Signaling via TNF receptor type 1 (TNFR1) was shown to be crucial in host d
efense against the intracellular pathogens L. monocytogenes, M. tuberculosi
s and M. bovis. To investigate the function of TNF and LT alpha in host def
ense against M. bovis, mice double deficient for TNF and LT alpha (TNF/LT a
lpha (-/-)), TNF/LT alpha (-/-) mice complemented with a murine LT alpha tr
ansgene (TNF-/-) and LT alpha (-/-) mice were infected with BCG and the ens
uing pathology was investigated. Control mice showed a normal host defense
with early clearance of bacteria. The granulomatous reaction in the liver w
as accompanied by recruitment of activated macrophages characterized by the
ir acid phosphatase positivity and differentiation into epithelioid cells a
s well as a coordinated expression of proinflammatory transcripts. In contr
ast, TNF/LT alpha (-/-) 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 LT alpha as a transgene into TNF/LT alpha (-/-) mice prolonged survival
but did not restore resistance to BCG. This, at least partially protective
role of LT alpha was further supported by data demonstrating that LT alpha
-deficient mice as well were susceptible to BCG infection. In contrast to
the deleterious effect of TNF/LT alpha deficiency in BCG infection, BCG-inf
ected TNF/LT alpha (-/-) mice were tolerant to LPS-induced shock. These res
ults demonstrate that TNF as well as LT alpha are involved in murine host d
efense against BCG and that absence of TNF/LT alpha protects BCG-infected m
ice from LPS mediated shock.