Inactivation of the Mycobacterium tuberculosis fadB4 gene results in increased virulence in host cell and mice

The genome of Mycobacterium tuberculosis encodes many proteins involved in fatty acid metabolism, a subset of which are required for virulence. The Mycobacterium tuberculosis fadB4 gene, which shares strong similarity with oxidoreductases and fatty acid synthases, is up-regulated during infection of macrophages and is predicted to protect the bacterium from the hostile environment of the host cell. In order to determine if fadB4 plays a role in the virulence of M. tuberculosis, we constructed a M. tuberculosis mutant in which the fadB4 had been disrupted (ΔfadB4). Surprisingly, ΔfadB4, grew more rapidly in host cells compared to wild-type M. tuberculosis or the ΔfadB4 or the gene-disrupted strain complemented with fadB4. In addition, macrophages infected with ΔfadB4 displayed reduced secretion of the cytokine TNF-α, suggesting a role for the FadB4 protein in influencing the pro-inflammatory host response to M. tuberculosis. After infection of mice, ΔfadB4 demonstrated an increased replication at early time-points post-infection compared to the growth of wild-type M. tuberculosis. This increased capacity of ΔfadB4 to replicate in vivo was reflected in the decreased time to death of immuno-deficient RAG-1−/− mice infected with M. tuberculosis lacking the fadB4 gene. Therefore fadB4 is part of the family of genes whose expression serves to regulate the virulence of M. tuberculosis within the host.