Essential mycobacterial gene glmM as an immunotherapeutic target against tuberculosis

Abstract

The limitations of TB treatment are the long duration and immune-dampening effects of anti-tuberculosis therapy. The cell wall of mycobacteria helps in its survival, pathogenicity, and virulence and provides resistance against different antibiotics. Hence, cell wall biosynthesis pathways and the enzymes involved are crucial and, thus, are good therapeutic targets. Here, we identify Mycobacterium tuberculosis (Mtb) GlmM, (GlmMMtb) involved in the UDP-GlcNAc synthesis pathway as an essential enzyme. Using the CRISPR interference-mediated gene silencing approach, we generated a conditional knockdown strain, Rv-glmMkD. Depletion of GlmMMtb affects the morphology and thickness of the cell wall. The Rv-glmMkD strain attenuated Mtb survival in vitro, in the host macrophages (ex vivo), and in a murine mice infection model (in vivo). Results suggest that the depletion of GlmMMtb induces M1 macrophage polarization, prompting a pro-inflammatory cytokine response, apparent from the upregulation of activation markers, including IFNɣ and IL-17 that resists the growth of Mtb. Collectively, these observations provide a rationale for exploring GlmMMtb as a potential therapeutic target.