inter-kingdom encounters: recent advances in molecular bacterium–fungus interactions
TRANSCRIPT
Curr Genet (2009) 55:233–243
DOI 10.1007/s00294-009-0241-2REVIEW
Inter-kingdom encounters: recent advances in molecular bacterium–fungus interactions
Mika T. Tarkka · Alain Sarniguet · Pascale Frey-Klett
Received: 16 December 2008 / Revised: 4 March 2009 / Accepted: 16 March 2009 / Published online: 1 April 2009© Springer-Verlag 2009
Abstract Interactions between bacteria and fungi are wellknown, but it is often underestimated how intimate and deci-sive such associations can be with respect to behaviour andsurvival of each participating organism. In this article wereview recent advances in molecular bacterium–fungus inter-actions, combining the data of diVerent model systems.Emphasis is given to the positive or negative consequencesthese interactions have on the microbe accommodatingplants and animals. Intricate mechanisms of antagonism andtolerance have emerged, being as important for the biologicalcontrol of plants against fungal diseases as for the humanbody against fungal infections. Bacterial growth promotersof fungal mycelium have been characterized, and these mayas well assist plant-fungus mutualism as disease developmentin animals. Some of the toxins that have been previouslyassociated with fungi are actually produced by endobacteria,and the mechanisms that lie behind the maintenance of suchexquisite endosymbioses are fascinating. Bacteria do cause
diseases in fungi, and a synergistic action between bacterialtoxins and extracellular enzymes is the hallmark of such dis-eases. The molecular study of bacterium–fungus associationshas expanded our view on microbial communication, and thispromising Weld shows now great potentials in medicinal,agricultural and biotechnological applications.
Keywords Antagonism · Disease · Mycorrhiza · Biocontrol · Quorum sensing · Secondary metabolites
Introduction
This review gathers together the latest information ongenetics and cell biology of bacterium–fungus interactions.We will show that despite the variety of niches where bac-teria and fungi interact, common themes of interaction areevident. How decisive such associations can be with respectto plants and animals that host fungi and bacteria will beemphasized. Our goal is to dissect the common functionalthemes that are the result of investigations with bacterium–fungus model systems, summarized in Fig. 1.
In general, bacteria and fungi interact in a variety of envi-ronments, including soils, animals, and foods. In soils theyare involved in nutrient turnover and delivery to plants (deBoer et al. 2005). The balance between pathogenic and non-pathogenic microbial communities governs the spread ofsoil-borne plant diseases, and distinct antagonistic micro-organisms inhibit soil-borne diseases by the production ofantagonistic metabolites (Weller et al. 2002). Bacteria cancomplement the work of symbiotic fungi in mycorrhizalsymbiosis, which is the most common symbiosis on earthand necessary for nutrient acquisition of most plant speciesunder natural conditions (Artursson et al. 2006; Frey-Klettet al. 2007). The outer and inner surfaces of the human body
Communicated by U. Kues.
M. T. Tarkka (&)UFZ, Department of Soil Ecology, Helmholtz Centre for Environmental Research, Theodor-Lieser-Strasse 4, 06120 Halle, Germanye-mail: [email protected]: http://www.ufz.de/index.php?de=11465
A. SarniguetINRA, Agrocampus Ouest-Université Rennes 1, UMR1099 BiO3P ‘Biologie des Organismes et des Populations Appliquée à la Protection des Plantes’, 35653 Le Rheu, France
P. Frey-KlettINRA, UMR1136 INRA-UHP ‘Interactions Arbres/Micro-organismes’, IFR 110, Centre de Nancy, 54280 Champenoux, France
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are colonised by fungi and bacteria, and we are only begin-ning to understand how important the fungus–bacteriuminteractions are for our health (Wargo and Hogan 2006).
Our article is supported by several reviews regarding otheraspects of this subject. The impact of bacterial volatiles onfungi was one of the topics of the review on bacterial signal-ling by Kai et al. (2008). Chemical cross-talk will only becovered here, if it is linked to characterized interaction mech-anisms, summarized in Fig. 2. For latest information on theecology of bacterium–fungus interactions, the reader shouldconsult the reviews by de Boer et al. (2005) on soil interac-tions, and Artursson et al. (2006) and Frey-Klett et al. (2007)on mycorrhiza-related features. Molecular fungal–bacterialinteractions were excellently treated by Wargo and Hogan in2006, but much knowledge has accumulated since then.
This review aims at summing up common themes thathave been revealed by the analysis of diverse in vitro bacte-rium–fungus co-culture systems. Wargo and Hogan endedtheir review on fungal–bacterial interactions in 2006 by thenote: “The mechanisms used by fungi and bacteria in theirassociation with the plant might not be very diVerent fromthose used on and within the mammalian host”. We presenthere the accumulating evidence that this hypothesis wasjustiWed.
