Cyclic AMP intoxication of macrophages by a Mycobacterium tuberculosis adenylate cyclase

Nisheeth Agarwal, et al. 2009. Nat. 460, 98-102

Speaker: Wei-Zhi, Wang(王緯智)                         Time: 15:00~16:00, Jan. 6, 2010

Commentator: Dr. Lien-I Hor(何漣漪老師)        Place: Room 601

Abstract:

Mycobacterium tuberculosis has several ways to evade killing by immune cells. One of strategies is to increase to intracellular cyclic AMP (cAMP) in macrophages. cAMP is a well-known secondary messenger. After the first messengers bind to G-protein-coupled receptors (GPCR), adenylate cyclase (AC) is activated to produce cAMP. The increase of cAMP level would promote cAMP response-element-binding protein (CREB) phosphorylation by protein kinase A (PKA). The phosphorylated CREB is a transcriptional factor which enters nucleus and regulates immune response in macrophages. It had been reported that cAMP burst occurs in macrophage in Mycobacterium bacteria infection, but the source and effects of cAMP are still unclear. First, the authors confirmed that cAMP burst and CREB phosphorylation occurs when macrophage were infected with live M. tuberculosis. To find out the major source of cAMP, the authors used a M. tuberculosis strain which overexpresses phosphdiesterase (PDE) to prove that cAMP was mainly produced by M. tuberculosis AC. In order to investigate the role of M. tuberculosis AC in pathogenesis, the authors used a M. tuberculosis mutant (JHU-0386), which is mutate on the gene Rv0386 and loses the ability to produce cAMP to infect WT and Tnfa-/- mice. The bacterial load of JHU-0386 was obviously decreased in WT mice but not in Tnfa-/- mice. All information indicated the Rv0386 is important for M. tuberculosis virulence. Finally, the authors provided a direct evidence to demonstrate that M. tuberculosis produce cAMP in macrophage during infection. The authors infected macrophages with M. tuberculosis strains pre-culture with [¹⁴C]-glycerol, and radiolabelled (bacterial-derived) cAMP levels were observed in cytoplasm of macrophages. In this study, the authors made clear that the source of cAMP is from M. tuberculosis and found out the major AC gene Rv0836 plays a role in M. tuberculosis virulence.

References:

1.      Bai, G., et al. 2009. cAMP levels within Mycobacterium tuberculosis and Mycobacterium bovis BCG increase upon infection of macrophages. FEMS Immunol. Med. Microbiol. 55, 68–73 .

2.      Lowrie, D. B., et al. 1975. Mycobacterium microti may protect itself from intracellular destruction by releasing cyclic AMP into phagosomes.Nature 254, 600–602.