All Title Author
Keywords Abstract

CO2 Acts as a Signalling Molecule in Populations of the Fungal Pathogen Candida albicans

DOI: 10.1371/journal.ppat.1001193

Full-Text   Cite this paper   Add to My Lib


When colonising host-niches or non-animated medical devices, individual cells of the fungal pathogen Candida albicans expand into significant biomasses. Here we show that within such biomasses, fungal metabolically generated CO2 acts as a communication molecule promoting the switch from yeast to filamentous growth essential for C. albicans pathology. We find that CO2-mediated intra-colony signalling involves the adenylyl cyclase protein (Cyr1p), a multi-sensor recently found to coordinate fungal responses to serum and bacterial peptidoglycan. We further identify Lys 1373 as essential for CO2/bicarbonate regulation of Cyr1p. Disruption of the CO2/bicarbonate receptor-site interferes selectively with C. albicans filamentation within fungal biomasses. Comparisons between the Drosophila melanogaster infection model and the mouse model of disseminated candidiasis, suggest that metabolic CO2 sensing may be important for initial colonisation and epithelial invasion. Our results reveal the existence of a gaseous Candida signalling pathway and its molecular mechanism and provide insights into an evolutionary conserved CO2-signalling system.


[1]  Almirante B, Rodríguez D, Park BJ, Cuenca-Estrella M, Planes AM, et al. (2005) Epidemiology and Predictors of Mortality in Cases of Candida Bloodstream Infection: Results from Population-Based Surveillance, Barcelona, Spain, from 2002 to 2003. J Clin Microbiol 43: 1829–1835.
[2]  Klevay MJ, Ernst EJ, Hollanbaugh JL, Miller JG, Pfaller MA, et al. (2008) Therapy and outcome of Candida glabrata versus Candida albicans bloodstream infection. Diag Microbiol Infect Dis 60: 273–277.
[3]  Leroy O, Gangneux J-P, Montravers P, Mira J-P, Gouin F, et al. (2009) 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.
[4]  Bodey GP (1986) Candidiasis in cancer patients. Am J Med 77: 13–19.
[5]  Odds FC (1988) Candida and candidosis A review and bibliography
[6]  Scully C, el-Kabir M, Samaranayake L (1994) Candida and oral candidosis: a review. Crit Rev Oral Biol Med 5: 125–157.
[7]  Farah C, Ashman R, Challacombe S (2000) Oral Candidosis. Clin Dermatol 18: 553–562.
[8]  Lo H-J, K?hler JR, DiDomenico B, Loebenberg D, Cacciapuoti A, et al. (1997) Nonfilamentous C. albicans Mutants Are Avirulent. Cell 90: 939–949.
[9]  Saville SP, Lazzell AL, Monteagudo C, Lopez-Ribot JL (2003) Engineered Control of Cell Morphology In Vivo Reveals Distinct Roles for Yeast and Filamentous Forms of Candida albicans during Infection. Eukaryotic Cell 2: 1053–1060.
[10]  Klengel T, Liang W-J, Chaloupka J, Ruoff C, Schroppel K, et al. (2005) Fungal Adenylyl Cyclase Integrates CO2 Sensing with cAMP Signaling and Virulence. Curr Biol 15: 2021–2026.
[11]  Buffo J, Herman M, Soll D (1984) A characterization of pH regulated dimorphism in Candida albicans. Mycopathologia 85: 21–30.
[12]  Rocha CRC, Schroppel K, Harcus D, Marcil A, Dignard D, et al. (2001) Signaling through Adenylyl Cyclase Is Essential for Hyphal Growth and Virulence in the Pathogenic Fungus Candida albicans. Mol Biol Cell 12: 3631–3643.
[13]  Kamenetsky M, Middelhaufe S, Bank EM, Levin LR, Buck J, et al. (2006) Molecular Details of cAMP Generation in Mammalian Cells: A Tale of Two Systems. J Mol Biol 362: 623–639.
[14]  Verstrepen KJ, Klis FM (2006) Flocculation, adhesion and biofilm formation in yeasts. Mol Microbiol 60: 5–15.
[15]  Fang H-M, Wang Y (2006) 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.
[16]  Xu X-L, Lee RTH, Fang H-M, Wang Y-M, Li R, et al. (2008) Bacterial Peptidoglycan Triggers Candida albicans Hyphal Growth by Directly Activating the Adenylyl Cyclase Cyr1p. Cell Host & Microbe 4: 28–39.
[17]  Hogan DA (2006) Talking to Themselves: Autoregulation and Quorum Sensing in Fungi. Eukaryot Cell 5: 613–619.
[18]  Shank E, Kolter R (2009) New developments in microbial interspecies signaling. Curr Opin Microbiol 12: 1–10.
[19]  Hughes DT, Sperandio V (2008) Inter-kingdom signalling: communication between bacteria and their hosts. Nat Rev Micro 6: 111–120.
[20]  Hornby JM, Jensen EC, Lisec AD, Tasto JJ, Jahnke B, et al. (2001) Quorum Sensing in the Dimorphic Fungus Candida albicans Is Mediated by Farnesol. Appl Environ Microbiol 67: 2982–2992.
[21]  Hogan DA, Vik A, Kolter R (2004) A Pseudomonas aeruginosa quorum-sensing molecule influences Candida albicans morphology. Mol Microbiol 54: 1212–1223.
[22]  Davis-Hanna A, Piispanen AE, Stateva LI, Hogan DA (2008) Farnesol and dodecanol effects on the Candida albicans Ras1-cAMP signalling pathway and the regulation of morphogenesis. Mol Microbiol 67: 47–62.
[23]  Palkova Z, Janderova B, Gabriel J, Zikanova B, Pospisek M, et al. (1997) Ammonia mediates communication between yeast colonies. Nature 390: 532–536.
[24]  Bahn Y-S, Cox GM, Perfect JR, Heitman J (2005) Carbonic Anhydrase and CO2 Sensing during Cryptococcus neoformans Growth, Differentiation, and Virulence. Curr Biol 15: 2013–2020.
[25]  Gewiss Mogensen E, Janbon Guilhem, Chaloupka James, Steegborn Clemens, Fu Man Shun, et al. (2006) Cryptococcus neoformans Senses CO2 through the Carbonic Anhydrase Can2 and the Adenylyl Cyclase Cac1. Eukaryotic Cell 5: 103–111.
[26]  Sharabi K, Lecuona E, Helenius IT, Beitel G, Sznajder JI, et al. (2009) Sensing, physiological effects and molecular response to elevated CO2 levels in eukaryotes. Journal of Cellular and Molecular Medicine 9999:
[27]  Christensen BE, Facer JF (1939) Simple wet combustion method for the determination of carbon, oxygen equivalence and empirical formula by iodic acid oxidation. J Am Chem Soc 61: 3001–3005.
[28]  Chen Y, Cann MJ, Litvin TN, Iourgenko V, Sinclair ML, et al. (2000) Soluble Adenylyl Cyclase as an Evolutionarily Conserved Bicarbonate Sensor. Science 289: 625–628.
[29]  Cann MJ, Hammer A, Zhou J, Kanacher T (2003) A Defined Subset of Adenylyl Cyclases Is Regulated by Bicarbonate Ion. J Biol Chem 278: 35033–35038.
[30]  Steegborn C, Litvin TN, Levin LR, Buck J, Wu H (2005) Bicarbonate activation of adenylyl cyclase via promotion of catalytic active site closure and metal recruitment. Nat Struct Mol Biol 12: 32–37.
[31]  Ghosh S, Navarathna DHMLP, Roberts DD, Cooper JT, Atkin AL, et al. (2009) Arginine-Induced Germ Tube Formation in Candida albicans Is Essential for Escape from Murine Macrophage Line RAW 264.7. Infect Immun 77: 1596–1605.
[32]  Belden WJ, Larrondo LF, Froehlich AC, Shi M, Chen C-H, et al. (2007) The band mutation in Neurospora crassa is a dominant allele of ras-1 implicating RAS signaling in circadian output. Genes & Dev 21: 1494–1505.
[33]  Park S, Lee K (2004) Inverted race tube assay for circadian clock studies of the Neurospora accessions. Fungal Genet Newslett 51: 12–14.
[34]  Helenius IT, Krupinski T, Turnbull DW, Gruenbaum Y, Silverman N, et al. (2009) Elevated CO2 suppresses specific Drosophila innate immune responses and resistance to bacterial infection. Proceedings of the National Academy of Sciences 106: 18710–18715.
[35]  De Smet , Hilde R, Bersten AD, Barr HA, Doyle IR (2007) Hypercapnic acidosis modulates inflammation, lung mechanics, and edema in the isolated perfused lung. Journal of Critical Care 22: 305–313.
[36]  Halbertsma FJJ, Vaneker M, Pickkers P, Snijdelaar DG, van Egmond J, et al. (2008) Hypercapnic acidosis attenuates the pulmonary innate immune response in ventilated healthy mice. Critical Care Medicine 36: 2403–2406.
[37]  O'Croinin DF, Nichol AD, Hopkins N, Boylan J, O'Brien S, et al. (2008) Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury. Critical Care Medicine 36: 2128–2135.
[38]  Ellner PD, Stoessel CJ, Drakeford E, Vasi F (1966) A new culture medium for clinical bacteriology. American Journal of Clinical Pathology 45: 502–504.
[39]  Thorpe TC, Wilson ML, Turner JE, DiGuiseppi JL, Willert M, et al. (1990) BacT/Alert: an automated colorimetric microbial detection system. J Clin Microbiol 28: 1608–1612.
[40]  Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234: 779–815.
[41]  Walther A, Wendland J (2003) An improved transformation protocol for the human fungal pathogen Candida albicans. Curr Genetics 42: 339–343.
[42]  MacCallum DM, Coste A, Ischer F, Jacobsen MD, Odds FC, et al. (2010) Genetic Dissection of Azole Resistance Mechanisms in Candida albicans and Their Validation in a Mouse Model of Disseminated Infection. Antimicrob Agents Chemother 54: 1476–1483.


comments powered by Disqus