Antagonism between bacteria and fungi
Microbes live closely associated with other organisms in nat-ural environments and compete with them for resources.Niche protection can be argued to be the driving force to pro-duce secondary metabolites, and the production of antimicro-bials during bacterium–fungus interactions has been a target
of various detailed studies, notably because of practical use.For instance, antagonistic action of microbes against patho-gens is expected to have a strong impact on plant health,which has crystallized in the development of biological con-trol agents. In so-called suppressive soils, for example, plantsare wholly protected by bacteria against soil-borne fungaldiseases. The value of fungus–bacterium interactions is alsogradually understood in medical research (Wargo and Hogan2006). Due to the AIDS pandemia, the number of fungalinfections has exploded in recent years (Klepser 2006). Fun-gal infections are eVectively inhibited by bacteria, and pro-tection against fungal infections could become an importantfunction for probiotics (Noverr and HuVnagle 2004). In thefollowing we give an update of some novel mechanisms ofantagonism in plant and human protection.
Antibiosis: complex mixtures with common ingredients
Bacteria interfere with phytopathogen micro-organisms bya multitude of mechanisms. These include competitive rootcolonisation, synthesis of antibiotics, production of lyticenzymes, detoxiWcation of toxins and degradation of viru-lence factors (Compant et al. 2005). For instance manyPseudomonas spp. protect plants by the production of anti-fungal compounds. Interestingly bacteria produce mixturesof antagonistic metabolites instead of single substances,preventing thus the development of resistance in the patho-gens (Challis and Hopwood 2003; Haas and Keel 2003;Mavrodi et al. 2006). Due to the various routes of inheri-tance in bacteria, including horizontal gene transfer as wellas natural transformation, some of the biosynthetic operonsfor antifungal metabolites have been detected from geo-graphically and taxonomically distinct bacterial isolates.
Fig. 1 Impacts of interactions on bacterial and fungal growth, secondary metabolite production, health, survival and virulence. These Wve categories indicate the various ways that the associations between bacte-ria and fungi inXuence the organisms. Bidirectional arrows indicate that the impact is possessed by bacteria and fungi. The outcome of the interactions is highly dependent on the biotic and abiotic factors that surround the micro-organisms. Adapted from Wargo and Hogan (2006)
•Growth-Antifungal and antibacterial compounds-Quorum sensing inhibitors-Morphology modulating compounds-Growth promoters
•Secondary metabolite production-Competition mediated increase-Specific suppression
•Health-Diseases of Agaricales
•Survival-Modification of the environment-Protection against competitors
•Virulence-Influence on virulence factor production-Production of virulence factors
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A good example of this is the production of the polyketideantifungal compound 2,4-diacetylphloroglucinol (DAPG)by various bacterial species. The DAPG is a highly eVec-tive antifungal substance and maybe the best characterizeddeterminant of suppressive soils, and its production corre-lates in general with high plant-protecting activity of Pseu-domonas isolates (Rezzonico et al. 2007). The study byFrapolli et al. (2007) indicated that at least six diVerentPseudomonas species produce DAPG, and pointed at a cos-mopolitan distribution of DAPG-producing pseudomonads.
Resistance mechanisms: pumping out and rendering antibiotics non-toxic
Defence mechanisms in plant pathogenic fungi againstantifungal compounds are being deciphered. These
include non-degradative mechanisms, enzymatic detoxiW-cation and degradation (Morrissey and Osbourn 1999).Fungi may employ diVerent mechanisms in concert toresist to the antibiotic activity. Transport by membranebound eZux pumps enables target organisms to tolerateexogenous toxic compounds, by releasing them out of thefungal cell. For example, the eZux pump BcAtrBprovides the Wrst line of defence for Botrytis cinereaagainst DAPG. Expression of BcatrB is induced by thesubstance and correlates with its laccase-mediated degra-dation (Schouten et al. 2008). Whereas B. cinerearequires tannic acid as a mediator for DAPG degradation,Fusarium oxysporum degrades it by another mechanism:by converting this antibiotic into the less toxic derivativesmonoacetyl-phloroglucinol and phloroglucinol (Schoutenet al. 2004).
Fig. 2 Source organisms, bio-logical activities and structures of secondary metabolites that have been implicated in fungus–bacterium interactions
Common name Producer Biological activities
Auxofuran Streptomyces sp. Fungal growth promotion
2,4-diacetylphloroglucinol Pseudomonas spp. Antibiosis, biological control
Fusaric acid Fusarium spp. Antibiosis, inhibits the production of antifungals by bacteria
Farnesol Candida albicans Fungal quorum sensing, inhibits the production of antifungals by bacteria
N-3-oxo-dodecanoyl- Various gram- Bacterial quorum sensing, l-homoserine lactone negative bacteria inhibits Candida filamentation
Patulin Aspergillus and Mycotoxin, inhibits the Penicillium spp. quorum sensing in bacteria
Rhizoxin Burkholderia spp. Phytotoxin, virulence factor
Patulin
OH
O
OO
O
N
O
O
OO
O O
O
OH
Rhizoxin
Fusaric Acid
N
O
OH
FarnesolOH
2,4-diacetylphloroglucinol
OH
O
O
OH
OH
NO
O O
O
N-3-oxo-dodecanoyl-l-homoserine lactone
O
O
OH
Auxofuran
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Cross-domain signalling: forcing the antagonist to attenuate toxin production
Fusarium species commonly produce fusaric acid, which isnot only toxic for eukaryotes and prokaryotes, but alsoinhibits the production of antifungal metabolites by bacteria(DuVy et al. 2003). Notz et al. (2002) showed that DAPGproduction by Pseudomonas Xuorescens CHA0 isrepressed by fusaric acid. They observed that fusaric acidconcentration of the culture medium negatively correlatedwith the degree of the expression level of phlA, Wrst gene ofthe DAPG biosynthetic operon (Notz et al. 2002). Theimpact of fusaric acid producing fungal strains on DAPGproduction was conWrmed in the rhizosphere of wheat, indi-cating ecological relevance. The production of phenazine-1-carboxamide in P. chlororaphis PCL1391 is suppressedby fusaric acid as well, due to strong down-regulation ofphenazine-1-carboxamide biosynthetic genes by the sub-stance (van Rij et al. 2005). Biocontrol bacteria have, how-ever, developed a way to recognize and colonise fusaricacid producing fungal strains. De Weert et al. (2004)observed that P. Xuorescens WCS365 is chemo-attractedand colonises fusaric acid producing strains of Fusariumoxysporum.
Pseudomonas aeruginosa limits the growth of Candidaalbicans, attacking the Wlamentous form of the fungus(Kerr 1994; Hogan and Kolter 2002). Similar to the fusaricacid action on Pseudomonas chlororaphis PCL1391, farne-sol production by C. albicans leads to decreased phenazineproduction in P. aeruginosa (Cugini et al. 2007). The addi-tion of farnesol leads to a decrease in the production of P.aeruginosa quinolone signal (QUI). This takes place due toa reduction in transcript levels of the pqsA gene of QUI bio-synthetic operon that encodes for anthranilate-coA ligase(Coleman et al. 2008). QUI acts in concert with other quo-rum sensing (QS) regulators, and controls the production ofextracellular proteases, hydrogen cyanine and phenazines,including pyocyanin. Reduction in the levels of QUI andpyocyanin are evident in C. albicans–P. aeruginosa co-cul-tures, suggesting that fungal farnesol production levels maybe suYcient for the inhibition of the PQS system in vivo(Cugini et al. 2007).
Quorum sensing: inhibitors, modulators and impacts across the two kingdoms
In a survey of QS inhibitors (QSI) from Penicillium spe-cies, Rasmussen et al. (2005) identiWed patulin and penicil-lic acid as potent inhibitors of QS of P. aeruginosa,aVecting the expression of 45 and 60% of the QS-regulatedgenes. Active quorum signalling by P. aeruginosa leads toan inhibition of neutrophils, but Rasmussen et al. (2005)observed that application of either Penicillium substance
overcame this inhibition. In pulmonary infection mousemodel patulin treatment even accelerated the clearance oflungs from P. aeruginosa.
Morphogenesis from yeast cells to Wlaments is importantin C. albicans infections. Hogan et al. (2004) showed thatP. aeruginosa inhibits Wlamentation and promotes thereversion to the yeast from in C. albicans by the productionof QS molecule N-3-oxo-dodecanoyl-L-homoserine lactone(3OC12,HSL). Compounds that were structurally related to3OC12,HSL aVected C. albicans Wlamentation at compara-ble concentrations. The earlier study of Hogan and Kolter(2002) showed that P. aeruginosa is able to invade the Wla-mentous form of C. albicans, and to kill the fungus. SeveralP. aeruginosa virulence factors that are involved in diseasedevelopment are involved in the killing of these fungal Wla-ments, but not the yeast cells (Hogan and Kolter 2002).
Because in their natural ecological niche ectomycorrhi-zal fungi are surrounded by QS-producing bacteria(Deveau, Uroz and Frey-Klett, unpublished), the impact oftwo N-acyl homoserine lactones (HSL) on gene expressionof the model ectomyccorrhizal fungus Laccaria bicolorwas monitored. N-Hexanoyl-L-homoserine lactone (C6-HSL) did not inXuence fungal gene expression. In contrast,the application of N-3-oxo-dodecanoyl-L-homoserine lac-tone (3OC12,HSL) led to diVerential expression of fungalgenes related to primary metabolism, polarized growth pro-cess and oxidative stress.
Fungi are not only able to perceive QS signal moleculesbut also to degrade them. Uroz and Heinonsalo (2008)described that three mycorrhizal and non-mycorrhizalfungi, belonging to Ascomycota and Basidiomycota lin-eages, hydrolysed C6-HSL by lactonase activity. In conclu-sion, bacterial QS molecules act as inter-kingdomsignalling molecules, and can be sensed and/or degraded bycertain fungi.
Docking on fungal cell walls and degrading the cell wall polysaccharides by bacteria
Attachment to fungal cell wall plays a key role in the killingof fungal cells by bacteria (Leveau and Preston 2008), ashas been documented for the antagonistic Cryptococcusneoformans–Staphylococcus aureus interaction. Saito andIkeda (2005) observed that the capsular polysaccharidesfrom C. neoformans bind to cells of S. aureus. The bindingwas necessary for the killing of C. neoformans, and itoccurred between mannotriose units in the fungal capsuleand S. aureus enzyme triose phosphate isomerase (Ikedaet al. 2007).
Fungal cell wall is a complex mixture of polysaccharidesand proteins, and its degradation involves a variety of bac-terial exoenzymes (Leveau and Preston 2008). Chitinaseactivity is a common feature of bacterial antagonists
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(de Boer et al. 2005; Kobayashi et al. 2002), and theinvolvement of �-glucanases has been well established(Hong and Meng 2003; Kim and Chung 2004). Synergismbetween these enzymes was suggested to be the key in theeYcient fungal cell wall degradation by Paenibacillusehimensis (Aktuganov et al. 2008). Whereas �-1,3-glucan-ase was observed to be the initiator of the cell wall hydroly-sis, the degradation process was reinforced by chitinases.
Streptomyces olivaceoviridis possesses strong chitinaseactivity that leads to killing of Aspergillus proliferanshyphae. Chitin binding protein Chb1 of S. olivaceoviridis(Schnellmann et al. 1994) is an important determinant ofthis antagonistic interaction. S. olivaceoviridis mutants thatwere deWcient of Chb1 were not able to suppress mycelialdevelopment of A. proliferans, and in co-cultures the fungalmycelium overgrew the bacterial Wlaments (Siemieniewiczand Schrempf 2007).
Inducing programmed cell death of a Wlamentous fungus
The phytopathogen Pseudomonas syringae competes withother epiphytic organisms, such as Wlamentous fungi, forresources. P. syringae is able to attach and extensively colo-nize the hyphae of the Wlamentous fungus Neurosporacrassa. Most investigated P. syringae strains have phcAgene, which shows homology to het-c gene of N. crassa(Wichmann et al. 2008). In N. crassa Het-c regulates a pro-grammed cell death pathway, termed as heterokaryonincompatibility. Ectopic expression of P. syringae phcA inN. crassa with a functional het-c background induces het-erokaryon incompatibility and cell death of the fungus. Thisillustrates a novel intimate molecular mechanism that couldprovide bacteria a strategy to exploit a nutrient limited envi-ronment by taking resources from Wlamentous fungus.
Suicide assistance: Gaeumannomyces graminis itself induces antagonism by Pseudomonas
Fungal pathogen may inXuence the interactions with bio-control bacteria in various ways. A commensal interactioncan take place, as has been shown during the confrontationof the pathogenic fungus Gaeumannomyces graminis var.tritici (Ggt) and the biocontrol bacterial strain P. Xuores-cens Pf29Arp (Barret et al. 2008). Ggt promotes the growthrate of Pf29Arp. Before contact, the mycelium induces bac-terial genes involved in the colonisation process like genesfrom the braCDEFG operon. This set of genes encodes ahigh-aYnity transport system speciWc for alanine and threo-nine amino acids in addition to branched-chain amino acids(Hoshino and Kose 1990). Some of these genes are inducedduring rhizosphere colonisation of P. Xuorescens SBW25as well (Rainey 1999) and the BraC transporter of P. putida06909 was reported to be involved in the colonisation of the
oomycete Phytophthora parasitica (Ahn et al. 2007). Mainchanges in gene expression patterns of Pf29Arp occur at thecontact with Ggt, and the up-regulated bacterial genes atthis stage encode stress response protein, patatin-like pro-tein and small-subunit of exodeoxyribonuclease VII, XseB(Barret et al. 2008). The up-regulation of Pf29Arp XseBgene was speciWc to its interaction with Ggt, but its func-tion of this gene has not been characterized yet. In thehuman pathogen Neisseria meningitis XseB participates inbacterial chromosome repairing and its production is stimu-lated by host contact (Morelle et al. 2005). The geneexpression response of Pf29Arp to Ggt is strongly modu-lated by the host plant (Barret and Sarniguet, unpublished).Especially necrotic roots exert a strong eVect on bacterialgene expression (Barret and Sarniguet, unpublished). Apool of Pf29Arp genes that are diVerentially expressed onGgt colonized roots are related to carbon metabolism and tooxidative stress. Some genes are speciWcally up-regulateddue to the presence of necrotic roots; these include, e.g. agene encoding a putative T6SS eVector (Barret and Sarniguet,unpublished).
Mutualistic interactions
Induced Wlamentation: perception of bacterial cell wall fragments by Candida
Candida albicans virulence is induced by the perception ofbacterial cell wall fragments, muramyl dipeptides that arepresent in minute amounts in the human serum (Xu et al.2008). Muramyl dipeptides activated Wlamentous growth ofC. albicans via adenylyl cyclase Cyr1. Intriguing similaritiesbetween fungal and human signalling cascades wererevealed, as a similar leucine rich repeat (LRR) region that ispresent in the fungal adenylyl cyclase and required for theperception of the cell wall fragments, exists in the Nod2receptor protein of humans. The human receptor protein rec-ognizes MDPs and is required for eVective pro-inXammatorysignalling cascade, indicating that the two LRR domains areboth needed for the perception of bacteria. The biologicalrole of Wlamentous growth upon bacterial recognitionremains obscure, but it may have important implications as tounderstanding the high frequency of Candida infections inthe intestine, given its abundance of bacterial cell wall frag-ments. Muramyl dipeptides may give a universal signal forfungi to recognize bacteria (Piispanen and Hogan 2008).
Complementing fungus-plant mutualism: mycorrhization helper bacteria
The majority of plants form mutualistic symbioses termedmycorrhizas with Wlamentous fungi. Mycorrhiza improves
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plant nutrient uptake, while the fungal partner gains carbo-hydrates from its host plant (Smith and Read 2008). Mycor-rhizas have been traditionally seen as bipartite relationshipsbetween plant roots and Wlamentous fungi, but recent dataindicates that bacteria are also involved. First of all, thehost plant and the fungal mycelium select for bacterialstrains beneWcial for the symbiosis (Frey-Klett et al. 2005).Second, fungal growth and mycorrhiza formation are pro-moted by bacteria, termed ‘Mycorrhization Helper Bacte-ria’ (MHB; Garbaye 1994). Not only do these bacteriapromote symbiosis formation, but they have also beenimplicated in complementing the functions of mycorrhizas,including nutrient acquisition and biological control of hostplants (Artursson et al. 2006; Frey-Klett et al. 2007; Tarkkaand Frey-Klett 2008). The following covers recent dataabout molecular MHB-fungus interactions.
Streptomyces–Amanita interaction: bacterial secondary metabolites and fungal gene expression
Streptomyces AcH505 promotes the extension of fungalmycelium and mycorrhiza formation by the symbiotic fun-gus Xy agaric Amanita muscaria and Norway spruce (Maieret al. 2004; Schrey et al. 2005; reviewed in Schrey andTarkka 2008). Streptomyces–Amanita interaction has a stronginXuence on the growth pattern of fungal hyphae. Thehyphal diameter and the mycelial density decreased in co-cultures with AcH505. The dense and polarised actin cap inhyphal tips of pure culture A. muscaria changed to a loos-ened and dispersed structures in co-culture. Supplementa-tion of growth medium with cell-free bacterial supernatantconWrmed that reduction in hyphal diameter and changes inthe cytoskeleton occurred at the same stage of growth, sug-gesting that they are interlinked (Schrey et al. 2007). Apartfrom changes in cell biology, the interaction with AcH505has a strong impact on gene expression levels in A. mus-caria. AcH505 modulated A. muscaria genes were relatedto signalling pathways (protein kinase A, PAK kinasehomolog), metabolism (acetoacyl CoA synthase, glutaminesynthase), cell structure (beta-glucanase), stress and growthresponse (cyclophilin 40; alpha tubulin), suggesting that thefungal physiology is strongly altered due to the contact withthe bacterium (Schrey et al. 2005). Some of the diVeren-tially expressed genes in A. muscaria were regulated as aresult of faster mycelial extension (Tarkka et al. 2006),while the expression of speciWc fungal genes was up-regu-lated in the presence of bacterial culture Wltrates (Schrey,Hampp and Tarkka, unpublished).
Whereas Streptomyces AcH505 promotes the extensionof A. muscaria, it inhibits the ectomycorrhizal fungus Heb-eloma cylindrosporum. Riedlinger et al. (2006) found thatAcH505 produced the fungal growth-promoter auxofuran,and two antifungal substances, WS-5995 B and C. Fungi
that were sensitive against WS-5995 B were found to beinhibited in co-cultures with AcH505 (Lehr et al. 2007). A.muscaria induced conditions that are favourable to fungalgrowth, promoted auxofuran and suppressed WS-5995 Bproduction by AcH505 (Riedlinger et al. 2006). Applica-tion of auxofuran to A. muscaria led to increased expres-sion level of the acetoacyl CoA synthase. This indicatedincreased production of ergosterol in the mycelium. In con-trast, cell stress-related genes AmCyp40 and Uga4 wereinduced by WS-5995 B. As GABA is used as an annihilatorof reactive oxygen species in fungi, this suggests that WS-5995 B causes oxidative stress. Recent data indicates thatA. muscaria responds extremely rapidly to fungal metabo-lites, since 5-min incubation with the antibiotic is enoughfor an increase in AmCyp40 expression levels (Schrey andTarkka, unpublished). Lehr et al. (2007) characterizedeleven WS-5995 B-sensitive and one WS-5995 B-tolerantstrains among a collection of fungal plant pathogen Hetero-basidion annosum isolates. Sensitivity against the antibioticis reXected by decreased expression levels of cell stress-related genes (Lehr, Adomas, Asiegbu, Hampp and Tarkka,unpublished). In conclusion, the observed changes in fun-gal growth pattern and gene expression levels are a goodexample of what impacts a blend of bacterial metabolitesmay possess on the interacting microbe.
Laccaria–Pseudomonas interaction: a complex metabolite cross-talk linked to gene regulations
Laccaria bicolor S238N is the Wrst fungus that formsmycorrhiza and whose genome has been sequenced (Martinet al. 2008). The fungus is commercially used in France forcontrolled mycorrhization of Douglas Wr seedlings, becauseit signiWcantly improves plant growth. Douglas Wr—L.bicolor ectomycorrhizas are surrounded by complex bacte-rial communities among which some pseudomonadsbehave as mycorrhization helper bacteria (MHB; Frey-Klett et al. 2007). The MHB P. Xuorescens strain BBc6R8signiWcantly improves the pre-symbiotic survival andgrowth of L. bicolor in the soil (Brule et al. 2001) as well asin vitro (Deveau et al. 2007). It is chemoattracted by fungalextracts but also by trehalose, a disaccharide in L. bicolormycelium. Conversely, BBc6R8 secretes thiamine whichpromotes fungal growth (Deveau and Frey-Klett, unpub-lished). Thiamine (vitamin B1) is an essential cofactor ofseveral enzymes of the central carbon metabolism, and ithas been previously associated with growth promotion ofthe yeasts Debaryomyces vanrijiae by Bacillus sp. TB-1(Rikhvanov et al. 1999) and of Saccharomyces cerevisiaeby rumen cellulolytic bacteria (Chaucheyras-Durand andFonty 2001). Co-culture with BBc6R8 led to altered growthpattern of L. bicolor mycelium; angles and numbers ofhyphal branches, as well as numbers of hyphal apices
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changed. Simultaneously, pleiotrophic alterations in fungaltranscriptome were observed, which varied in time (Deveauet al. 2007). An early stage BBc6R8-responsive fungalgene sharing 54% similarity at the protein level to tectoninII of Physarum polycephalum, was identiWed. In P. poly-cephalum, tectonins may be involved in the aggregation ofbacteria during the phagocytosis process (Huh et al. 1998).In L. bicolor, the tectonin orthologue could thus play a rolein cell recognition and/or fungal cell interaction with P.Xuorescens BBc6R8. Interestingly, the transcription of thetectonin gene was also increased by P. Xuorescens Pf29Astrain and by the mycophagous bacterial strain Collimonasfungivorans Ter331 which contrary to the strains BBc6R8and Pf29A inhibited the in vitro growth of L. bicolor(Deveau et al. 2007).
Bacteria in fungal hyphae: roles in nutrition and extraordinary symbioses
The ectomycorrhizal fungus L. bicolor S238N is producedas commercial inoculum for forest nurseries and hostsendocellular bacteria from Paenibacillus. We have recentlyobserved that the Paenibacillus isolate from L. bicolorS238N fermentor culture (Bertaux et al. 2003) is a myco-rrhization helper bacterium (Frey-Klett, unpublished).
The occurrence of endocellular bacteria is well estab-lished among the Glomeromycota fungi, a phylum consist-ing mostly of arbuscular mycorrhizal fungi. Gigasporamargarita forms arbuscular mycorrhiza and hosts a popula-tion of �-proteobacteria. ClassiWed as Candidatus Glome-ribacter gigasporarum, they are vertically transmittedthrough fungal spore generations (Bianciotto et al. 2004).One interesting hypothesis is that the endobacteria promotenutrition in mycorrhizal symbiosis. The DNA region con-taining putative nitrogen Wxing nif genes and belonging tothe endosymbiont was characterized by Minerdi et al.(2001), but the presence of nif genes could not be con-Wrmed in a later investigation (Jargeat et al. 2004). Theendobacteria of G. margarita do, however aVect the growthpattern of fungal mycelium (Lumini et al. 2007). Spores ofthe fungus without its bacterial symbiont had a distinct phe-notype. Distinct patterns of cytoplasm organization, vacu-ole morphology, cell wall organization, lipid bodies andpigment granules were observed. The absence of bacteriaseverely aVected hyphal elongation and branching afterroot exudate treatment, suggesting that Candidatus Glome-ribacter gigasporarum is important for optimal develop-ment of its fungal host. Anca et al. (2009) showed that thedevelopmental status of fungal hyphae inXuences endobac-terial gene expression. The ftsZ gene of the endocellularbacterium, marker gene for bacterial division, was up-regu-lated during the symbiotic phases of its host fungus; insidethe plant as well as while extending to the soil. Application
of plant metabolite, strigolactone, to fungal spores also ledto increased ftsZ expression levels, indicating complex sig-nalling in this association.
Geosiphon pyriformis is closely related to arbuscularmycorrhizal fungi. An intriguing endosymbiosis takes placebetween G. pyriformis and a cyanobacterium (Nostoc punc-tiforme). The fungal role may be the transport of mineralnutrients to the bacterium, and its gain is carbohydrates.Schüssler et al. (2006) reported the transport of glucose,mannose, galactose and fructose by a fungal transporter.
Dangerous companions: increased disease due to concerted action of Burkholderia–Rhizopus endosymbiosis
There exists a phytopathogenic alliance inside the genusRhizopus, causing a serious plant disease that is termed asrice seedling blight. The key virulence factor of this plantdisease is the phytotoxin rhizoxin, a potent cell cycle inhib-itor that kills plant and animal cells. Due to its excellent invitro antitumoural activities, rhizoxin is under clinicalinvestigation. While rhizoxin is a phytotoxin, the data fromanimal diseases, mucormycoses, indicate no signiWcant rolefor this substance. Ibrahim et al. (2008) and Partida-Martinez et al. (2008) showed that Rhizopus species frommucormycoses are devoid of symbionts or rhizoxin.
Rhizoxin is not a fungal metabolite but in fact producedby bacteria, belonging to the genus Burkholderia, whichreside within the mycelium of Rhizopus (Partida-Martinezand Hertweck 2005). Endobacteria are often very diYcultto get in culture, but Partida-Martinez and Hertweck (2005)were not only able to culture the Burkholderia endosymbi-ont in vitro, but also to produce bacterium free Rhizopusmycelium. This enabled them to examine the roles of thepartners of this intriguing relationship. According to Kochpostulates, bacterium free fungus was not able to producerhizoxin, but the production commenced again after theacquisition of Burkholderia. A specialised mechanism hasevolved during evolution that guarantees the persistence ofthe Rhizopus–Burkholderia endosymbiosis. Burkholderia isnecessary for vegetative reproduction of Rhizopus, forspore production (Partida-Martinez et al. 2007c). By label-ling the bacteria with GFP and introducing them to hyphaeby laserbeam transformation techniques, the authors wereable to visualize the colonization of fungal hyphae by thebacteria, their migration within the hyphae, and their pres-ence in fungal spores (Partida-Martinez et al. 2007c).
Two representatives of the bacterial endosymbionts wereclassiWed, Burkholderia rhizoxina sp. nov. and Burkholde-ria endofungorum sp. nov (Partida-Martinez et al. 2007b).Scherlach et al. (2006) reported the successful isolation andlarge-scale fermentation of the bacterial endosymbiontBurkholderia rhizoxina in pure culture, which resulted in asigniWcantly elevated production of antimitotic rhizoxin
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derivatives. Numerous novel natural and semisyntheticvariants of rhizoxin were isolated, and their structures werefully elucidated. Rhizoxin biosynthesis involves typicalpolyketide synthase (PKS), as well as nonribosomal peptidesynthetase modules. By using KS (ketosynthase) primers inPCR, type I PKS genes were exclusively detected in thegenomic DNA of rhizoxin producers. Next, Partida-Martinezand Hertweck (2007) isolated the entire gene cluster thatcodes for the rhizoxin megasynthase and accessoryenzymes. The identity of the rhizoxin biosynthesis genecluster was proven by the inactivation of acyl transferasedomain encoding rhiG gene: The resulting mutant wasincapable of rhizoxin production. Rhizopus shows self-resistance to rhizoxin.
Schmitt et al. (2008) correlated rhizoxin resistance withthe nature of fungal b-tubulin sequences, and conveyed it toa single amino acid position of fungal b -tubulin. Their dataindicated that rhizoxin sensitivity represents an ancestralcharacter state in fungi, and that the evolution of rhizoxinresistance took place in the ancestor of resistant Zygomy-cota. This suggests that it was an important step in thedevelopment of the Rhizopus–Burkholderia endosymbiosis(Schmitt et al. 2008).
In addition to phytopathogens, the genus Rhizopusincludes cosmopolitan soil fungi. These are implicated inthe spoilage of foods, which comprise fruits, nuts, and veg-etables. Colonisation of foods by Rhizopus species maybecome a serious risk for consumers, since endobacteria insaprophytic Rhizopus species produce rhizonin, a hepato-toxic cyclopeptide (Partida-Martinez et al. 2007a).
Sick of bacteria: white blotch and cavity spot diseases of Agaricales
Pseudomonas species are common pathogens of Basidio-mycetes. Pseudomonas tolaasii causes brown blotch in thewhite button mushroom Agaricus bisporus, characterizedby pitting and browning on the surface of the mushrooms(Burlinson et al. 2008). Already low densities of P. toolasiithat are present in the casing surface of mushrooms pro-voke severe epidemics of this disease, which makes theprotection of mushrooms diYcult (Soler-Rivas et al. 1999).Also other Pseudomonas species, including P. reactans,cause similar disease symptoms due to comparable diseasedeterminants.
When applied directly to the mushroom surface, P. tola-asii culture Wltrates cause blotch symptoms identical tothose caused by the organism. The causal factors, the extra-cellular toxins tolaasins, disrupt membranes and cause col-lapse of fungal hyphae. P. reactans, instead, producesanother lipodepsipeptide called the White Line InducingPrinciple (WLIP). Tolaasin production by P. tolaasii as
well as WLIP production by P. reactans is necessary forvirulence (Soler-Rivas et al. 1999; Lo Cantore et al. 2006).Lo Cantore et al. (2006) clearly demonstrated that the anti-fungal activity of toolasin I was higher than that of WLIP;this was compensated by comparably higher productionrates of WLIP in vitro. Coraiola et al. (2006) observed thatboth lipodepsipeptides were able to induce the release ofcalcium from vesicles. Their activity was dependent on theconcentration of the toxin as well as on the composition ofthe vesicles. Lo Cantore et al. (2006) showed that WLIPhad a greater hemolytic activity than toolasin I, and in theassays of Coraiola et al. (2006) only WLIP showed a deter-gent-like activity.
The establishment of brown blotch disease developmenthas been well detailed (Soler-Rivas et al. 1999). Startingfrom chemotaxis, bacterial adhesion takes place, followedby the secretion of the toxins, fungal membrane breakdown,hyphal collapse, and ending with coloring reactions. A largecollection of A. bisporus strains has been tested against P.toolasii, but none of the strains thus far has been found to becompletely resistant to the bacterium. Genetic mechanismsbehind increased resistance are currently unknown. Thework of Tsukamoto et al. (2002) with toolasin detoxifyingbacteria from fruiting bodies of wild Agaricales mushroomsmay open a way for bioprotection of brown blotch. Toolasindetoxifying isolates strongly suppressed brown blotchdevelopment in mushroom cultivation. Now, the nature ofdetoxifying agents should be revealed.
Like Pseudomonas spp., Burkholderia gladioli pv. aga-ricicola is also an important pathogen in the mushroomindustry. It causes a form of soft rot, cavity spot, in commer-cially important mushrooms including cultivated Agaricusspecies (Gill and Tsuneda 1997). To characterize diseasedeterminants, avirulent mutants of B. gladioli pv. agaricicolaBG164R were generated by Chowdhury and Heinemann(2006). Following transposon mediated mutagenesis, theauthors presented mutants able to inhibit hyphal growth, butunable to provoke soft rot. This was against the suggestionafter earlier analyses (Gill and Tsuneda 1997), that inhibi-tion of mycelial growth is necessary for disease develop-ment. Characterization of six mutant strains that no longercaused the disease revealed that all mutations mapped togenes of the general type II secretory pathway (GSP). Sinceextracellular protease- and chitinase-activities were decreasedin the mutant strains, the authors suggest that proteases andchitinases may belong to the virulence factors secreted bythe GSP (Chowdhury and Heinemann 2006).
Conclusions
The ensemble of bacterium–fungus model systems hasincreased during the last few years, and the recent progress
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of this promising Weld shows now great potentials in medic-inal, agricultural and biotechnological applications. Agrowing number of examples suggest that the associationshave a function in serving as a framework or facilitatingfungal interactions with animals and plants. For the intraf-ungal bacteria, their roles are only beginning to be resolved.Secondary metabolites have been identiWed that orchestratethe associations. There are several lines of evidence forcross-domain signalling, resulting from re-evaluations offunctions of previously characterized metabolites, as wellas from isolations of novel substances. Even in areas aswell investigated as bacterium–fungus antagonism, novelmechanisms have surfaced. This indicates that further stud-ies will be necessary to deWne the exact physiological func-tions that bacteria and fungi express and to delineate morethe functional similarities and diVerences between theseassociations, whatever their ecological niches. The maintools to eYciently Wll these gaps in knowledge have beendeveloped within the last decade during the study of somemodel species, and a major challenge is now to developfunctional microscopic tools allowing the analysis of thefungal–bacterial relationships at the cell-cell interface. It isalso to validate in situ the relevance of the proposed mecha-nisms. Broader biological questions surrounding the under-lying molecular mechanisms of bacterium–fungusinteractions, in carefully studied in vitro model systems,should allow the elucidation of novel interaction mecha-nisms in the future.
Acknowledgments M. T. Tarkka would like to thank Silvia Schrey,Nina Lehr, Margret Ecke, Hans-Peter Fiedler, Julia Riedlinger, DirkSchulz, and Rüdiger Hampp for their experimental and intellectualeVort, the German Science Foundation and Helmholtz-Gemeinschaftfor Wnancial support, and Ursula Kües and Stefan Hohmann for thekind invitation to write this review. PFK would like to thank A.Deveau, J. Bertaux, C. Brulé and B. Palin for their experimental con-tribution to the analysis of the interactions between bacteria and forestmycorrhizal fungi, INRA and Lorraine Region for funding the re-searches. AS would like to thank M. Barret, M. Boutin and A.-Y.Guillerm-Erckelboudt for their experimental contributions in the analysisof the interactions between bacteria and pathogenic fungi, and INRAand Bretagne Region for funding the research.
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