Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The myriad roles of cyclic AMP in microbial pathogens: from signal to sword

Nature Reviews Microbiology volume 10, pages 27–38 (2012)Cite this article

Subjects

Key Points

  • Cyclic AMP (cAMP) is a universal second messenger that is synthesized by adenylyl cyclases (ACs), which are often activated post-translationally in response to environmental signals. AC activation can be direct but often involves interaction with receptors and/or cofactors that transmit the activating signal. The signal is then transduced to downstream effector proteins through the binding of cAMP to specialized proteins.

  • cAMP is widely used by microbial pathogens and their mammalian hosts to regulate cellular processes in response to environmental signals, providing numerous opportunities for pathogens to manipulate their host environments during infection.

  • Bacterial pathogens have developed many strategies for elevating cAMP levels in host cells. This can suppress the innate immune responses of macrophages and can cause diarrhoea by activating ion channels in mucosal epithelial cells to secrete excessive amounts of fluid. Such strategies include direct production of cAMP by secreted bacterial AC toxins, secretion of cAMP from bacteria, or stimulation of host ACs to overproduce cAMP through the use of ADP-ribosylating toxins and aberrant activation of AC-stimulating pathways.

  • Pathogens often use cAMP to regulate expression of virulence-associated genes, and this subversion may be coordinated with environmental signals present within the host. These regulatory pathways are complex and are specially adapted in each organism.

  • Most bacteria use cAMP-responsive protein (Crp)-family transcription factors, which are directly activated by cAMP, to regulate this gene expression. Eukaryotic pathogens such as fungi and protozoa use a kinase intermediate (the protein kinase A complex) to activate their transcription factors via the cAMP pathway; a family of cAMP-binding EPAC (exchange proteins activated by cAMP) proteins may represent a new class of cAMP-activated transcription factors in eukaryotes.

Abstract

All organisms must sense and respond to their external environments, and this signal transduction often involves second messengers such as cyclic nucleotides. One such nucleotide is cyclic AMP, a universal second messenger that is used by diverse forms of life, including mammals, fungi, protozoa and bacteria. In this review, we discuss the many roles of cAMP in bacterial, fungal and protozoan pathogens and its contributions to microbial pathogenesis. These roles include the coordination of intracellular processes, such as virulence gene expression, with extracellular signals from the environment, and the manipulation of host immunity by increasing cAMP levels in host cells during infection.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cyclic AMP translates environmental signals into regulatory outcomes.
Figure 2: Genetic regulation by cyclic AMP signalling in Pseudomonas aeruginosa.
Figure 3: Genetic regulation by cyclic AMP signalling in Vibrio cholerae.
Figure 4: Genetic regulation by cyclic AMP signalling in Mycobacterium tuberculosis.
Figure 5: Bacterial manipulation of host cyclic AMP levels.
Figure 6: Cyclic AMP signalling pathways in fungal pathogens.
Figure 7: Model for cyclic AMP signalling leading to exocytosis in Plasmodium spp. sporozoites.

Similar content being viewed by others

References

  1. Baumann, A., Lange, C. & Soppa, J. Transcriptome changes and cAMP oscillations in an archaeal cell cycle. BMC Cell Biol. 8, 21–40 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Beavo, J. A. & Brunton, L. L. Cyclic nucleotide research — still expanding after half a century. Nature Rev. Mol. Cell Biol. 3, 710–718 (2002).

    Article  CAS  Google Scholar 

  3. Insel, P. A., Zhang, L., Murray, F., Yokouchi, H. & Zambon, A. C. Cyclic AMP is both a pro-apoptotic and anti-apoptotic second messenger. Acta Physiol. (Oxf.) 26 May 2011 (doi:10.1111/j.1748-1716.2011.02273.x).

    Article  CAS  PubMed  Google Scholar 

  4. Tojima, T., Hines, J. H., Henley, J. R. & Kamiguchi, H. Second messengers and membrane trafficking direct and organize growth cone steering. Nature Rev. Neurosci. 12, 191–203 (2011).

    Article  CAS  Google Scholar 

  5. Camilli, A. & Bassler, B. L. Bacterial small-molecule signaling pathways. Science 311, 1113–1116 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rumbaugh, K. P. Convergence of hormones and autoinducers at the host/pathogen interface. Anal. Bioanal. Chem. 387, 425–435 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Gomelsky, M. cAMP, c-di-GMP, c-di-AMP and now cGMP: bacteria use them all! Mol. Microbiol. 79, 562–565 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Romling, U. Great times for small molecules: c-di-AMP, a second messenger candidate in bacteria and archaea. Sci. Signal. 1, pe39 (2008).

    Article  PubMed  Google Scholar 

  9. Dalebroux, Z. D., Svensson, S. L., Gaynor, E. C. & Swanson, M. S. ppGpp conjures bacterial virulence. Microbiol. Mol. Biol. Rev. 74, 171–199 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Potrykus, K. & Cashel, M. (p)ppGpp: still magical? Annu. Rev. Microbiol. 62, 35–51 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Springett, G. M., Kawasaki, H. & Spriggs, D. R. Non-kinase second-messenger signaling: new pathways with new promise. Bioessays 26, 730–738 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Simeoni, L., Smida, M., Posevitz, V., Schraven, B. & Lindquist, J. A. Right time, right place: the organization of membrane proximal signaling. Semin. Immunol. 17, 35–49 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Tang, W. J., Yan, S. & Drum, C. L. Class III adenylyl cyclases: regulation and underlying mechanisms. Adv. Second Messenger Phosphoprotein Res. 32, 137–151 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Botsford, J. L. & Harman, J. G. Cyclic AMP in prokaryotes. Microbiol. Rev. 56, 100–122 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Kamenetsky, M. et al. Molecular details of cAMP generation in mammalian cells: a tale of two systems. J. Mol. Biol. 362, 623–639 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Altarejos, J. Y. & Montminy, M. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nature Rev. Mol. Cell Biol. 12, 141–151 (2011).

    Article  CAS  Google Scholar 

  17. Kolb, A., Busby, S., Buc, H., Garges, S. & Adhya, S. Transcriptional regulation by cAMP and its receptor protein. Annu. Rev. Biochem. 62, 749–795 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Kresge, N., Simoni, R. D. & Hill, R. L. Earl W. Sutherland's discovery of cyclic adenine monophosphate and the second messenger system. J. Biol. Chem. 280, e39–e40 (2005).

    CAS  Google Scholar 

  19. Serezani, C. H., Ballinger, M. N., Aronoff, D. M. & Peters-Golden, M. Cyclic AMP: master regulator of innate immune cell function. Am. J. Respir. Cell. Mol. Biol. 39, 127–132 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Botsford, J. L. Cyclic nucleotides in procaryotes. Microbiol. Rev. 45, 620–642 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Gorke, B. & Stulke, J. Carbon catabolite repression in bacteria: many ways to make the most out of nutrients. Nature Rev. Microbiol. 6, 613–624 (2008).

    Article  CAS  Google Scholar 

  22. Masure, H. R., Shattuck, R. L. & Storm, D. R. Mechanisms of bacterial pathogenicity that involve production of calmodulin-sensitive adenylate cyclases. Microbiol. Rev. 51, 60–65 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhan, L. et al. The cyclic AMP receptor protein, CRP, is required for both virulence and expression of the minimal CRP regulon in Yersinia pestis biovar microtus. Infect. Immun. 76, 5028–5037 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Petersen, S. & Young, G. M. Essential role for cyclic AMP and its receptor protein in Yersinia enterocolitica virulence. Infect. Immun. 70, 3665–3672 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rickman, L. et al. A member of the cAMP receptor protein family of transcription regulators in Mycobacterium tuberculosis is required for virulence in mice and controls transcription of the rpfA gene coding for a resuscitation promoting factor. Mol. Microbiol. 56, 1274–1286 (2005). This is the first study to implicate a cAMP signalling pathway in M. tuberculosis virulence.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Smith, R. S., Wolfgang, M. C. & Lory, S. An adenylate cyclase-controlled signaling network regulates Pseudomonas aeruginosa virulence in a mouse model of acute pneumonia. Infect. Immun. 72, 1677–1684 (2004). This paper provides the first direct evidence that cAMP is required for P. aeruginosa virulence through its control of the T3SS, and shows that the class III AC CyaB is more crucial to this phenotype than the class I AC CyaA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Curtiss, R. 3rd & Kelly, S. M. Salmonella typhimurium deletion mutants lacking adenylate cyclase and cyclic AMP receptor protein are avirulent and immunogenic. Infect. Immun. 55, 3035–3043 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Bai, G., Knapp, G. S. & McDonough, K. A. Cyclic AMP signalling in mycobacteria: redirecting the conversation with a common currency. Cell. Microbiol. 13, 349–358 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Wang, M. et al. Microbial hijacking of complement–Toll-like receptor crosstalk. Sci. Signal. 3, ra111 (2010).

    Google Scholar 

  30. Lee, H. J., Park, S. J., Choi, S. H. & Lee, K. H. Vibrio vulnificus rpoS expression is repressed by direct binding of cAMP-cAMP receptor protein complex to its two promoter regions. J. Biol. Chem. 283, 30438–30450 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fuentes, J. A., Jofre, M. R., Villagra, N. A. & Mora, G. C. RpoS- and Crp-dependent transcriptional control of Salmonella Typhi taiA and hlyE genes: role of environmental conditions. Res. Microbiol. 160, 800–808 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Hengge-Aronis, R. Signal transduction and regulatory mechanisms involved in control of the σS (RpoS) subunit of RNA polymerase. Microbiol. Mol. Biol. Rev. 66, 373–395 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fong, J. C. & Yildiz, F. H. Interplay between cyclic AMP-cyclic AMP receptor protein and cyclic di-GMP signaling in Vibrio cholerae biofilm formation. J. Bacteriol. 190, 6646–6659 (2008). This work shows that cAMP–Crp controls biofilm formation in V. cholerae by regulating the expression of a set of genes encoding diguanylyl cyclases and PDEs. This link to c-di-GMP second-messenger signalling is an example of cAMP signal amplification by its regulation of other global regulators.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim, T. J. et al. Direct transcriptional control of the plasminogen activator gene of Yersinia pestis by the cyclic AMP receptor protein. J. Bacteriol. 189, 8890–8900 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhan, L. et al. Direct and negative regulation of the sycO-ypkA-ypoJ operon by cyclic AMP receptor protein (CRP) in Yersinia pestis. BMC Microbiol. 9, 178 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nielsen, A. T. et al. A bistable switch and anatomical site control Vibrio cholerae virulence gene expression in the intestine. PLoS Pathog. 6, e1001102 (2010). This article discusses how cAMP signalling integrates localized environmental signals with virulence gene expression in V. cholerae during infection. It also demonstrates that cAMP–Crp controls a bistable switch that allows a subpopulation of bacteria to continue to express virulence factors for an extended period of time in rice water stools of patients with cholera. This may facilitate transmission without decreasing fitness.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yahr, T. L., Vallis, A. J., Hancock, M. K., Barbieri, J. T. & Frank, D. W. ExoY, an adenylate cyclase secreted by the Pseudomonas aeruginosa type III system. Proc. Natl Acad. Sci. USA 95, 13899–13904 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Engel, J. & Balachandran, P. Role of Pseudomonas aeruginosa type III effectors in disease. Curr. Opin. Microbiol. 12, 61–66 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Wolfgang, M. C., Lee, V. T., Gilmore, M. E. & Lory, S. Coordinate regulation of bacterial virulence genes by a novel adenylate cyclase-dependent signaling pathway. Dev. Cell 4, 253–263 (2003). This study identifies cAMP and the cAMP-binding protein Vfr as regulators of the expression of virulence genes expression, including those genes encoding the T3SS, in P. aeruginosa.

    Article  CAS  PubMed  Google Scholar 

  40. Lory, S., Wolfgang, M., Lee, V. & Smith, R. The multi-talented bacterial adenylate cyclases. Int. J. Med. Microbiol. 293, 479–482 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Suh, S. J. et al. Effect of vfr mutation on global gene expression and catabolite repression control of Pseudomonas aeruginosa. Microbiology 148, 1561–1569 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. West, S. E., Sample, A. K. & Runyen-Janecky, L. J. The vfr gene product, required for Pseudomonas aeruginosa exotoxin A and protease production, belongs to the cyclic AMP receptor protein family. J. Bacteriol. 176, 7532–7542 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fuchs, E. L. et al. The Pseudomonas aeruginosa Vfr regulator controls global virulence factor expression through cyclic AMP-dependent and -independent mechanisms. J. Bacteriol. 192, 3553–3564 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Fuchs, E. L. et al. In vitro and in vivo characterization of the Pseudomonas aeruginosa cyclic AMP (cAMP) phosphodiesterase CpdA, required for cAMP homeostasis and virulence factor regulation. J. Bacteriol. 192, 2779–2790 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Endoh, T. & Engel, J. N. CbpA: a polarly localized novel cyclic AMP-binding protein in Pseudomonas aeruginosa. J. Bacteriol. 191, 7193–7205 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Skorupski, K. & Taylor, R. K. Cyclic AMP and its receptor protein negatively regulate the coordinate expression of cholera toxin and toxin-coregulated pilus in Vibrio cholerae. Proc. Natl Acad. Sci. USA 94, 265–270 (1997). This paper describes some of the earliest evidence that cAMP has a role in virulence gene expression in V. cholerae . Recent studies have revealed just how extensive this role is.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Liang, W., Pascual-Montano, A., Silva, A. J. & Benitez, J. A. The cyclic AMP receptor protein modulates quorum sensing, motility and multiple genes that affect intestinal colonization in Vibrio cholerae. Microbiology 153, 2964–2975 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Beyhan, S., Bilecen, K., Salama, S. R., Casper-Lindley, C. & Yildiz, F. H. Regulation of rugosity and biofilm formation in Vibrio cholerae: comparison of VpsT and VpsR regulons and epistasis analysis of vpsT, vpsR, and hapR. J. Bacteriol. 189, 388–402 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Hammer, B. K. & Bassler, B. L. Quorum sensing controls biofilm formation in Vibrio cholerae. Mol. Microbiol. 50, 101–104 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Zhu, J. & Mekalanos, J. J. Quorum sensing-dependent biofilms enhance colonization in Vibrio cholerae. Dev. Cell 5, 647–656 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Matson, J. S., Withey, J. H. & DiRita, V. J. Regulatory networks controlling Vibrio cholerae virulence gene expression. Infect. Immun. 75, 5542–5549 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Miller, M. B., Skorupski, K., Lenz, D. H., Taylor, R. K. & Bassler, B. L. Parallel quorum sensing systems converge to regulate virulence in Vibrio cholerae. Cell 110, 303–314 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Liang, W., Sultan, S. Z., Silva, A. J. & Benitez, J. A. Cyclic AMP post-transcriptionally regulates the biosynthesis of a major bacterial autoinducer to modulate the cell density required to activate quorum sensing. FEBS Lett. 582, 3744–3750 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhu, J. et al. Quorum-sensing regulators control virulence gene expression in Vibrio cholerae. Proc. Natl Acad. Sci. USA 99, 3129–3134 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zahid, M. S. et al. The cyclic AMP (cAMP)-cAMP receptor protein signaling system mediates resistance of Vibrio cholerae O1 strains to multiple environmental bacteriophages. Appl. Environ. Microbiol. 76, 4233–4240 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Li, C. C., Merrell, D. S., Camilli, A. & Kaper, J. B. ToxR interferes with CRP-dependent transcriptional activation of ompT in Vibrio cholerae. Mol. Microbiol. 43, 1577–1589 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shenoy, A. R. & Visweswariah, S. S. New messages from old messengers: cAMP and mycobacteria. Trends Microbiol. 14, 543–550 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. McCue, L. A., McDonough, K. A. & Lawrence, C. E. Functional classification of cNMP-binding proteins and nucleotide cyclases with implications for novel regulatory pathways in Mycobacterium tuberculosis. Genome Res. 10, 204–219 (2000). This investigation is the first to identify an unusually large number of putative AC-encoding genes and cAMP-binding proteins in M. tuberculosis , suggesting that cAMP signalling constitutes a potentially key (but overlooked) signal transduction system in mycobacteria.

    Article  CAS  PubMed  Google Scholar 

  59. Shenoy, A. R., Sreenath, N. P., Mahalingam, M. & Visweswariah, S. S. Characterization of phylogenetically distant members of the adenylate cyclase family from mycobacteria: Rv1647 from Mycobacterium tuberculosis and its orthologue ML1399 from M. leprae. Biochem. J. 387, 541–551 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Linder, J. U., Hammer, A. & Schultz, J. E. The effect of HAMP domains on class IIIb adenylyl cyclases from Mycobacterium tuberculosis. Eur. J. Biochem. 271, 2446–2451 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Linder, J. U., Schultz, A. & Schultz, J. E. Adenylyl cyclase Rv1264 from Mycobacterium tuberculosis has an autoinhibitory N-terminal domain. J. Biol. Chem. 277, 15271–15276 (2002). This paper provides the first evidence for direct pH-mediated activation of an AC from M. tuberculosis.

    Article  CAS  PubMed  Google Scholar 

  62. Tews, I. et al. The structure of a pH-sensing mycobacterial adenylyl cyclase holoenzyme. Science 308, 1020–1023 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Bai, G., Schaak, D. D. & McDonough, K. A. cAMP levels within Mycobacterium tuberculosis and Mycobacterium bovis BCG increase upon infection of macrophages. FEMS Immunol. Med. Microbiol. 55, 68–73 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Padh, H. & Venkitasubramanian, T. A. Adenosine 3′, 5′-monophosphate in Mycobacterium phlei and Mycobacterium tuberculosis H37Ra. Microbios 16, 183–189 (1976).

    CAS  PubMed  Google Scholar 

  65. Agarwal, N., Lamichhane, G., Gupta, R., Nolan, S. & Bishai, W. R. Cyclic AMP intoxication of macrophages by a Mycobacterium tuberculosis adenylate cyclase. Nature 460, 98–102 (2009). This work demonstrates that cAMP produced by a specific bacterial AC during M. tuberculosis infection is secreted into macrophages and contributes to virulence.

    Article  CAS  PubMed  Google Scholar 

  66. Bai, G., McCue, L. A. & McDonough, K. A. Characterization of Mycobacterium tuberculosis Rv3676 (CRPMt), a cyclic AMP receptor protein-like DNA binding protein. J. Bacteriol. 187, 7795–7804 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Gazdik, M. A., Bai, G., Wu, Y. & McDonough, K. A. Rv1675c (cmr) regulates intramacrophage and cyclic AMP-induced gene expression in Mycobacterium tuberculosis-complex mycobacteria. Mol. Microbiol. 71, 434–448 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Nambi, S., Basu, N. & Visweswariah, S. S. cAMP-regulated protein lysine acetylases in mycobacteria. J. Biol. Chem. 285, 24313–24323 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ahuja, N., Kumar, P. & Bhatnagar, R. The adenylate cyclase toxins. Crit. Rev. Microbiol. 30, 187–196 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Krueger, K. M. & Barbieri, J. T. The family of bacterial ADP-ribosylating exotoxins. Clin. Microbiol. Rev. 8, 34–47 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Carbonetti, N. H. Pertussis toxin and adenylate cyclase toxin: key virulence factors of Bordetella pertussis and cell biology tools. Future Microbiol. 5, 455–469 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Carbonetti, N. H., Artamonova, G. V., Andreasen, C. & Bushar, N. Pertussis toxin and adenylate cyclase toxin provide a one-two punch for establishment of Bordetella pertussis infection of the respiratory tract. Infect. Immun. 73, 2698–2703 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Smith, N., Kim, S. K., Reddy, P. T. & Gallagher, D. T. Crystallization of the class IV adenylyl cyclase from Yersinia pestis. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 62, 200–204 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kim, C. et al. Antiinflammatory cAMP signaling and cell migration genes co-opted by the anthrax bacillus. Proc. Natl Acad. Sci. USA 105, 6150–6155 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Yeager, L. A., Chopra, A. K. & Peterson, J. W. Bacillus anthracis edema toxin suppresses human macrophage phagocytosis and cytoskeletal remodeling via the protein kinase A and exchange protein activated by cyclic AMP pathways. Infect. Immun. 77, 2530–2543 (2009). This study shows that, in addition to the inhibition of macrophage function caused through PKA-controlled pathways, cAMP produced by B. anthracis ET during infection disables macrophages through a PKA-independent pathway that requires newly identified EPAC proteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Maldonado-Arocho, F. J., Fulcher, J. A., Lee, B. & Bradley, K. A. Anthrax oedema toxin induces anthrax toxin receptor expression in monocyte-derived cells. Mol. Microbiol. 61, 324–337 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Rossi Paccani, S. et al. The adenylate cyclase toxins of Bacillus anthracis and Bordetella pertussis promote Th2 cell development by shaping T cell antigen receptor signaling. PLoS Pathog. 5, e1000325 (2009). This article details the effects on host immunity of the AC toxins from B. anthracis and B. pertussis , and provides evidence that the cAMP produced by these toxins is immunosuppressive and drives T H 2-type responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Guo, Q. et al. Protein-protein docking and analysis reveal that two homologous bacterial adenylyl cyclase toxins interact with calmodulin differently. J. Biol. Chem. 283, 23836–23845 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Vojtova, J., Kamanova, J. & Sebo, P. Bordetella adenylate cyclase toxin: a swift saboteur of host defense. Curr. Opin. Microbiol. 9, 69–75 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Young, J. A. & Collier, R. J. Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu. Rev. Biochem. 76, 243–265 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Tang, W. J. & Guo, Q. The adenylyl cyclase activity of anthrax edema factor. Mol. Aspects Med. 30, 423–430 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lowrie, D. B., Aber, V. R. & Jackett, P. S. Phagosome-lysosome fusion and cyclic adenosine 3′:5′-monophosphate in macrophages infected with Mycobacterium microti, Mycobacterium bovis BCG or Mycobacterium lepraemurium. J. Gen. Microbiol. 110, 431–441 (1979).

    Article  CAS  PubMed  Google Scholar 

  83. Kozubowski, L., Lee, S. C. & Heitman, J. Signalling pathways in the pathogenesis of Cryptococcus. Cell. Microbiol. 11, 370–380 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Hogan, D. A. & Sundstrom, P. The Ras/cAMP/PKA signaling pathway and virulence in Candida albicans. Future Microbiol. 4, 1263–1270 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Brakhage, A. A. & Liebmann, B. Aspergillus fumigatus conidial pigment and cAMP signal transduction: significance for virulence. Med. Mycol. 43 (Suppl. 1), S75–S82 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Ramanujam, R. & Naqvi, N. I. PdeH, a high-affinity cAMP phosphodiesterase, is a key regulator of asexual and pathogenic differentiation in Magnaporthe oryzae. PLoS Pathog. 6, e1000897 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hall, R. A. & Muhlschlegel, F. A. A multi-protein complex controls cAMP signalling and filamentation in the fungal pathogen Candida albicans. Mol. Microbiol. 75, 534–537 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Casadevall, A. & Perfect, J. R. Cryptococcus neoformans. (American Society for Microbiology Press, Washington DC,1998).

    Book  Google Scholar 

  89. Pukkila-Worley, R. & Alspaugh, J. A. Cyclic AMP signaling in Cryptococcus neoformans. FEMS Yeast Res. 4, 361–367 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Xue, C., Bahn, Y. S., Cox, G. M. & Heitman, J. G protein-coupled receptor Gpr4 senses amino acids and activates the cAMP-PKA pathway in Cryptococcus neoformans. Mol. Biol. Cell. 17, 667–679 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Maeng, S. et al. Comparative transcriptome analysis reveals novel roles of the Ras and cyclic AMP signaling pathways in environmental stress response and antifungal drug sensitivity in Cryptococcus neoformans. Eukaryot. Cell 9, 360–378 (2010). This work shows that the cAMP signalling pathway is distinct from the Ras signalling pathway in C. neoformans . It also explores the role of cAMP-dependent gene products on antifungal-drug sensitivity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hu, G. et al. Transcriptional regulation by protein kinase A in Cryptococcus neoformans. PLoS Pathog. 3, e42 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Pukkila-Worley, R. et al. Transcriptional network of multiple capsule and melanin genes governed by the Cryptococcus neoformans cyclic AMP cascade. Eukaryot. Cell 4, 190–201 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Alspaugh, J. A., Perfect, J. R. & Heitman, J. Cryptococcus neoformans mating and virulence are regulated by the G-protein α subunit GPA1 and cAMP. Genes Dev. 11, 3206–3217 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. D'Souza, C. A. et al. Cyclic AMP-dependent protein kinase controls virulence of the fungal pathogen Cryptococcus neoformans. Mol. Cell Biol. 21, 3179–3191 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Granger, D. L., Perfect, J. R. & Durack, D. T. Virulence of Cryptococcus neoformans. Regulation of capsule synthesis by carbon dioxide. J. Clin. Invest. 76, 508–516 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Mogensen, E. G. et al. Cryptococcus neoformans senses CO2 through the carbonic anhydrase Can2 and the adenylyl cyclase Cac1. Eukaryot. Cell 5, 103–111 (2006). This paper finds that bicarbonate directly activates the AC that is required for virulence in C. neoformans , and that one of two carbonic anhydrases is required for fungal growth when CO 2 levels are limiting, so that bicarbonate can be generated.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Klengel, T. et al. Fungal adenylyl cyclase integrates CO2 sensing with cAMP signaling and virulence. Curr. Biol. 15, 2021–2026 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bahn, Y. S., Cox, G. M., Perfect, J. R. & Heitman, J. Carbonic anhydrase and CO2 sensing during Cryptococcus neoformans growth, differentiation, and virulence. Curr. Biol. 15, 2013–2020 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Leroy, O. et al. Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France (2005–2006). Crit. Care Med. 37, 1612–1618 (2009).

    Article  PubMed  Google Scholar 

  101. Fang, H. M. & Wang, Y. RA domain-mediated interaction of Cdc35 with Ras1 is essential for increasing cellular cAMP level for Candida albicans hyphal development. Mol. Microbiol. 61, 484–496 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Park, H. et al. Role of the fungal Ras-protein kinase A pathway in governing epithelial cell interactions during oropharyngeal candidiasis. Cell. Microbiol. 7, 499–510 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Giacometti, R., Kronberg, F., Biondi, R. M. & Passeron, S. Catalytic isoforms Tpk1 and Tpk2 of Candida albicans PKA have non-redundant roles in stress response and glycogen storage. Yeast 26, 273–285 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Harcus, D., Nantel, A., Marcil, A., Rigby, T. & Whiteway, M. Transcription profiling of cyclic AMP signaling in Candida albicans. Mol. Biol. Cell 15, 4490–4499 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Maidan, M. M. et al. The G protein-coupled receptor Gpr1 and the Gα protein Gpa2 act through the cAMP-protein kinase A pathway to induce morphogenesis in Candida albicans. Mol. Biol. Cell 16, 1971–1986 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kumamoto, C. A. & Vinces, M. D. Contributions of hyphae and hypha-co-regulated genes to Candida albicans virulence. Cell. Microbiol. 7, 1546–1554 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Hnisz, D., Majer, O., Frohner, I. E., Komnenovic, V. & Kuchler, K. The Set3/Hos2 histone deacetylase complex attenuates cAMP/PKA signaling to regulate morphogenesis and virulence of Candida albicans. PLoS Pathog. 6, e1000889 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Xu, X. L. et al. Bacterial peptidoglycan triggers Candida albicans hyphal growth by directly activating the adenylyl cyclase Cyr1p. Cell Host Microbe 4, 28–39 (2008). This investigation demonstrates that MDPs can directly activate the AC that controls virulence-associated signalling in C. albicans.

