Differential effects of TNF and LTalpha in the host defense against M. bovis BCG.
Signaling via TNF receptor type 1 (TNFR1) was shown to be crucial in host defense against the intracellular pathogens L. monocytogenes, M. tuberculosis and M. bovis. To investigate the function of TNF and LTalpha in host defense against M. bovis, mice double deficient for TNF and LTalpha (TNF / LTalpha (- / -)), TNF / LTalpha (- / -) mice complemented with a murine LTalpha transgene (TNF(- / -)) and LTalpha (- / -) mice were infected with BCG and the ensuing pathology was investigated. Control mice showed a normal host defense with early clearance of bacteria. The granulomatous reaction in the liver was accompanied by recruitment of activated macrophages characterized by their acid phosphatase positivity and differentiation into epithelioid cells as well as a coordinated expression of proinflammatory transcripts. In contrast, TNF / LTalpha (- / -) mice showed no comparable recruitment of activated macrophages in the liver. Furthermore, these mice showed extensive necrotic pulmonary lesions with massive growth of acid fast bacilli. Reintroduction of LTalpha as a transgene into TNF / LTalpha (- / -) mice prolonged survival but did not restore resistance to BCG. This, at least partially protective role of LTalpha was further supported by data demonstrating that LTalpha -deficient mice as well were susceptible to BCG infection. In contrast to the deleterious effect of TNF / LTalpha deficiency in BCG infection, BCG-infected TNF / LTalpha (- / -) mice were tolerant to LPS-induced shock. These results demonstrate that TNF as well as LTalpha are involved in murine host defense against BCG and that absence of TNF / LTalpha protects BCG-infected mice from LPS mediated shock.
Bopst
M
M
Institute of Toxicology, Swiss Federal Institute of Technology, Schwerzenbach, Switzerland.
Garcia
I
I
Guler
R
R
Olleros
M L
ML
Rülicke
T
T
Müller
M
M
Wyss
S
S
Frei
K
K
Le Hir
M
M
Eugster
H P
HP
D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D015870:Gene Expression; D006099:Granuloma / Q000276:immunology; D007121:Immunocompetence / Q000276:immunology; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D009163:Mycobacterium bovis / Q000276:immunology*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
D018925:Chemokines; D016207:Cytokines; D008233:Lymphotoxin-alpha; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse