Mycobacterium tuberculosis (Mtb) promotes its survival by secreting a range of virulence factors that modulate immunity. As a result, protective immunity to tuberculosis (TB) is exceedingly difficult to achieve, whether by vaccination or natural infection. One clear correlate of protection from TB is an effective CD4 T cell response that leads to production of interferon gamma (IFN??. However, a long-standing question is why even a robust IFN? response fails to effectively control Mtb at the site of infection in the lung. Recent work has shown that the lung, and in particular the granuloma, is an immunosuppressive environment and that the most protective Mtb- specific T cells are systematically excluded from these sites where they are needed the most. While the mechanisms for this spatial exclusion are not fully understood, the immunosuppressive cytokine transforming growth factor ? (TGF?? is emerging as a potent factor of T cell subversion in TB. TGF? strongly co-localizes with Mtb in the granuloma, suggesting that Mtb may directly activate TGF? to subvert this microenvironment, disable CD4 T cell function, and extinguish IFN? signaling. We now show that Mtb lysate and culture filtrate protein can indeed effectively activate TGF? from its inert latent precursor. This activity is heat-labile, secreted by Mtb, and is inhibited by serine hydrolase inhibitors. Here, we will test the hypothesis that Mtb secretes a serine protease virulence factor that directly processes and activates TGF? to suppress productive CD4 T cell activation at the site of Mtb infection. This project aims to identify a new and direct host-pathgen interaction and a mechanism of Mtb pathogenesis that underlies the immune system?s failure to control Mtb infection.
The immune response to tuberculosis can be ineffective. This project seeks to identify a new Mycobacterium tuberculosis virulence factor that subverts the activation of T cells. This factor highlights a new mechanism of pathogenesis and could be a new therapeutic target.
