Cyclic AMP intoxication of macrophages by a Mycobacterium tuberculosis adenylate cyclase

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Abstract
A previously unknown virulence mechanism has been identified for Mycobacterium tuberculosis: intoxication of host macrophages by bacterial-derived cyclic AMP. It was known that M. tuberculosis induces increased cyclic AMP levels in infected macrophages; this cyclic AMP is now shown to be produced by bacterial adenylate cyclase, and to enhance virulence presumably through the activation of downstream signalling pathways. The cyclic AMP stimulates host TNF-α (tumour necrosis factor-α) and causes more extensive liver disease and improved bacterial survival in infected mice. This work highlights signal transduction interference by M. tuberculosis as a possible new target for antituberculosis drugs. Mycobacterium tuberculosis induces a cyclic AMP (cAMP) burst within infected macrophages that influences cell signalling, but the underlying mechanism for this increase in cAMP remains unclear. It is now shown that it is produced by a bacterial adenylate cyclase that facilitates delivery of bacterial-derived cAMP into the macrophage cytoplasm, presumably enhancing virulence through the activation of downstream signalling pathways. With 8.9 million new cases and 1.7 million deaths per year, tuberculosis is a leading global killer that has not been effectively controlled1,2. The causative agent, Mycobacterium tuberculosis, proliferates within host macrophages where it modifies both its intracellular and local tissue environment, resulting in caseous granulomas with incomplete bacterial sterilization3,4. Although infection by various mycobacterial species produces a cyclic AMP burst within macrophages that influences cell signalling, the underlying mechanism for the cAMP burst remains unclear5,6,7. Here we show that among the 17 adenylate cyclase genes present in M. tuberculosis, at least one (Rv0386) is required for virulence. Furthermore, we demonstrate that the Rv0386 adenylate cyclase facilitates delivery of bacterial-derived cAMP into the macrophage cytoplasm. Loss of Rv0386 and the intramacrophage cAMP it delivers results in reductions in TNF-α production via the protein kinase A and cAMP response-element-binding protein pathway, decreased immunopathology in animal tissues, and diminished bacterial survival. Direct intoxication of host cells by bacterial-derived cAMP may enable M. tuberculosis to modify both its intracellular and tissue environments to facilitate its long-term survival.