Differential effects of TNF and LTα in the host defense againstM. bovis BCG

Abstract

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. Toinvestigate the function of TNF and LTα in host defense against M. bovis, mice double deficient for TNF and LTα (TNF / LTα – / –), TNF / LTα – / – mice complemented with a murine LTα transgene (TNF– / –) and LTα – / – 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 / LTα – / – 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 LTα as a transgene into TNF / LTα – / – mice prolonged survival but did not restore resistance to BCG. This, at least partially protective role of LTα was further supported by data demonstrating that LTα ‐deficient mice as well were susceptible to BCG infection. In contrast to the deleterious effect of TNF / LTα deficiency in BCG infection, BCG‐infected TNF / LTα – / – mice were tolerant to LPS‐induced shock. These results demonstrate that TNF as well as LTα are involved in murine host defense against BCG and that absence of TNF / LTα protects BCG‐infected mice from LPS mediated shock.

Transmembrane TNF Induces an Efficient Cell-Mediated Immunity and Resistance toMycobacterium bovisBacillus Calmette-Guérin Infection in the Absence of Secreted TNF and Lymphotoxin-α

“…This is probably less predominant in M. tuberculosis infection, in which the production of soluble factors results in more efficient response, although the unique presence of Tm TNF without soluble TNF or LT-␣ confers an important protection. Previously, it has been shown that inability to use TNF and LT-␣ in tg mice, TNF Ϫ/Ϫ mice, or LT-␣ Ϫ/Ϫ mice renders animals highly susceptible to M. tuberculosis and BCG infections (23)(24)(25)(26)45). Reduction of immune surveillance in mycobacterial infections leads to the excessive proliferation of intracellular bacteria in macrophages.…”

“…Neutralization of TNF with anti-TNF Abs or with soluble TNFR1-Ig fusion protein during M. bovis and M. tuberculosis infections or the absence of a functional TNF gene increased sensitivity by inhibiting macrophage differentiation and the development of well-differentiated granulomas, resulting in mycobacterial overgrowth and rapid animal death (20 -24). Recently, it has been shown that lymphotoxin-␣ (LT-␣) is also required for host defense against BCG and M. tuberculosis infections (25,26). A contribution of cell surface-bound LT-␣ 1 ␤ 2 in protective immunity against BCG infection has been reported (27).…”

Mycobacterium tuberculosisSubverts Innate Immunity to Evade Specific Effectors

“…In particular, TNF-␣ (10) and lymphotoxin (11) have been demonstrated crucial for granuloma formation and for limiting pathology, and therapies aimed at blocking TNF-␣ do increase the risk of reactivation tuberculosis in humans (12). However, in vitro experiments have failed to demonstrate that TNF-␣ can arm macrophages to kill intracellular bacilli (13).…”

Leprosy and the Human Genome

“…The C allele alters the binding site of the transcriptional repressor (158). The abrogation of the LTA signaling pathway in mice is associated with increased susceptibility to intracellular pathogens (38,116). Attempts to validate LTA SNP associations were made in two additional case-control studies in India (364 patients with leprosy and 371 controls) and Brazil (209 leprosy patients and 192 healthy controls) ( Table 1).…”