    Article  CAS  PubMed  Google Scholar 

  109. Zou, H., Fang, H. M., Zhu, Y. & Wang, Y. Candida albicans Cyr1, Cap1 and G-actin form a sensor/effector apparatus for activating cAMP synthesis in hyphal growth. Mol. Microbiol. 75, 579–591 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Rodriguez, A., Martinez, I., Chung, A., Berlot, C. H. & Andrews, N. W. cAMP regulates Ca2+-dependent exocytosis of lysosomes and lysosome-mediated cell invasion by trypanosomes. J. Biol. Chem. 274, 16754–16759 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. Usynin, I., Klotz, C. & Frevert, U. Malaria circumsporozoite protein inhibits the respiratory burst in Kupffer cells. Cell. Microbiol. 9, 2610–2628 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Ono, T. et al. Adenylyl cyclase α and cAMP signaling mediate Plasmodium sporozoite apical regulated exocytosis and hepatocyte infection. PLoS Pathog. 4, e1000008 (2008). This study shows that ACα is required for regulated exocytosis in Plasmodium spp. sporozoites and that its deletion results in a 50% decrease in parasite infectivity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Kebaier, C. & Vanderberg, J. P. Initiation of Plasmodium sporozoite motility by albumin is associated with induction of intracellular signalling. Int. J. Parasitol. 40, 25–33 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Beraldo, F. H., Almeida, F. M., da Silva, A. M. & Garcia, C. R. Cyclic AMP and calcium interplay as second messengers in melatonin-dependent regulation of Plasmodium falciparum cell cycle. J. Cell Biol. 170, 551–557 (2005). This article indicates that the synchronization of the blood stage cell cycle of Plasmodium spp. by melatonin is mediated through the interplay of cAMP and Ca2+ signalling in the parasite.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Gazarini, M. L. et al. Melatonin triggers PKA activation in the rodent malaria parasite Plasmodium chabaudi. J. Pineal Res. 50, 64–70 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Merckx, A. et al. Plasmodium falciparum regulatory subunit of cAMP-dependent PKA and anion channel conductance. PLoS Pathog. 4, e19 (2008). This work demonstrates that, in Plasmodium falciparum -infected red blood cells, anion conductance of the erythrocyte membrane is modulated by cAMP through the regulation of an anion channel.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Leykauf, K. et al. Protein kinase A dependent phosphorylation of apical membrane antigen 1 plays an important role in erythrocyte invasion by the malaria parasite. PLoS Pathog. 6, e1000941 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Dyer, M. & Day, K. Expression of Plasmodium falciparum trimeric G proteins and their involvement in switching to sexual development. Mol. Biochem. Parasitol. 110, 437–448 (2000).

    Article  CAS  PubMed  Google Scholar 

  119. Kaushal, D. C., Carter, R., Miller, L. H. & Krishna, G. Gametocytogenesis by malaria parasites in continuous culture. Nature 286, 490–492 (1980).

    Article  CAS  PubMed  Google Scholar 

  120. Read, L. K. & Mikkelsen, R. B. Comparison of adenylate cyclase and cAMP-dependent protein kinase in gametocytogenic and nongametocytogenic clones of Plasmodium falciparum. J. Parasitol. 77, 346–352 (1991).

    Article  CAS  PubMed  Google Scholar 

  121. Eaton, M. S., Weiss, L. M. & Kim, K. Cyclic nucleotide kinases and tachyzoite-bradyzoite transition in Toxoplasma gondii. Int. J. Parasitol. 36, 107–114 (2006). This report implicates both PKA and the cyclic GMP-dependent kinase in the cycling between the tachyzoite and bradyzoite life stages in T. gondii.

    Article  CAS  PubMed  Google Scholar 

  122. Bao, Y., Weiss, L. M., Braunstein, V. L. & Huang, H. Role of protein kinase A in Trypanosoma cruzi. Infect. Immun. 76, 4757–4763 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Santos, D. O. & Oliveira, M. M. Effect of cAMP on macromolecule synthesis in the pathogenic protozoa Trypanosoma cruzi. Mem. Inst. Oswaldo Cruz 83, 287–292 (1988).

    Article  CAS  PubMed  Google Scholar 

  124. Gonzales-Perdomo, M., Romero, P. & Goldenberg, S. Cyclic AMP and adenylate cyclase activators stimulate Trypanosoma cruzi differentiation. Exp. Parasitol. 66, 205–212 (1988).

    Article  CAS  PubMed  Google Scholar 

  125. Rangel-Aldao, R. et al. Cyclic AMP as an inducer of the cell differentiation of Trypanosoma cruzi. Biochem. Int. 17, 337–344 (1988).

    CAS  PubMed  Google Scholar 

  126. Schoijet, A. C. et al. Defining the role of a FYVE domain in the localization and activity of a cAMP phosphodiesterase implicated in osmoregulation in Trypanosoma cruzi. Mol. Microbiol. 79, 50–62 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Oberholzer, M. et al. The Trypanosoma brucei cAMP phosphodiesterases TbrPDEB1 and TbrPDEB2: flagellar enzymes that are essential for parasite virulence. FASEB J. 21, 720–731 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Vassella, E., Reuner, B., Yutzy, B. & Boshart, M. Differentiation of African trypanosomes is controlled by a density sensing mechanism which signals cell cycle arrest via the cAMP pathway. J. Cell Sci. 110, 2661–2671 (1997). This study shows that cell cycle-mediated regulation of bloodstream forms of African trypanosomes is controlled by cAMP signalling.

    CAS  PubMed  Google Scholar 

  129. Bee, A. et al. Transformation of Leishmania mexicana metacyclic promastigotes to amastigote-like forms mediated by binding of human C-reactive protein. Parasitology 122, 521–529 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Rodriguez, M., Kim, B., Lee, N. S., Veeranki, S. & Kim, L. MPL1, a novel phosphatase with leucine-rich repeats, is essential for proper ERK2 phosphorylation and cell motility. Eukaryot. Cell 7, 958–966 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Frederick, J. & Eichinger, D. Entamoeba invadens contains the components of a classical adrenergic signaling system. Mol. Biochem. Parasitol. 137, 339–343 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Swierczewski, B. E. & Davies, S. J. A schistosome cAMP-dependent protein kinase catalytic subunit is essential for parasite viability. PLoS Negl. Trop. Dis. 3, e505 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank J. Heitman for his enthusiastic encouragement of this exploration. K.A.M. also acknowledges support from the US National Institutes of Health, National Institute of Allergy and Infectious Diseases (grant AI06349905).

Author information

Authors and Affiliations

  1. New York State Department of Health, Wadsworth Center, 120 New Scotland Avenue, PO Box 22002, Albany, New York, 12201-2002, New York, USA

    Kathleen A. McDonough

  2. Department of Biomedical Sciences, University at Albany, SUNY, Albany, New York, 12201, New York, USA

    Kathleen A. McDonough

  3. Department of Medical Parasitology, New York University School of Medicine, New York, 10010, New York, USA

    Ana Rodriguez

Authors
  1. Kathleen A. McDonough
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ana Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathleen A. McDonough.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Kathleen A. McDonough's homepage

Glossary

Second messenger

A small molecule that relays signals from a receptor to one or more targets inside a cell. The signal often originates outside the cell, although intracellular signals are also transmitted by second messengers in bacteria.

Effectors

Downstream functional targets that are activated by second messengers in response to specific signal transduction events. The same term is also used to refer to virulence factors that are injected into host cells by bacterial secretion systems.

cAMP receptor protein family

(Crp family). A family of global regulatory factors that contain cyclic AMP-binding and DNA-binding domains and are associated with positive and negative gene regulation in some bacteria. Binding of cAMP typically induces a conformational change that increases the DNA-binding activity of Crps.

Cyclic di-GMP

A second messenger that is used exclusively in bacteria and has been associated with regulation of biofilm formation, motility and expression of virulence factors.

Bistable switch

A regulatory mechanism that allows reversible toggling between two stable states.

Regulon

A set of genes or operons for which expression is controlled by a common regulatory factor.

AB toxin

A toxin that comprises active (A) and binding (B) protein subunits. The A subunits are responsible for the toxic activity, but they require the B subunits for delivery into their target cells.

TH1-to-TH2 switch

A switch in the elicited immune response from a T helper 1 (TH1)-type response, which promotes the killing of pathogens within cells, to a TH2-type response, which drives production of antibodies to neutralize toxins or extracellular pathogens. Pathogens can evade host immunity by tipping the balance towards the type of immune response that is least effective against them.

M. tuberculosis-complex bacteria

A group of related mycobacterial species (Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canettii and Mycobacterium microti) that are capable of causing the disease tuberculosis.

Ras

A subfamily of small GTPases that control signalling cascades in eukaryotic cells, resulting in transmission of regulatory signals from outside the cell to the nucleus.

Pseudohyphae

Filamentous fungal cells that form when budding yeast cells remain connected, forming a string of cells. They differ from true hyphae by their method of growth.

Globular actin

Individual actin subunits that polymerize into the long actin filaments which contribute to many eukaryotic processes, including maintenance of cell structure, motility, cell division and cell signalling.

Sporozoite

A form of Plasmodium spp.parasites that is generated in the mosquito and transmitted to the mammalian host, where it infects a hepatocyte.

Gametocyte

The sexual form of Plasmodium spp. parasites. Gametocytes are generated within infected erythrocytes in the mammalian host and are transmitted to the mosquito.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McDonough, K., Rodriguez, A. The myriad roles of cyclic AMP in microbial pathogens: from signal to sword. Nat Rev Microbiol 10, 27–38 (2012). https://doi.org/10.1038/nrmicro2688

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro2688

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology