Depletion of essential mycobacterial gene glmM reduces pathogen survival and induces host-protective immune responses...

The limitations of TB treatment are the long duration and immune-dampening effects of anti-tuberculosis therapy. The Cell wall plays a crucial role in survival and virulence; hence, enzymes involved in its biosynthesis are good therapeutic targets. Here, we identify Mycobacterium tuberculosis (Mtb) GlmM, (GlmM_Mtb) engaged in the UDP-GlcNAc synthesis pathway as an essential enzyme. We generated a conditional knockdown strain, Rv-glmM_kD using the CRISPR interference-mediated gene silencing approach. Depletion of GlmM_Mtb affects the morphology and thickness of the cell wall. The Rv-glmM_kD 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 GlmM_Mtb 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. These observations provide a rationale for exploring GlmM_Mtb as a potential therapeutic target.