Mycobacterium tuberculosis prevents inflammasome activation

Mycobacterium tuberculosis (Mtb) parasitizes host macrophages and subverts host innate and adaptive immunity. Several cytokines elicited by Mtb are mediators of mycobacterial clearance or are involved in tuberculosis pathology. Surprisingly, interleukin-1 beta (IL-1 beta), a major proinflammatory cytokine, has not been implicated in host-Mtb interactions. IL-1 beta is activated by processing upon assembly of the inflammasome, a specialized inflammatory caspase-activating protein complex. Here, we show that Mtb prevents inflammasome activation and IL-1 beta processing. An Mtb gene, zmp1, which encodes a putative Zn2+ metalloprotease, is required for this process. Infection of macrophages with zmp1-deleted Mtb triggered activation of the inflammasome, resulting in increased IL-1 beta secretion, enhanced maturation of Mtb containing phagosomes, improved mycobacterial clearance by macrophages, and lower bacterial burden in the lungs of aerosol-infected mice. Thus, we uncovered a previously masked role for IL-1 beta in the control of Mtb and a mycobacterial system that prevents inflammasome and, therefore, IL-1 beta activation.