A novel tumor necrosis factor (TNF) mimetic peptide prevents recrudescence of Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection in CD4+ T cell-depleted mice

Abstract

Abstract Tumor necrosis factor (TNF) is required to control mycobacterial infections, but its therapeutic value is limited by its in vivo instability and toxicity. The efficacy of a nontoxic TNF-mimetic peptide (TNF70–80) was tested in mice infected with Mycobacterium bovis bacillus Calmette-Guerin (BCG).In vitro TNF70–80 and recombinant human TNF (hTNF) acted with interferon gamma (IFN-γ) to reduce bacterial replication and to induce synthesis of bactericidal nitric oxide (NO) in BCG-infected, bone marrow-derived murine macrophages. The dose-dependent inhibitory effect on bacterial replication was blocked by neutralizing anti-IFN-γ and anti-hTNF mAbs. Further,n-monomethyl-l-arginine (n-MMA) and a soluble TNF-receptor I (TNFRI-IgG) blocked bacterial growth and NO synthesis. Therefore, the peptide acted with IFN-γ via induction of NO synthase and signaled through TNFRI receptors. Concomitantin vivo treatment with TNF70–80 or hTNF prevented reactivation of chronic BCG infection in mice depleted of CD4+ T cells by injecting anti-CD4 antibodies. Granuloma number and bacterial load were comparable in treated, T cell-depleted mice and in chronically infected, intact animals. Thus, TNF70–80 and hTNF can modulate recrudescent BCG infection in CD4+ T cell-deficient mice.