Correction of Defective Host Response to Mycobacterium Bovis BCG Infection in TNF-Deficient Mice by Bone Marrow Transplantation

Abstract

SUMMARY:Tumour necrosis factor-␣ (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-Gué rin (BCG) infection of mice is not contained, leading to fatal disease. Because type 1 TNF receptor binds both TNF and lymphotoxin-␣, 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-1␣), 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. (Lab Invest 2000, 80:901-914).

A role for c-Myc in regulating anti-mycobacterial responses

“…For instance, in conjunction with TGF-β, IL-6 has been suggested to initiate the differentiation of T H 17 cells, leading to the subsequent maintenance of granulomas and the expression of memory responses (40). Additionally, TNF-α produced from macrophages plays an important role in suppressing the intracellular growth of mycobacteria and involving in the formation of granulomas to prevent dissemination of mycobacterial infection (41,42). Furthermore, these cytokines induced by TLR and its MyD88-IRAK1-dependent signaling pathway can lead to protection against not only mycobacteria (43) but also other intracellular pathogens such as Listeria monocytogenes and Toxoplasma gondii (44).…”

Chronic pneumonia despite adaptive immune response to Mycobacterium bovis BCG in MyD88-deficient mice

“…The relative resistance of MyD88-deficient mice contrasts with the rapid death observed in the absence of TNF after systemic BCG infection, usually within 2-3 months. 40,41 However, low levels of local TNF suffice to prevent mortality in TNF-deficient mice infected with TNF-expressing recombinant BCG. 42 ).…”

Réponse adaptative à la tuberculose en l’absence de MyD88

“…En effet, les souris déficientes en TNF meurent 3 à 5 semaines après une infection par M. tb ou par la souche vaccinale atténuée M. bovis BCG (bacille de Calmette-Guérin) [1,2]. Nous nous sommes attachés à comprendre les évé-nements en amont de l'expression du TNF, notamment les mécanismes molé-culaires de la reconnaissance des structures spécifiques aux mycobactéries par des récepteurs de l'hôte.…”

“…Nous avons étu-dié le rôle de ces récepteurs TLR dans la réponse à la tuberculose et la transmission de leur signal, notamment par la voie de signalisation MyD88 (myeloid differentiation protein 88) (Figure 1). Plusieurs études ont montré un phéno-type relativement limité des souris défi-cientes en TLR2 et/ou TLR4 à l'infection aiguë à M. tb [4][5][6][7], ou à M. bovis BCG [8,9], contrairement à l'extrême sensibilité des souris déficientes en TNF [1,2]. Cependant, l'absence de TLR2 ou TLR4 semble conduire à un défaut du contrôle à long terme de l'infection chronique à M. tb [4,7].…”