We will discuss fungal communication in the context of fundamental biological functions including mating, growth, morphogenesis, and the regulation of fungal virulence determinants. We will address intraspecies but also interkingdom signaling by systematically discussing the sender of the message, the molecular message, and receiver. Analyzing communication shows the close coevolution of fungi with organisms present in their environment giving insights into multispecies communication. A better understanding of the molecular mechanisms underlying microbial communication will promote our understanding of the “fungal communicome.” 1. Introduction Any form of communication requires the existence of three obligatory components: a sender, a message, and a receiver. The process starts with the release of a message by a sender and ends with the understanding of the message by a receiver. This type of cycle has been developed with different degrees of complexity from prokaryote to higher eukaryotes optimizing fitness and adaptation for individual members and populations. The nature and mode of action of communication is as diverse as the response to the information it carries. Inter- and intraspecies communication has been widely studied analyzing the exchange of information between fungi and bacteria or fungi and plant cells [1, 2]. This review will focus predominantly on intraspecies fungal communication addressing key biological functions including mating, growth, morphological switching, or the regulation of virulence factor expression (Figure 1). We will show that in the fungal kingdom most of these mechanisms are controlled by a variety of messengers including small peptides, alcohols, lipids, and volatile compounds. Figure 1: Schematic representation of fungal intra and interspecies communication. The “sender” is an organism from the fungal kingdom and the “receiver” can be from any kingdom. Genes involved in messenger synthesis are represented as brown hexagons. Proteins involved in secretion or receiving the message are in orange and blue. 2. Peptides: Pheromones Pheromones have been known to act as an informative molecule since 1959 [3] and were reported to be involved in the sexual cycle of fungi in 1974 [4]. In the fungal kingdom, they are involved in the reconnaissance of compatible sexual partner to promote plasmogamy and karyogamy between two opposite mating types followed by meiosis. Taking the example of the extensively described sexual cycle of Saccharomyces cerevisiae, pheromones are diffusible peptides called a-factor (12 aa) when produced by
M. T. Tarkka, A. Sarniguet, and P. Frey-Klett, “Inter-kingdom encounters: recent advances in molecular bacterium-fungus interactions,” Current Genetics, vol. 55, no. 3, pp. 233–243, 2009.
L. M. Hereford and L. H. Hartwell, “Sequential gene function in the initiation of Saccharomyces cerevisiae DNA synthesis,” Journal of Molecular Biology, vol. 84, no. 3, pp. 445–461, 1974.
J. P. McGrath and A. Varshavsky, “The yeast STE6 gene encodes a homologue of the mammalian multidrug resistance P-glycoprotein,” Nature, vol. 340, no. 6232, pp. 400–404, 1989.
R. J. Anderegg, J. M. Becker, Y. Jiang, et al., “Structure of Saccharomyces cerevisiae mating hormone a-factor. Identification of S-farnesyl cysteine as a structural component,” Journal of Biological Chemistry, vol. 263, no. 34, pp. 18236–18240, 1988.
A. Gartner, K. Nasmyth, and G. Ammerer, “Signal transduction in Saccharomyces cerevisiae requires tyrosine and threonine phosphorylation of FUS3 and KSS1,” Genes and Development, vol. 6, no. 7, pp. 1280–1292, 1992.
R. J. Bennett and A. D. Johnson, “Completion of a parasexual cycle in Candida albicans by induced chromosome loss in tetraploid strains,” EMBO Journal, vol. 22, no. 10, pp. 2505–2515, 2003.
K. J. Daniels, T. Srikantha, S. R. Lockhart, C. Pujol, and D. R. Soll, “Opaque cells signal white cells to form biofilms in Candida albicans,” EMBO Journal, vol. 25, no. 10, pp. 2240–2252, 2006.
S. Yi, N. Sahni, K. J. Daniels, et al., “Self-induction of a/a or {alpha}/{alpha} biofilms in candida albicans is a pheromone-based paracrine system requiring switching,” Eukaryot Cell, vol. 10, no. 6, pp. 753–760, 2011.
R. Dumitru, D. H. M. L. P. Navarathna, C. P. Semighini et al., “In vivo and in vitro anaerobic mating in Candida albicans,” Eukaryotic Cell, vol. 6, no. 3, pp. 465–472, 2007.
M. Bubnick and A. G. Smulian, “The MAT1 locus of Histoplasma capsulatum is responsive in a mating type-specific manner,” Eukaryotic Cell, vol. 6, no. 4, pp. 616–621, 2007.
S. Poggeler, “Genomic evidence for mating abilities in the asexual pathogen Aspergillus fumigates,” Current Genetics, vol. 42, no. 3, pp. 153–160, 2002.
M. Paoletti, C. Rydholm, E. U. Schwier et al., “Evidence for sexuality in the opportunistic fungal pathogen Aspergillus fumigates,” Current Biology, vol. 15, no. 13, pp. 1242–1248, 2005.
J. Heitman, B. Allen, J. A. Alspaugh, and K. J. Kwon-Chung, “On the origins of congenic MATα and MATa strains of the pathogenic yeast Cryptococcus neoformans,” Fungal Genetics and Biology, vol. 28, no. 1, pp. 1–5, 1999.
G. Bakkeren, J. K？mper, and J. Schirawski, “Sex in smut fungi: structure, function and evolution of mating-type complexes,” Fungal Genetics and Biology, vol. 45, supplement 1, pp. S15–S21, 2008.
C. M. Waters and B. L. Bassler, “Quorum sensing: cell-to-cell communication in bacteria,” Annual Review of Cell and Developmental Biology, vol. 21, pp. 319–346, 2005.
J. M. Hornby, E. C. Jensen, A. D. Lisec, et al., “Quorum sensing in the dimorphic fungus Candida albicans is mediated by farnesol,” Applied and Environmental Microbiology, vol. 67, no. 7, pp. 298229–298292, 2001.
J. M. Hornby and K. W. Nickerson, “Enhanced production of farnesol by Candida albicans treated with four azoles,” Antimicrobial Agents and Chemotherapy, vol. 48, no. 6, pp. 2305–2307, 2004.
J. M. Hornby, B. W. Kebaara, and K. W. Nickerson, “Farnesol biosynthesis in Candida albicans: cellular response to sterol inhibition by zaragozic acid B,” Antimicrobial Agents and Chemotherapy, vol. 47, no. 7, pp. 2366–2369, 2003.
D. D. Mosel, R. Dumitru, J. M. Hornby, A. L. Atkin, and K. W. Nickerson, “Farnesol concentrations required to block germ tube formation in Candida albicans in the presence and absence of serum,” Applied and Environmental Microbiology, vol. 71, no. 8, pp. 4938–4940, 2005.
M. Kruppa, B. P. Krom, N. Chauhan, A. V. Bambach, R. L. Cihlar, and R. A. Calderone, “The two-component signal transduction protein Chk1p regulates quorum sensing in Candida albicans,” Eukaryotic Cell, vol. 3, no. 4, pp. 1062–1065, 2004.
A. Davis-Hanna, A. E. Piispanen, L. I. Stateva, and D. A. Hogan, “Farnesol and dodecanol effects on the Candida albicans Ras1-cAMP signalling pathway and the regulation of morphogenesis,” Molecular Microbiology, vol. 67, no. 1, pp. 47–62, 2008.
B. W. Kebaara, M. L. Langford, D. H. M. L. P. Navarathna, R. Dumitru, K. W. Nickerson, and A. L. Atkin, “Candida albicans Tup1 is involved in farnesol-mediated inhibition of filamentous-growth induction,” Eukaryotic Cell, vol. 7, no. 6, pp. 980–987, 2008.
T. Sato, T. Watanabe, T. Mikami, and T. Matsumoto, “Farnesol, a morphogenetic autoregulatory substance in the dimorphic fungus Candida albicans, inhibits hyphae growth through suppression of a mitogen-activated protein kinase cascade,” Biological and Pharmaceutical Bulletin, vol. 27, no. 5, pp. 751–752, 2004.
S. C. Chung, T. I. Kim, C. H. Ahn, J. Shin, and K. B. Oh, “Candida albicans PHO81 is required for the inhibition of hyphal development by farnesoic acid,” FEBS Letters, vol. 584, no. 22, pp. 4639–4645, 2010.
S. Kim, E. Kim, D. S. Shin, H. Kang, and K. B. Oh, “Evaluation of morphogenic regulatory activity of farnesoic acid and its derivatives against Candida albicans dimorphism,” Bioorganic and Medicinal Chemistry Letters, vol. 12, no. 6, pp. 895–898, 2002.
R. Shchepin, J. M. Hornby, E. Burger, T. Niessen, P. Dussault, and K. W. Nickerson, “Quorum sensing in Candida albicans: probing farnesol's mode of action with 40 natural and synthetic farnesol analogs,” Chemistry and Biology, vol. 10, no. 8, pp. 743–750, 2003.
G. Ramage, S. P. Saville, B. L. Wickes, and J. L. López-Ribot, “Inhibition of Candida albicans biofilm formation by farnesol, a quorum-sensing molecule,” Applied and Environmental Microbiology, vol. 68, no. 11, pp. 5459–5463, 2002.
A. Deveau, A. E. Piispanen, A. A. Jackson, and D. A. Hogan, “Farnesol induces hydrogen peroxide resistance in Candida albicans yeast by inhibiting the Ras-cyclic AMP signaling pathway,” Eukaryotic Cell, vol. 9, no. 4, pp. 569–577, 2010.
K. Weber, B. Schulz, and M. Ruhnke, “The quorum-sensing molecule E, E-farnesol—its variable secretion and its impact on the growth and metabolism of Candida species,” Yeast, vol. 27, no. 9, pp. 727–739, 2010.
K. Dichtl, F. Ebel, F. Dirr, F. H. Routier, J. Heesemann, and J. Wagener, “Farnesol misplaces tip-localized Rho proteins and inhibits cell wall integrity signalling in Aspergillus fumigates,” Molecular Microbiology, vol. 76, no. 5, pp. 1191–1204, 2010.
K. Machida, T. Tanaka, Y. Yano, S. Otani, and M. Taniguchi, “Farnesol-induced growth inhibition in Saccharomyces cerevisiae by a cell cycle mechanism,” Microbiology, vol. 145, no. 2, pp. 293–299, 1999.
K. Machida, T. Tanaka, K. I. Fujita, and M. Taniguchi, “Farnesol-induced generation of reactive oxygen species via indirect inhibition of the mitochondrial electron transport chain in the yeast Saccharomyces cerevisiae,” Journal of Bacteriology, vol. 180, no. 17, pp. 4460–4465, 1998.
C. P. Semighini, J. M. Hornby, R. Dumitru, K. W. Nickerson, and S. D. Harris, “Farnesol-induced apoptosis in Aspergillus nidulans reveals a possible mechanism for antagonistic interactions between fungi,” Molecular Microbiology, vol. 59, no. 3, pp. 753–764, 2006.
C. Volker, R. A. Miller, W. R. McCleary et al., “Effects of farnesylcysteine analogs on protein carboxyl methylation and signal transduction,” Journal of Biological Chemistry, vol. 266, no. 32, pp. 21515–21522, 1991.
A. Dietrich, A. Scheer, D. Illenberger, Y. Kloog, Y. I. Henis, and P. Gierschik, “Studies on G-protein α·βγ heterotrimer formation reveal a putative S-prenyl-binding site in the α subunit,” Biochemical Journal, vol. 376, no. 2, pp. 449–456, 2003.
A. C. Colabardini, P. A. De Castro, P. F. De Gouvêa et al., “Involvement of the Aspergillus nidulans protein kinase C with farnesol tolerance is related to the unfolded protein response,” Molecular Microbiology, vol. 78, no. 5, pp. 1259–1279, 2010.
M. A. Jabra-Rizk, T. F. Meiller, C. E. James, and M. E. Shirtliff, “Effect of farnesol on Staphylococcus aureus biofilm formation and antimicrobial susceptibility,” Antimicrobial Agents and Chemotherapy, vol. 50, no. 4, pp. 1463–1469, 2006.
S. Ghosh, B. W. Kebaara, A. L. Atkin, and K. W. Nickerson, “Regulation of aromatic alcohol production in Candida albicans,” Applied and Environmental Microbiology, vol. 74, no. 23, pp. 7211–7218, 2008.
H. Chen, M. Fujita, Q. Feng, J. Clardy, and G. R. Fink, “Tyrosol is a quorum-sensing molecule in Candida albicans,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 14, pp. 5048–5052, 2004.
M. A. Alem, M. D. Oteef, T. H. Flowers, and L. J. Douglas, “Production of tyrosol by Candida albicans biofilms and its role in quorum sensing and biofilm development,” Eukaryotic Cell, vol. 5, no. 10, pp. 1770–1779, 2006.
L. A. Hazelwood, J. M. Daran, A. J. A. Van Maris, J. T. Pronk, and J. R. Dickinson, “The Ehrlich pathway for fusel alcohol production: a century of research on Saccharomyces cerevisiae metabolism,” Applied and Environmental Microbiology, vol. 74, no. 8, pp. 2259–2266, 2008.
S. Kügler, T. S. Sebghati, L. G. Eissenberg, and W. E. Goldman, “Phenotypic variation and intracellular parasitism by Histoplasma capsulatum,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 16, pp. 8794–8798, 2000.
J. M. Hornby, S. M. Jacobitz-Kizzier, D. J. McNeel, E. C. Jensen, D. S. Treves, and K. W. Nickerson, “Inoculum size effect in dimorphic fungi: extracellular control of yeast-mycelium dimorphism in Ceratocystis ulmi,” Applied and Environmental Microbiology, vol. 70, no. 3, pp. 1356–1359, 2004.
A. Mosblech, I. Feussner, and I. Heilmann, “Oxylipins: structurally diverse metabolites from fatty acid oxidation,” Plant Physiology and Biochemistry, vol. 47, no. 6, pp. 511–517, 2009.
A. M. Calvo, L. L. Hinze, H. W. Gardner, and N. P. Keller, “Sporogenic effect of polyunsaturated fatty acids on development of Aspergillus spp,” Applied and Environmental Microbiology, vol. 65, no. 8, pp. 3668–3673, 1999.
D. I. Tsitsigiannis, T. M. Kowieski, R. Zarnowski, and N. P. Keller, “Three putative oxylipin biosynthetic genes integrate sexual and asexual development in Aspergillus nidulans,” Microbiology, vol. 151, no. 6, pp. 1809–1821, 2005.
D. I. Tsitsigiannis, R. Zarnowski, and N. P. Keller, “The lipid body protein, PpoA, coordinates sexual and asexual sporulation in Aspergillus nidulans,” Journal of Biological Chemistry, vol. 279, no. 12, pp. 11344–11353, 2004.
D. I. Tsitsigiannis, T. M. Kowieski, R. Zarnowski, and N. P. Keller, “Endogenous lipogenic regulators of spore balance in Aspergillus nidulans,” Eukaryotic Cell, vol. 3, no. 6, pp. 1398–1411, 2004.
D. I. Tsitsigiannis and N. P. Keller, “Oxylipins act as determinants of natural product biosynthesis and seed colonization in Aspergillus nidulans,” Molecular Microbiology, vol. 59, no. 3, pp. 882–892, 2006.
A. Tag, J. Hicks, G. Garifullina et al., “G-protein signalling mediates differential production of toxic secondary metabolites,” Molecular Microbiology, vol. 38, no. 3, pp. 658–665, 2000.
T. Shimizu, “Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation,” Annual Review of Pharmacology and Toxicology, vol. 49, pp. 123–150, 2009.
S. H. Brown, J. B. Scott, J. Bhaheetharan et al., “Oxygenase coordination is required for morphological transition and the host-fungus interaction of Aspergillus flavus,” Molecular Plant-Microbe Interactions, vol. 22, no. 7, pp. 882–894, 2009.
T. E. A. McDonald, “Signaling events connecting mycotoxin biosynthesis and sporulation in Aspergillus and Fusarium spp. Takamatsu,” in Proceedings of the International Symposium of Mycotoxicology, Co. Bookish, Ed., New Horizon of Mycotoxicology for Assuring Food Safety, 2004.
O. M. Sebolai, C. H. Pohl, P. J. Botes et al., “3-hydroxy fatty acids found in capsules of Cryptococcus neoformans,” Canadian Journal of Microbiology, vol. 53, no. 6, pp. 809–812, 2007.
S. Nigam, R. Ciccoli, I. Ivanov, M. Sczepanski, and R. Deva, “On mechanism of quorum sensing in Candida albicans by 3(R)-hydroxy-tetradecaenoic acid,” Current Microbiology, vol. 62, no. 1, pp. 55–63, 2011.
P. Venter, J. L. F. Kock, G. Sravan Kumar et al., “Production of 3R-hydroxy-polyenoic fatty acids by the yeast Dipodascopsis uninucleata,” Lipids, vol. 32, no. 12, pp. 1277–1283, 1997.
G. Pohnert, “Phospholipase A2 activity triggers the wound-activated chemical defense in the diatom Thalassiosira rotula,” Plant Physiology, vol. 129, no. 1, pp. 103–111, 2002.
J. R. Erb-Downward and M. C. Noverr, “Characterization of prostaglandin E2 production by Candida albicans,” Infection and Immunity, vol. 75, no. 7, pp. 3498–3505, 2007.
Y. Shibata, R. A. Henriksen, I. Honda, R. M. Nakamura, and Q. N. Myrvik, “Splenic PGE2-releasing macrophages regulate Th1 and Th2 immune responses in mice treated with heat-killed BCG,” Journal of Leukocyte Biology, vol. 78, no. 6, pp. 1281–1290, 2005.
E. R. Fedyk and R. P. Phipps, “Prostaglandin E2 receptors of the EP2 and EP4 subtypes regulate activation and differentiation of mouse B lymphocytes to IgE-secreting cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 20, pp. 10978–10983, 1996.
M. Ayasse, R. J. Paxton, and J. Teng？, “Mating behavior and chemical communication in the order Hymenoptera,” Annual Review of Entomology, vol. 46, pp. 31–78, 2001.
N. Fries, “Effects of volatile organic compounds on the growth and development of fungi,” Transactions of the British Mycological Society, vol. 60, pp. 1–21, 1973.
Z. Palkova, B. Janderova, J. Gabriel, B. Zikanova, M. Pospisek, and J. Forstova, “Ammonia mediates communication between yeast colonies,” Nature, vol. 390, no. 6659, pp. 532–536, 1997.
J. M. Cooney and D. R. Lauren, “Trichoderma/pathogen interactions: measurement of antagonistic chemicals produced at the antagonist/pathogen interface using a tubular bioassay,” Letters in Applied Microbiology, vol. 27, no. 5, pp. 283–286, 1998.
M. Nemcovic, L. Jakubikova, I. Viden, and V. Farkas, “Induction of conidiation by endogenous volatile compounds in Trichoderma spp,” FEMS Microbiology Letters, vol. 284, no. 2, pp. 231–236, 2008.
G. Muthukumar, E. C. Jensen, A. W. Nickerson, M. K. Eckles, and K. W. Nickerson, “Photomorphogenesis in Penicillium isariaeforme: exogenous calcium substitytes for light,” Photochemistry and Photobiology, vol. 53, no. 2, pp. 297–291, 1991.
G. S. Chitarra, T. Abee, F. M. Rombouts, M. A. Posthumus, and J. Dijksterhuis, “Germination of penicillium paneum Conidia is regulated by 1-octen-3-ol, a volatile self-inhibitor,” Applied and Environmental Microbiology, vol. 70, no. 5, pp. 2823–2829, 2004.
G. S. Chitarra, T. Abee, F. M. Rombouts, and J. Dijksterhuis, “1-Octen-3-ol inhibits conidia germination of Penicillium paneum despite of mild effects on membrane permeability, respiration, intracellular pH, and changes the protein composition,” FEMS Microbiology Ecology, vol. 54, no. 1, pp. 67–75, 2005.
F. P. Schiestl, F. Steinebrunner, C. Schulz et al., “Evolution of “pollinator”-attracting signals in fungi,” Biology Letters, vol. 2, no. 3, pp. 401–404, 2006.
J. R. Vakil, M. R. Raghavendra Rao, and P. K. Bhattacharyya, “Effect of CO2 on the germination of conidiospores of Aspergillus niger,” Archiv für Mikrobiologie, vol. 39, no. 1, pp. 53–57, 1961.
M. G. Smart, K. M. Howard, and R. J. Bothast, “Effect of carbon dioxide on sporulation of Alternaria crassa and Alternaria cassia,” Mycopathologia, vol. 118, no. 3, pp. 167–171, 1992.
S. Park and K. Lee, “Inverted race tube assay for circadian clock studies of the neurospora accessions,” Fungal Genetics Newsletter, vol. 51, pp. 12–14, 2004.
D. L. Granger, J. R. Perfect, and D. T. Durack, “Virulence of Cryptococcus neoformans. Regulation of capsule synthesis by carbon dioxide,” Journal of Clinical Investigation, vol. 76, no. 2, pp. 508–516, 1985.
Y. S. Bahn, G. M. Cox, J. R. Perfect, and J. Heitman, “Carbonic anhydrase and CO2 sensing during Cryptococcus neoformans growth, differentiation, and virulence,” Current Biology, vol. 15, no. 22, pp. 2013–2020, 2005.
G. Huang, T. Srikantha, N. Sahni, S. Yi, and D. R. Soll, “CO(2) regulates white-to-opaque switching in Candida albicans,” Current Biology, vol. 19, no. 4, pp. 330–334, 2009.
T. Klengel, W. J. Liang, J. Chaloupka et al., “Fungal adenylyl cyclase integrates CO2 sensing with cAMP signaling and virulence,” Current Biology, vol. 15, no. 22, pp. 2021–2026, 2005.
R. A. Hall, L. De Sordi, D. M. Maccallum, et al., “CO(2) acts as a signalling molecule in populations of the fungal pathogen Candida albicans,” PLoS Pathogens, vol. 6, no. 11, Article ID e1001193, 2010.
S. Ghosh, D. H. M. L. P. Navarathna, D. D. Roberts et al., “Arginine-induced germ tube formation in Candida albicans is essential for escape from murine macrophage line RAW 264.7,” Infection and Immunity, vol. 77, no. 4, pp. 1596–1605, 2009.
P. Richard, B. M. Bakker, B. Teusink, K. Van Dam, and H. V. Westerhoff, “Acetaldehyde mediates the synchronization of sustained glycolytic oscillations in populations of yeast cells,” European Journal of Biochemistry, vol. 235, no. 1-2, pp. 238–241, 1996.
B. Chance, R. W. Estabrook, and A. Ghosh, “Damped sinusoidal oscillations of cytoplasmic reduced pyridine nucleotide in yeast cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 51, pp. 1244–1251, 1964.
A. Betz and J. U. Becker, “Phase dependent phase shifts induced by pyruvate and acetaldehyde in oscillating NADH of yeast cells,” Journal of Interdisciplinary Cycle Research, vol. 6, no. 2, pp. 167–173, 1975.
W. Weber, M. Daoud-El Baba, and M. Fussenegger, “Synthetic ecosystems based on airborne inter-and intrakingdom communication,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 25, pp. 10435–10440, 2007.
