin and Mycobacterium tuberculosis infections.
To study the specific role of transmembrane tumor necrosis factor (TmTNF) in host defense mechanisms against bacillus Calmette-Guerin (BCG) and Mycobacterium tuberculosis infections, we compared the immune responses of TNF/lymphotoxin (LT)-alpha(-/-) mice expressing a noncleavable transgenic TmTNF (TmTNF tg) to those of TNF/LT-alpha(-/-) and wild-type mice. Susceptibility of TNF/LT-alpha(-/-) mice to BCG infection was associated with impaired induction of systemic RANTES but not of monocyte chemoattractant protein 1 (MCP-1), the development of excessive local and systemic Th1-type immune responses, and a substantially reduced inducible nitric oxide synthase (iNOS) activity. Resistance of TmTNF tg mice to BCG infection was associated with efficient activation of iNOS in granulomas and with the regulated release of local and systemic chemokines and Th1-type cytokines. However, M. tuberculosis infection of TmTNF tg mice resulted in longer survival and enhanced resistance compared to TNF/LT-alpha(-/-) mice but higher sensitivity than wild-type mice. TmTNF tg mice exhibited reduced pulmonary iNOS expression and showed an exacerbated cellular infiltration in the lungs despite a modest bacillary content. Our data thus indicate a role for TmTNF in host defense against mycobacteria by contributing to induction and regulation of Th1-type cytokine and chemokine expression leading to development of bactericidal granulomas expressing iNOS, which critically determines susceptibility versus resistance of the host to mycobacterial infections.
Olleros
Maria L
ML
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
Guler
Reto
R
Vesin
Dominique
D
Parapanov
Roumen
R
Marchal
Gilles
G
Martinez-Soria
Eduardo
E
Corazza
Nadia
N
Pache
Jean-Claude
JC
Mueller
Christoph
C
Garcia
Irene
I
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D006099:Granuloma / Q000276:immunology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000473:pathology; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009163:Mycobacterium bovis / Q000276:immunology*; D019001:Nitric Oxide Synthase / Q000276:immunology / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology* / Q000473:pathology* / Q000662:veterinary; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D016207:Cytokines; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse