Cyclic di-AMP in Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) is the etiologic agent of tuberculosis (TB), which is the leading cause of death worldwide by a single bacterial pathogen. This bacterium encodes a diadenylate cyclase, which is a homolog of Bacillus subtilis DNA integrity scanning protein A (DisA) and converts ATP into cyclic di-adenosine monophosphate (cyclic di-AMP). Mtb also possesses a DHH/DHHA1 family cyclic di-AMP phosphodiesterase, CnpB, which degrades cyclic di-AMP into AMP. Interestingly, elevating cyclic di-AMP levels by either overexpression of Mtb disA or deletion of cnpB in this pathogen results in significant virulence attenuation in a mouse pulmonary TB model. It has also been shown that cyclic di-AMP from Mtb activates autophagy and limits the growth of bacteria within infected cells. These findings indicate that cyclic di-AMP plays an important role in TB pathogenesis. Mtb exports cyclic di-AMP via an undefined mechanism, which induces a type I interferon response in a STING-dependent manner within the infected host. In contrast, the current live vaccine strain M. bovis BCG is unable to secrete cyclic di-AMP and is defective in inducing a type I interferon response. Thus, enabling the vaccine strain to induce type I interferon may provide better protection against infection of Mtb.