molecular bacteria-fungi interactions: effects on

MI67CH18-Hertweck ARI 12 August 2013 11:12

Molecular Bacteria-FungiInteractions: Effects onEnvironment, Food,and MedicineKirstin Scherlach, Katharina Graupner,and Christian HertweckLeibniz Institute for Natural Product Research and Infection Biology, Hans Knoll Institute,07745 Jena, Germany; email: [email protected]

Annu. Rev. Microbiol. 2013. 67:375–97

First published online as a Review in Advance onJune 26, 2013

The Annual Review of Microbiology is online atmicro.annualreviews.org

This article’s doi:10.1146/annurev-micro-092412-155702

Copyright c© 2013 by Annual Reviews.All rights reserved

Keywords

endofungal bacteria, endophytes, mushroom diseases, quorum sensing,secondary metabolites, symbiosis

Abstract

This review focuses on bacteria-fungi interactions mediated by secondarymetabolites that occur in the environment and have implications formedicine and biotechnology. Bipartite interactions that affect agricultureas well as relationships involving additional partners (plants and animals) arediscussed. The advantages of microbial interplay for food production andthe risks regarding food safety are presented. Furthermore, recent devel-opments in decoding the impact of bacteria-fungi interactions on infectionprocesses and their implications for human health are highlighted. In addi-tion, this reviews aims to demonstrate how the understanding of complexmicrobial interactions found in nature can be exploited for the discovery ofnew therapeutics.

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Secondarymetabolites: organiccompounds that arenot essential for thegrowth of an organismbut are often endowedwith potent biologicalactivities to warrantsurvival of the species

Contents

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376BACTERIA-FUNGI INTERACTIONS IN THE ENVIRONMENT . . . . . . . . . . . . . . 376

Bipartite Bacteria-Fungi Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376Tripartite Bacteria-Fungi-Plant Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379Tripartite Bacteria-Fungi-Animal Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382

BACTERIA-FUNGI INTERACTIONS: EFFECTS ON FOODPRODUCTION AND SAFETY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384

BACTERIA-FUNGI INTERACTIONS: EFFECTS ON MEDICINE . . . . . . . . . . . . . 386Bacteria and Fungi as Coacting Human Pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386Exploiting Bacteria-Fungi Interactions for Drug Discovery . . . . . . . . . . . . . . . . . . . . . . . 388

CONCLUSIONS AND PERSPECTIVES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

INTRODUCTION

The discovery of penicillin is one of the first documented observations of an interaction betweenbacteria and fungi mediated by small molecules. Historically molecular intergeneric interactionswere regarded mainly as growth-inhibiting interactions; however, modern research revealed thatmicrobial cross talk forms an integral part of our environment and covers various aspects beyondsimple antibiosis. There are instances in which natural products alter phenotypes and developmen-tal processes, such as sporulation or biofilm formation, and serve as virulence factors in symbioticand pathogenic associations involving additional partners. Specialized mutualistic relationshipshave evolved in which a host organism harbors a symbiont to make use of its chemical synthe-sis capabilities to combat competitors or to maintain a certain lifestyle. The growing number ofstudies published in the past few years that report discoveries in this field points to an excitingemerging area of research. Our increasing understanding of the complex networks in microbialecology will not only help us understand fundamental biological processes but also lead to the dis-covery of new virulence factors and drug candidates. This review highlights recent contributionsto the understanding of bacteria-fungi interactions mediated by secondary metabolites that occurin the environment and affect medicine and biotechnology.

BACTERIA-FUNGI INTERACTIONS IN THE ENVIRONMENT

Bipartite Bacteria-Fungi Interactions

Microbes ubiquitously occur in the environment and colonize almost every ecological niche. Be-cause of this high abundance, different species coinhabit certain habitats and as a consequenceinteract with each other. Such encounters probably represent the driving force to produce sec-ondary metabolites that regulate the coexistence and survival of different species.

Interactions via antibiosis. Production of antimicrobial compounds provides a growth advan-tage for an organism that enables its survival in a competitive environment (112). A huge numberof antibiotic and antifungal natural products have been identified since the beginning of thegolden age of antibiotics, and many of these compounds have been applied in medicine (11).Besides the medicinal importance, these works provided valuable insights into the ecological

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Imaging massspectrometry:analytical techniquethat combines theuniversal detectioncapability of massspectrometry withmicroscopic imagingtechniques and thusallows the visualizationof biomolecules inbiological matrices

function of the compounds and demonstrated how intricate and finely tuned bacteria-fungi in-teractions in nature are. This is reflected by the different strategies that bacteria and fungi haveevolved to combat secreted antimicrobial compounds. For example, Schoonbeek et al. (145) re-ported that broad-spectrum antibiotics produced by Pseudomonas spp. (2,4-diacetylphloroglucinol,phenazine-1-carboxylic acid, and phenazine-1-carboxamide) induce the expression of several ABCtransporter genes in the plant pathogenic fungus Botrytis cinerea, thus ensuring the efflux of toxicmetabolites. Fusarium spp. produce the mycotoxin fusaric acid, which is able to repress the pro-duction of 2,4-diacetylphloroglucinol in Pseudomonas fluorescens CHA0 by reducing the expressionof the responsible biosynthetic genes (110). In return, the biocontrol strain P. fluorescens WCS365profits from the mycotoxin, as it appears to be a chemoattractant for this species (42). Theseworks also denote that antibiotics not only are chemical warfare agents, but presumably havenumerous additional functions in the microbial interplay. For instance, at subinhibitory con-centrations, antibiotics may stimulate or depress bacterial gene expression at the transcriptionlevel and thus affect virulence and metabolic and adaptive functions (58). Thus, secreted sec-ondary metabolites might have manifold functions that we are only beginning to understand,and further studies are needed to uncover the precise roles of natural products in microbialecology.

Bacteria as inducers of mushroom diseases. Bacteria-fungi interactions adapt to changingenvironmental conditions. Within one genus of bacteria, organisms can be found that exert ei-ther beneficial or detrimental effects on a fungal host. Well-studied examples are the interactionsbetween various Pseudomonas species and the cultivated mushrooms Agaricus bisporus and Pleu-rotus ostreatus (3). Whereas Pseudomonas putida stimulates the fructification of A. bisporus (109,129), other pseudomonads cause mushroom diseases (94, 136). Brown blotch disease, initiated byP. tolaasii and other Pseudomonas spp., accounts for significant crop losses in mushroom farming.Typical symptoms include a dark brown discoloration of the mushroom caps accompanied bycharacteristic lesions on the basidiocarp (152). The causal agents are tensioactive lipopeptidesnamed tolaasins that are produced by the bacteria (30). Tolaasins are cyclic lipodepsipeptidesconsisting of 18 amino acids with β-hydroxy-octanoic acid at the N terminus (9). Tolaasin I,which is considered the main virulence factor, exhibits antimicrobial activity and is highly resis-tant to enzymatic degradation (128). The characteristic symptoms of the disease are due to theability of tolaasin to disrupt the fungal cell membrane by forming transmembrane pores (20, 33).Other known bacterial mushroom pathogens include Pseudomonas gingeri (ginger blotch disease),P. costantinii, P. aeruginosa, and P. fluorescens (56, 106). A related bacterium, Pseudomonas ‘reactans,’has been proposed as a biocontrol strain to reduce blotch diseases, even though it is classified asa mushroom pathogen (151). P. ‘reactans’ produces in culture an extracellular peptide called thewhite line inducing principle (WLIP), which is able to precipitate tolaasins (98). Pretreatment ofA. bisporus with the isolated peptide protects the mushroom from brown blotch symptoms causedby infection with P. tolaasii (3). WLIP consists of nine amino acids and an N-terminal fatty acid,representing a potent biosurfactant with antimicrobial properties (98). The molecular basis forthe biosynthesis of this peptide in P. putida was recently established (133).

Graupner et al. (60) described the first insights into the pathogenicity factors of Janthinobac-terium agaricidamnosum, which causes soft rot disease of A. bisporus (97). By monitoring theinfection process with imaging mass spectrometry, the authors identified the lipopeptide jagaricinas a potent virulence factor. Genome mining and molecular genetic studies unequivocally estab-lished that jagaricin is biosynthesized by a nonribosomal peptide synthetase. Furthermore, potentantifungal properties of jagaricin were described, which indicates that the discovery of virulence

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Defensins: cationicpeptides produced byeukaryotes thatfunction as hostdefense molecules

γ-Butyrolactones:signaling moleculesproduced mainly bystreptomycetes thatregulate antibioticproduction andmorphologicaldifferentiation

Nonribosomalpeptide synthetases(NRPS):multifunctionalenzymes that catalyzethe biosynthesis ofpeptides

Polyketide synthase(PKS):multifunctionalenzyme that catalyzesthe oligomerization ofactivated smallcarboxylic acids;analogous to fatty acidsynthesis

factors involved in mushroom diseases may also contribute to the development of antifungaltherapeutics.

Similarly, the discovery of the first defensin from a fungus, plectasin, underlined the impor-tance of studying natural bacteria-fungi interactions. Plectasin was isolated from the saprophyticascomycete Pseudoplectania nigrella and acts by directly binding the bacterial cell wall precursorlipid II (65, 107, 143). Owing to this rare mode of action, the fungal defensin represents a promisinglead for the development of new antibacterial agents.

Bacteria-fungi interactions in lichens. Lichens are mutualistic associations between fungi andphotoautotrophic organisms, i.e., green algae and cyanobacteria (43). The symbiotic partners formcomplex and exposed structures that enable growth in diverse and even extreme environments thatusually are not favorable for the individual species (61). Secondary metabolites are hypothesizedto contribute to the ability of lichens to survive in such rather hostile environments. For ex-ample, lichens can endure high-UV exposition by synthesizing pigments that act as UV filters(19). Moreover, it was shown several decades ago that lichen extracts possess antibiotic properties(25), suggesting potential defense strategies of lichens. In many cases the mycobiont produces thesecondary metabolites (1, 38). However, more recent studies indicate that the photoautotrophicbacterial partner may also contribute biosynthetic capabilities. Yang et al. (165) reported theformation of chlorinated γ-butyrolactones called nostoclides by cultures of the cyanobacteriumNostoc sp. that were isolated from the lichen Peltigera canina. These compounds display moder-ate cytotoxic properties and may function as signalling molecules. Another well-known class ofcyanobacterial metabolites are the microcystins, which are produced by a Nostoc species recoveredfrom the lichen Pannaria pezizoides (116). These cyclic heptapeptides were isolated from multiplegenera of cyanobacteria and are strong hepatotoxins (45, 157). The biosynthesis of microcystinsby a large multifunctional enzyme complex containing both nonribosomal peptide synthetase(NRPS) and polyketide synthase (PKS) modules is well studied (44). Kaasalainen et al. (82) haveshown that microcystins are also produced in situ in the lichen and suggest that these peptidesact as deterrents for animal grazers. Cox et al. (35) analyzed Nostoc strains, among others, thatwere isolated from diverse lichens and found that the formation of a neurotoxic amino acid, β-N-methylamino-L-alanine, seems to be a common principle in cyanobacteria. Cryptophycins arehighly potent tubulin-depolymerizing polyketides isolated from cultures of the lichen cyanobac-terial symbiont Nostoc sp. ATCC 53789 (101). Because of their strong cytostatic activities, severalsemisynthetic derivatives were evaluated as potential anticancer agents (150). The finding thatlichen-derived cyanobacteria produce a number of highly toxic metabolites suggests an importantfunction of the bacterial partner for the ecological fitness of the mutualistic association.

Furthermore, the close intergeneric association between fungi and photosynthetic organismsmay be influenced by additional microbial partners (61). In many cases, lichens harbor a stableconsortium of various nonphotoautotrophic microorganisms including parasitic fungi and evenendosymbiotic organisms (61). These coinhabiting species contribute to the mutualism, for ex-ample, via secretion of secondary metabolites. Gonzalez et al. (59) isolated actinomycetes fromlichens collected in tropical and cold areas and evaluated their biosynthetic capabilities. By PCRtargeting secondary-metabolite-encoding biosynthetic genes, the authors proved the high biosyn-thetic potential of the lichen-associated bacteria. Furthermore, the prevalence of these genes wascorrelated to antimicrobial activities of the culture extracts (59). He et al. (68) isolated the bis-naphthopyrones lichenicolins A and B from a lichen-associated fungus and reported antibacterialactivity of lichenicolin A against gram-positive bacteria, suggesting an ecological function of theassociated microorganisms.


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Siderophores: ferricion-chelating agentsproduced by bacteriaand fungi to sequesteriron from theenvironment

Tripartite Bacteria-Fungi-Plant Interactions

In many cases, the microbial interplay is even more complex and involves additional partners.Both bacteria and fungi live in close association with higher organisms and may exert beneficialas well as detrimental effects on the coinhabiting species.

Bacteria-fungi interactions in the mycorrhizosphere. Fungi and bacteria are essential com-ponents of terrestrial ecosystems (17). The root system of several plant species interacts with fungito form a symbiotic alliance called mycorrhiza (17, 153). Through this mutualistic interaction,plants benefit from enhanced access to minerals, and fungi profit from the carbohydrates of rootexudates (17). Whereas such trophic interactions have been extensively studied and were the focusof a number of comprehensive reviews (5, 17, 48), only a little is known about the mechanismscontrolling these associations.

Among soil microbes, the arbuscular mycorrhizal fungi (AM fungi) represent one of the mostimportant classes, as they not only significantly influence the growth of plants but also impact thedevelopment of other microbes coinhabiting the terrestrial ecosystem (5, 17). AM fungi belongto the phylum Glomeromycota, and the establishment of a symbiotic relationship with plants isusually not host specific (103). To engage in this mutualism, both partners have to communicate,for example, via the exchange of signal molecules (67, 123). Plants secrete phytohormones suchas strigolactones to stimulate fungal metabolism and hyphal branching (2, 12). Fungi respond viaso-called Myc factors that control plant gene expression (17). In many cases this bipartite mutu-alism is extended to a third bacterial partner. Several studies indicated the presence of bacteria inthe mycorrhizosphere (40, 108). Bacteria colonize mycorrhized roots, fungal hyphae, spores, andfruiting bodies and even occur in the fungal cytoplasm. Their effect on the plant-fungus micro-habitat is dynamic and multifaceted, ranging from the production of plant hormones to alleviatingstress and controlling pathogens (5, 17). The cooperation may vary in accordance with the currentecophysiological state. Specific bacterial populations may facilitate the mycorrhizal establishment(mycorrhization helper bacteria), for example, by excretion of organic acids that serve as a carbonsource for fungi (49). To ensure a stable physical interaction with the fungi, bacteria produceextracellular polymers that aid attachment to the fungal surface (14). Soil prokaryotes may alsostimulate the growth of the fungi by triggering the germination of fungal spores (24, 70, 71).Tylka et al. (158) proposed that volatile compounds secreted by streptomycetes positively impactAM fungal germination. Later, bacteria-produced auxofurans were identified as positive effectorson fungal development (130) (Figure 1). Other important functions of such soil bacteria are thedetoxification of the fungal habitat and the protection against plant pathogens. Removal of fun-gal waste products or changing the level of siderophores may facilitate mycorrhizal growth (50).Budi et al. (24) reported that a Paenibacillus strain isolated from Glomus mosseae spores inhibits anumber of different plant fungal pathogens, thus showing a broad spectrum of activity. Bharadwajet al. (13) also studied the effect of AM fungal spore–associated bacteria on plant pathogens andevaluated the formation of siderophores. They found that a high number of bacteria inhibit thegrowth of the plant pathogen Rhizoctonia solani, although the active compounds have not beenidentified in this study. In addition, it was shown that 16 of 57 antagonistic isolates (fluorescentpseudomonads) produce siderophores (13). Because such bacterial chelators have a higher affin-ity to ferric iron than fungal siderophores, it was suggested that the production of these smallmolecules might contribute to the antagonistic activity against fungal pathogens (13). Citernesiet al. (31) studied the influence of the biocontrol compound iturin A2, secreted by Bacillus subtilisstrain M51, on AM fungi (31). The saprophytic growth of the fungus G. mosseae was inhibited byiturin A2 and no retardation in growth or establishment of symbiosis was noticed in the presence


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O

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Symbiotic microorganisms

Pathogenic microorganisms

Mycorrhizosphere Endophytes

Rhizoxin

WF-1360F

Auxofuran1H-indole-3-

acetic acid

Figure 1Tripartite bacteria-fungus-plant interactions (specifically a pathogenic interaction causing rice seedlingblight). Symbiotic interactions in the mycorrhizosphere and in plant tissues and chemical mediators areshown. Double-headed arrow indicates interaction; stop lines indicate inhibition; orange ovals highlight theposition further modified by the fungus to increase phytotoxicity.

of the tomato host plant (Lycopersicon esculentum), whereas infection with competing species washindered. On the other hand, the fungal partner also might influence coinhabiting species viathe secretion of chemical substances. Besides nutritional effects, the exudation of antibiotics is animportant fungal contribution to the mutualism. Thus, the fungus ensures the specific growth ofsymbiosis-promoting bacteria and prevents infection with antagonistic prokaryotes (40).

An even more complex network of cross-species interaction is exemplified by the interplay ofbacteria living in the cytosol of AM fungi and their plant symbionts. Biancotto et al. (16) described“Candidatus Glomeribacter gigasporarum,” an endobacterium of the AM fungus Gigaspora mar-garita. Various insights into the lifestyle and maintenance of this mutualistic relationship weregained (15, 79, 100, 137, 138). Full genome sequencing of the obligate endobacterium allowed afirst glance into the evolution of the symbiosis and its ecological impact. Bioinformatic analysis ofthe sequence data suggested that the endobacteria could have the potential to synthesize vitaminB12, antibiotic-, and toxin-resistant molecules, which may contribute to the ecological fitness ofthe fungal host (53).


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Endosymbioticbacteria: bacteria thatlive inside anotherorganism

Type III secretionsystem: a proteinstructure found inbacteria that is used totranslocate proteinsinto the cytosol ofeukaryotes (also calledinjectisome)

Bacteria as mediators of fungal virulence. A similarly intriguing tripartite relationship has beendescribed in the context of rice seedling blight. This plant disease is caused by the zygomyceteRhizopus microsporus and accounts for severe losses in agriculture in Asia (76). The fungus utilizesantimitotic toxins synthesized by its bacterial endosymbionts to destroy the rice seedlings (76, 77,120) (Figure 1). The polyketide macrolide rhizoxin binds to the β-tubulin of the rice plant cellsand causes mitotic arrest (155, 156). This leads to the characteristic symptom of the plant disease,a swelling of the seedling tips, and finally results in the death of the plant offspring. Isolationand axenic cultivation of the endosymbiotic bacteria Burkholderia rhizoxinica (119) provided clearevidence that the toxin complex is actually produced by the mutualistic bacteria (141). Toxinogenicendofungal bacteria were shown to occur in a number of Rhizopus spp. isolated from geographicallydistant regions, which points to the ecological importance of the bacteria-fungi relationship (90).

Cloning, sequencing, and functional analysis of the rhizoxin biosynthetic gene cluster provideddetailed insights into the formation of the toxin by a huge hybrid PKS/NRPS assembly line (87,88, 121). In addition to metabolic dependence, other remarkable facets of the symbiotic alliancehave been disclosed. Sequencing of the genome of the intracellular symbiont provided valuableinsights into the bacterial genetic equipment (92) and allowed deductions regarding the evolutionand metabolic interconnection of the host-symbiont relationship (93). Schmitt et al. (142) revealedhow the fungal host acquired resistance to the antimitotic toxin. By correlating rhizoxin sensitivitywith the type of β-tubulin sequences, the authors showed that rhizoxin resistance is predictableaccording to the character state of β-tubulin residue 100 (142). These findings also suggest thatendosymbiosis became possible through a shift from parasitism to mutualism in insensitive fungi.To guarantee the persistence of the mutualism during host reproduction, a finely tuned systemof fungal vegetative reproduction and transmission of endosymbionts has evolved. It was foundthat the bacteria strictly control the sporulation of Rhizopus and ensure the exclusive dispersal ofspores harboring endosymbionts (122). Moreover, the unusual mutualism has been refined throughadditional symbiosis factors such as a Type III secretion system (91) and a novel lipopolysaccharideO-antigen that sets the symbionts into stealth mode by decorating the outer membrane of theendosymbionts (96).

In a recent study, the close intergeneric interaction of the allied organisms was further disclosed.Driven by the observation that the bacteria solely produce rhizoxin derivatives harboring onlyone epoxy moiety, whereas in coculture bis-epoxides are formed, Scherlach et al. (139) studied thecontribution of the fungus to the biosynthesis of the endobacterial toxin. Through a combinationof genetic and chemical analyses it was demonstrated that the fungal host specifically tailors thebacterial metabolite to increase the phytotoxic potency (139) (Figure 1). This first example of asymbiotic synergism in the biosynthesis of a secondary metabolite that has biological significancehighlights the importance of metabolic bacteria-fungi interactions in the ecosystem.

Interactions among endophytes. Endophytes are microbes that colonize living tissues of plantswithout causing any immediate or visible negative effects (126). The impact of such symbioticassociation on the plant ecosystem is diverse and is not fully understood (4). Many endophytes havethe potential to produce bioactive secondary metabolites and are therefore regarded as a valuablesource for drug discovery (86, 126, 154). Especially, compounds with antimicrobial propertieswere frequently isolated from endophytes, suggesting these metabolites protect against harmfulmicrobes such as phytopathogens. Some endophytes were even described as producing typical plantmetabolites when cultured outside their host plant (166). In most cases a plant is colonized not bya single endophyte, but rather by a high number of different species either coinhabiting differenttissue compartments or even occurring as endobacteria in the hyphae of a fungal endophyte (72).Therefore, it is conceivable that complex patterns of microbial interactions occur within the plant


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Indoleacetic acid:a phytohormone thataffects growth anddevelopment of plants

to ensure the beneficial outcome of the mutualism. Diffusible chemical signals that coordinatethe individuals in these populations might mediate the interaction. Bandara et al. (7) undertookfirst attempts to study the interaction between endophytic fungi and bacteria in vitro showing thecolonization of fungal mycelia by bacteria and the influence of biofilm formation on antimicrobialeffects and production of indoleacetic acid–like substances (7) (Figure 1). Up to now the potentialof endophytic interspecies cross talk had hardly been exploited for the discovery of novel naturalproducts (86). Most studies focusing on the isolation of secondary metabolites from endophyteshave been carried out utilizing only axenic cultures. However, it can be assumed that a cocultureof different species usually coinhabiting a plant might lead to the formation of novel compoundsas has recently been described for cocultures of actinomycetes and ascomycetes (see below).

Tripartite Bacteria-Fungi-Animal Interactions

The lifestyle and the survival of animals in tripartite animal-bacteria-fungi interactions dependon the bacteria-fungi interplay. A remarkable example of the impact of bacteria-fungi interactionson insects is the symbiosis of the European beewolf digger wasp (Philanthus triangulum) withStreptomyces spp. (83). The female wasps carry the bacteria in their antennal glands and distributethem to the brood cell within the ground. Larvae harbor symbiotic bacteria in their cocoons thatprotect them against pathogenic microorganisms. It was shown that the streptomycete symbiontis capable of producing a mixture of antibiotics containing streptochlorin (Figure 2) and eightderivatives of piericidin under environmental conditions (85). Inhibition tests pointed toward a

Bacteria

Fungus

AnimalsMycangimycin

Streptochlorin

Violacein

Dentigerumycin

HN

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Figure 2Schematic showing different tripartite interactions among bacteria, fungi, and animals. Selected naturalproducts mediating these interplays are displayed. Double-headed arrows indicate symbiotic interaction;bolts indicate damaging effect (dashed bolts indicate decreased damage due to bacteria-fungi interaction);stop lines indicate inhibition.


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Chytridiomycosis:infectious disease ofamphibians causingtissue erosion, weightloss, and death

Ovipositional gallery:breeding galleryconstructed by beetlesunder the bark of a tree

synergistic mode of action for the produced broad-spectrum antibiotic mixture, which is activeagainst not only entomopathogenic fungi but also bacteria (85). Current research in this field re-vealed that natural-product-producing Actinobacteria, which live in association with insects, mightbe a common theme in nature (e.g., 127). Poulsen et al. (127) cultivated Streptomyces isolates fromsolitary mud dauber wasps and demonstrated that several isolates produce antifungal and antibac-terial secondary metabolites. The screening even led to the discovery of the novel macrocycliclactam sceliphrolactam. However, evidence for a protective role of these newly discovered naturalproducts remains to be proven (127).

With respect to the amphibians a more specific bacteria-fungi interaction can be found. Thecutaneous bacterium Janthinobacterium lividum protects its amphibian hosts against the fungusBatrachochytrium dendrobatidis, which causes the lethal disease chytridiomycosis (22, 66). The bac-terial secondary metabolites violacein (Figure 2) and indole-3-carboxaldehyde have been identi-fied as the active compounds on the skin of the red-backed salamander (Plethodon cinereus) (22) andmountain yellow-legged frog (Rana muscosa) (66). Knowledge about this beneficial bacteria-fungiantagonism could prove to be helpful to cope with chytridiomycosis. This disease is an impor-tant issue as it threatens about one-third of the amphibian population worldwide with extinction.Becker et al. (10) and Harris et al. (66) demonstrated independently that amphibians treated withJ. lividum are protected against a B. dendrobatidis infection. Hence, a carefully considered use ofJ. lividum as a biological chytridiomycosis protectant could help control the disease and preventthe decline of amphibian populations. Although other amphibian skin-inhabiting bacteria havebeen discovered, J. lividum has been studied most intensely (10, 21, 22, 66).

In the marine environment few bacteria-fungi interactions that impact animals have beenreported. Gil-Turnes et al. (55) discovered a symbiosis between Alteromonas sp. and embryos of theshrimp Palaemon macrodactylus, in which bacteria inhabiting the shrimps’ surface confer resistanceagainst infections of the fungus Lagenidium callinectes by producing 2,3-indolinedione (55).

A more complex interaction between bacteria and fungi occurs in association with the southernpine beetle (Dendroctonus frontalis). The beetle harbors the symbiotic fungus Entomocorticum sp. Aand inoculates the ovipositional galleries with the symbiont. Within these galleries, Entomocorticumsp. A supplies the developing beetle larvae with nutrition. However, this mutualistic relationshipis endangered by the pathogenic fungus Ophiostoma minus, as this fungus is capable of overgrow-ing Entomocorticum sp. A (84). Scott et al. (147) reported that the beneficial mutualism betweenD. frontalis and Entomocorticum sp. A is protected by a third participant, a previously unknownactinomycete, that produces the antifungal compound mycangimycin (Figure 2). This naturalproduct inhibits the antagonistic fungus O. minus but has only minor effects on the symbiontEntomocorticum sp. A (147).

The probably best-studied and most sophisticated insect-bacteria-fungus interaction is the tri-partite mutualism between the leaf-cutting ants (Acromyrmex spp.), the garden fungus Leucoagaricusgongylophorus, and actinomycete bacteria. The ants grow the fungus L. gongylophorus in so-calledfungal gardens and supply it with food. In turn, L. gongylophorus serves itself as a nutritional sourcefor the ants. In order to protect their fungal gardens from necrotrophic fungi such as Escovopsis spp.,ants have formed a symbiosis with antibiotic-producing Actinobacteria of the genera Streptomyces,Pseudonocardia, and Amycolatopsis (8). These bacteria were acquired by either vertical transmission(Pseudonocardia) or sampling from the soil (Streptomyces and Amycolatopsis) (8). Several antifungalsecondary metabolites, such as candicidin (63), dentigerumycin (115), valinomycin, antimycin,actinomycin (144), and a nystatin-like compound (8), have been isolated (Figure 2). Yet, Seipkeet al. (148) showed that there are still more natural products remaining to be discovered fromActinobacteria engaged in symbioses with insects. Sen et al. (149) gave this story an interestingtwist; they showed that the secondary metabolites produced by the investigated bacterial species


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Lactic acid bacteria(LAB): gram-positivebacteria that producelactic acid as the mainend product duringfermentation

Pseudonocardia and Amycolatopsis display nonspecific broad antifungal activity. Subsequently, theproduced natural products can inhibit or kill the beneficial fungus L. gongylophorus as well. Hence,ants could damage their fungal garden by subjecting them to actinobacterial secretions.

BACTERIA-FUNGI INTERACTIONS: EFFECTS ON FOODPRODUCTION AND SAFETY

Many food fermentations are carried out with mixed consortia of microorganisms, which can beyeasts, filamentous fungi, lactic acid bacteria (LAB), and/or acetic acid bacteria. These coculturescontribute to the aroma, flavor, and texture of food, and usually they also enhance the shelf life offermented products (39) (Figure 2). Mixed bacteria-fungus fermenting cultures are employed inthe production of alcoholic beverages such as wine (46) and beer (134), dairy products (161) suchas cheese (34) and kefir (99), and sourdough (52, 159), among others. However, investigationsof the molecular interactions between bacteria and fungi during fermentation are limited. Thegrowth of bacterial starter cultures can be enhanced by yeasts, but the molecular mechanism hasnot yet been elucidated (34, 161).

The molecular interplay between antifungal metabolite-producing LAB and spoilage fungiin baked goods, beer, and cheese has been investigated in more detail (39, 52, 134, 135, 159).Organic acids (lactic, acetic, propionic, and phenyllactic), hydroxy fatty acids, hydrogen peroxide,cyclic dipeptides, and reuterin, as well as uncharacterized phenolic and proteinaceous substances,are antifungal compounds produced by LAB (39) (Figure 3). In addition, yeasts can inhibit thegrowth of the spoilage bacteria Listeria monocytogenes in smear cheese (27, 57). Increasing effort isbeing devoted to research on fermenting microorganisms that inhibit spoilage bacteria and fungi,as the demand for additive-free food rises. Moreover, the usage of inhibitory starter cultures couldreduce the risk of food spoilage by mycotoxin-producing molds or pathogenic bacteria. Such foodpoisoning represents a substantial public health risk and causes severe economic losses. Anotheremerging research field to counter food poisoning is the biotransformation and biodegradationof mycotoxins by microorganisms (78) (Figure 2). Mycotoxins such as aflatoxin, zearalenone,fumonisin, and trichothecene contaminate food and feedstuff, leading to toxic reactions uponuptake. Several bacteria are able to transform or even degrade such fungal toxins (75). However,the microbial degradation processes have to be carefully evaluated as not all biotransformationreactions warrant a detoxification of the mycotoxins. Furthermore, it has to be assessed whether thetransformed product is still stable after uptake by humans and animals. Although many investigatedbacteria show promising transformation and degradation abilities, the usage of biotransformingenzymes isolated from these organisms seems to be more advantageous to treatments with livingmicroorganisms (78).

In contrast to the beneficial effects of microbial cocultures for food production, bacteria-fungiinteractions may also cause food spoilage and thus have a major impact on human health (89)(Figure 3). Tempe bongkrek, a popular, coconut-derived dish in Southeast Asia, is produced byfermentation of coconut press cake using the fungus Rhizopus oligosporus (23, 51). Unfortunately,the fungal culture is often contaminated with a bacterium, Burkholderia gladioli pv. cocovene-nans (32). These bacteria are known to produce two toxins, bongkrekic acid (bon) and toxoflavin,which account for a number of lethal intoxications after consumption of tempe bongkrek (51).Bongkrekic acid is a polyunsaturated fatty acid and efficiently inhibits oxidative phosphorylationin mitochondria through blockage of adenine nucleotide translocation (41). Oral intake causesstrong hyperglycemia followed by hypoglycemia and death. The foodborne toxin is derived froma polyketide pathway, as was found by stable isotope labeling (131) and molecular studies of bonbiosynthesis (104). Through sequencing of the genome of B. gladioli and functional analyses of


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Fungus

Bacteria

Foods

Aroma

Flavor

Texture

Biotransformation ofmycotoxins

Unknowncompound

Rhizoxin S2

Rhizonin

Toxoflavin

Reuterin

Propionic acid

cyclo(Phe-Pro)

ON

OCH3

O

O

OHO

OHCOOH

NHHN

H3CN

H3CN

NH

HNNCH3

CH3

NCH3

OO

O

OO

O

OO O

N

N

NNO

O

O

O

O

OO

OCH3

H

H

HN

N

O

OH

OHO

O

OH

Aflatoxin

Figure 3Schematic illustration of bacteria-fungi interactions that affect food production and spoilage. Double-headed arrows indicate mutualinteraction; bolts indicate spoilage (dashed bolts indicate decreased spoilage due to bacteria-fungi interaction; bold bolts indicateincreased spoilage due to bacteria-fungi interaction); stop lines indicate inhibition.

trans-AT PKS:a subclass of modulartype I polyketidesynthases in which themodules lackindividual AT domains

the bon gene locus new insights into the complex polyketide assembly by a trans-AT PKS weregained. The other toxin produced by the contamination is the azapteridine toxoflavin, a yellowpigment that was discovered as early as 1934. Latuasan & Berends (95) postulated that toxoflavinis poisonous due to the generation of hydrogen peroxide. Toxoflavin is also considered the mainvirulence factor of Burkholderia glumae, a bacterium causing bacterial panicle blight of rice (64).

Two other metabolites of fungus-associated Burkholderia spp., rhizonin and rhizoxin, are ofsimilar toxicological importance. Actually, the cyclopeptide rhizonin was believed to be the firstmycotoxin identified from the Zygomycota (81, 163). However, rhizonin is in fact produced byendosymbiotic bacteria living in the fungal cytosol of Rhizopus microsporus, as had been shown


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Sufu: a fermentedsoybean productproduced by solid statefermentation of tofufollowed by an agingstep in brinecontaining salt andalcohol

Mucormycosis:fungal infection causedby Mucorales

previously for the phytotoxin rhizoxin (118). Because some subspecies of R. microsporus are usedfor the fermentation of soybeans (e.g., for sufu and tempe production), a potential risk for humanhealth arises from the toxinogenic symbiosis. Rhizonin is produced by Burkholderia endofungorum,the endosymbiont of a R. microsporus strain originally isolated from groundnuts in Mozambique(119). The cyclic peptide is highly toxic to mammals as it causes serious hepatic lesions (163).The cytotoxic polyketide rhizoxin from Burkholderia rhizoxinica is produced during fermentationof soybeans with Rhizopus sp. for sufu production (132). Because some of the produced derivativesbelong to the strongest antimitotic agents known to date (141), a severe health risk may arisefor the consumer. These results underline the urgent necessity to consider potential detrimentaleffects resulting from bacteria-fungi interactions during food production to warrant food safety(89).

BACTERIA-FUNGI INTERACTIONS: EFFECTS ON MEDICINE

Bacteria and Fungi as Coacting Human Pathogens

Even though humans are colonized by numerous microorganisms, little is known about the molec-ular interaction among these organisms. However, this research area deserves particular attentionbecause often mixed-species infections generate a complex scenario. The significance of under-standing microbial interactions within human hosts is highlighted even further by the fact thatthe disease outcome of mixed bacteria-fungi infections can differ from single-species infections(124), so that alternative treatment methods have to be applied. Usually, opportunistic pathogensare involved in such multispecies infections. As a consequence, immunocompromised individualsare more prone to becoming infected. The bacteria-fungi interactions during an infection canbe characterized as either neutral (the interaction has no impact on the disease outcome), syner-gistic (bacterial and fungal pathogens act together against the human host), or antagonistic (themicroorganisms inhibit each other).

Rhizopus oryzae is responsible for about 60–80% of all human mucormycosis cases (75). Takinginto consideration that Rhizopus fungi have been found in association with endosymbiotic, toxin-producing bacteria (89), it appears plausible that R. oryzae too may harbor endosymbionts. Exam-inations of clinical isolates identified bacteria-associated fungi as well as bacteria-free fungi (75,117). Utilizing mouse and fly models, Ibrahim et al. (75) investigated the impact of the endosym-biotic bacteria on the infection outcome. No difference in virulence was observed between thefungi harboring bacterial endosymbionts and those without bacteria, although the endobacteria-produced rhizoxin displays cytotoxic activity itself. Apparently, the Rhizopus sp.–Burkholderia sp.interaction is an example of a neutral interaction during infection (Figure 4). Still, it remainsunclear whether the same behavior can be expected during human infections.

Several synergistic interactions between human pathogenic fungi and bacteria have been dis-covered and described. One intensely studied interaction is the coinfection of the yeast Cryptococcusneoformans and the bacterium Klebsiella aerogenes (Figure 4). Thereby, melanin is an important vir-ulence factor for C. neoformans (28). Surprisingly, the yeast is not capable of synthesizing melaninon its own, so that C. neoformans depends on exogenous substrate. K. aerogenes supplies dopamine,which can be utilized for melanization by C. neoformans (47). The pigmentation protects the mi-croorganisms not only against environmental stress but also against the human immune defense(28). Another example of enhanced fungal virulence due to interspecies interplay is mixed biofilmsof the yeast Candida albicans and the bacterium Streptococcus gordonii, which occur together in theoral cavity (Figure 4). It was shown that S. gordonii promotes hyphal growth and biofilm formationof C. albicans (6). Both filamentous growth and biofilm formation contribute to the virulence of


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Fungus

Human

Bacteria

No BFI

Neutral BFI

Antagonistic BFI

Synergistic BFI

Rhizoxi

n S2

Farnesol

Pyocyanin

3-oxo-C12-HSL

Melanin

AI-2

Dopamine

ON

OCH 3

O OOH

OO

H COO

H

NCH

3

N

OH

NH

O

O

OO

OH

HN

O

ON

HHO

HO

NH2

O

OBO

HO

HO OH

HO

Figure 4Different medically important bacteria-fungi interactions (BFI). Double-headed arrows indicate interaction;bolts indicate disease (dashed bolts indicate less virulence due to bacteria-fungi interaction; bold boltsindicate enhanced virulence due to bacteria-fungi interaction); stop lines indicate inhibition. Abbreviations:3-oxo-C12-HSL, 3-oxo-C12-homoserine lactone; AI-2, autoinducer-2.

Autoinducer-2:small, diffusiblequorum-sensingmolecule forinterspeciescommunication

the yeast (124). Bamford et al. (6) demonstrated that this interaction occurs via both physical andchemical signals. The physical interaction takes place via adherence, and the interspecies signalmolecule autoinducer-2 serves as chemical signal (6).

The yeast C. albicans is involved in antagonistic bacteria-fungi interactions, too. An intenselystudied opponent of C. albicans is Pseudomonas aeruginosa (Figure 4). Both opportunistic pathogenshave been frequently isolated from burn victims (62) and cystic fibrosis patients (74). P. aeruginosaproduces a range of secondary metabolites that inhibit or even kill C. albicans. One of thesenatural products is the antifungal phenazine pyocyanin (124). Notably, the pyocyanin precursor5-methyl-phenazine-1-carboxylic acid (5MPCA) is even more potent than its end product (54).Morales et al. (105) revealed the mechanism by which the antifungal activity is conferred. Theredox-active 5MPCA generates reactive oxygen species (ROS) such as H2O2 and O2

−. In addition,5MPCA reacts with amine moieties within proteins, thus impairing important cellular structures


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Quorum-sensing(QS) molecules:small diffusiblemolecules employedby bacteria to regulatetheir cell-density-dependent behavior

Silent biosyntheticpathways: conditionin which secondarymetabolite geneclusters are notexpressed (e.g., undercommon laboratoryculture conditions)

and enzymes. The covalently bound 5MPCA derivatives keep their redox activity and hence theirability to produce ROS. Both effects promote fungal cell death (105).

In addition, C. albicans and P. aeruginosa interact via the quorum-sensing (QS) molecules far-nesol and 3-oxo-C12-homoserine lactone (3-oxo-C12-HSL), which are produced by C. albicansand P. aeruginosa, respectively (73). The fungal QS molecule inhibits the swarming ability ofP. aeruginosa (102) and reduces the production of the antifungal pyocyanin (37). The bacterial QSmolecule 3-oxo-C12-HSL is structurally related to farnesol and might act as a structural analog(73). 3-oxo-C12-HSL reduces the yeast’s virulence by repressing filamentation (73). Likewise,other bacteria, such as Xanthomonas campestris, Burkholderia cenocepacia, and Streptococcus mutans,produce farnesol mimics that repress hyphal growth of C. albicans. These interspecies signals havebeen identified as cis-2-methyl-11-dodecenoic acid (162), cis-2-dodecenoic acid (18), and trans-2-decenoic acid (160), respectively. Furthermore, S. mutans produces another QS molecule, thecompetence-stimulating peptide, which represses germ tube formation of C. albicans (80).

Investigations of these diverse bacteria-fungi interactions occurring in humans have shownthat the outcome of an interspecies infection ranges from virulence enhancement to antagonisticinteraction. Therefore, treatment for mixed-species infection should be carefully measured, as anincreasing growth of C. albicans, for example, was observed after antibacterial therapy of a mixedinfection of P. aeruginosa and the yeast (26). However, in infections where bacteria contribute tothe virulence of a fungus, an additional antibacterial treatment might be required. Also, furtherresearch on molecular antagonistic interactions might serve new treatment options or hithertounknown points of attack.

Exploiting Bacteria-Fungi Interactions for Drug Discovery

The interplay between different microorganisms at the molecular level has generated a vast chem-ical diversity. The complex interactions of fungi and bacteria in nature are mediated by secondarymetabolites that have a specific function for the producing organism, for example, to ensure sur-vival in a competitive environment. Therefore, many microorganisms have a huge biosyntheticpotential as has been revealed by various whole-genome sequencing projects (69, 164). The expres-sion of the biosynthetic gene clusters is usually tightly regulated to meet the varying requirementsof a changing environment, and it appears that most natural product biosynthesis genes are silentin pure cultures. Thus, the majority of secondary metabolites remains untapped.

Surprisingly, only a limited number of studies have exploited the potential of bacteria-fungiinteractions for drug discovery. Although coculturing approaches have been widely used forindustrial purposes (e.g., production of food and beverages), little is known about secondarymetabolism in cocultures (140). Several years ago it was shown that mixed fermentations couldhave an influence on the production of secondary metabolites. Whereas initially the impact of thecocultured organism was assessed mainly by an increase in the biological (i.e., antibiotic) activity ofa culture extract or a yield improvement in the production of a certain compound (125), followingresearch focused on the discovery of new natural products resulting from either combinedbiosynthetic pathways or the activation of previously silent pathways. Cueto et al. (36) cultured amarine Pestalotia species together with an unidentified, antibiotic-resistant marine bacterium andthus elicited the biosynthesis of the benzophenone pestalone. The compound, which is producedonly in coculture, displays potent antibacterial activity against methicillin-resistant Staphylo-coccus aureus and vancomycin-resistant Enterococcus faecium. In another study, a marine-derivedEmericella species was challenged by coculturing it with the actinomycete Salinispora arenicola(114). Thus, the production of two new cyclic depsipeptides, emericellamides A and B, wasenhanced 100-fold, which enabled their structural elucidation. Emericellamides possess moderate


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Histoneacetyltransferases:acetylate-conservedlysine residues ofhistone

antibacterial activities against methicillin-resistant S. aureus. The emericellamide biosyntheticgenes were discovered via a gene deletion approach in the model organism Aspergillus nidulans,offering the possibility to engineer novel analogues (29). Four new diterpenoids, libertellenonesA–D, were discovered by coculturing the marine fungus Libertella sp. with an unidentified marinebacterium (113). This bacterium seemed to specifically induce the formation of these compoundsin this fungal species as no new metabolites could be detected in 49 other cocultures with thesame bacterium. Zuck et al. (167) described the production of formyl-xanthocillin analogues byusing a mixed culture of Aspergillus fumigatus and Streptomyces peucetius.

In a more systematic approach, Schroeckh et al. (146) employed microarray-based monitoringto study the expression of cryptic biosynthetic gene clusters in the model fungus A. nidulansafter induction through the interaction with actinomycetes sharing the same habitat. Of 58 testedspecies, one strain (Streptomyces rapamycinicus) was detected that triggers the formation of thearchetypal polyketide orsellinic acid along with the typical lichen metabolite lecanoric acid andtwo complex polyphenols with anti-osteoporosis activity. Molecular genetic studies allowed forthe first time the identification of the long-sought-after genetic locus for the biosynthesis oforsellinic acid, one of the simplest fungal polyketides. Further insights into the mechanism ofthe intimate interaction of both organisms were gained by studying the regulation of fungalgene expression. By a systematic deletion of 36 out of 40 acetyltransferase-encoding genes andby chromatin immunoprecipitation experiments, it was revealed that the bacterium induces ahistone modification in the fungus via the main histone acetyltransferase complex Saga/Ada (111).These results demonstrate the complexity of bacteria-fungi interactions and imply the yet-to-be-discovered potential of studying microbial cross talk.

CONCLUSIONS AND PERSPECTIVES

Various examples of bacteria-fungi interactions highlighted in this review illustrate that mixedconsortia of microorganisms are widespread and can be found in a variety of places including soil,plants, animals, and humans and in food production. The more we understand these interactionsamong bacteria and fungi, the more we realize that such interplays affect not only environmentalprocesses (e.g., growth of plants or diseases of plants, animals, fungi), but also our everyday life (e.g.,food production, food spoilage, human disease control). However, the molecular basis of someimportant interkingdom interactions remains elusive. Moreover, one can presume that a plethoraof bacteria-fungi interactions awaits discovery. From a translational point of view, knowledge ofbacteria-fungi interactions can be exploited for beneficial use in many ways. Microorganisms thatcontrol growth of spoilage or pathogenic organisms can replace synthetic chemicals used in thefood industry or during animal husbandry, fulfilling consumer demand for additive-free food andorganic farming. Obviously, the application of living organisms must be carefully considered. Insome cases it might be more suitable to use specific enzymes or natural products isolated froman organism instead of the whole microbe. Natural product discovery has always been essentialfor drug development. Utilizing cocultures in natural product-screening processes can aid thediscovery of novel secondary metabolites that are not produced in the absence of particular stimuli.Another important medical benefit that can be gained from understanding the molecular basicsof bacteria-fungi interactions involved in human diseases is the identification of new therapeutictargets to combat pathogens.

However, humans will be able to take advantage of bacteria-fungi interactions only ifthey fully appreciate the molecular interplay. We expect future research to contribute greatlyto our understanding of bacteria-fungi interactions and to provide new avenues for novelapplications.


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DISCLOSURE STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings thatmight be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

K.S. and K.G. contributed equally to this review. We thank the International Leibniz ResearchSchool for Microbial and Biomolecular Interactions (ILRS) and the Jena School for MicrobialCommunication ( JSMC) of the German Excellence Initiative for supporting the authors’ originalresearch in this area.

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MI67-FrontMatter ARI 12 August 2013 12:26

Annual Review ofMicrobiology

Volume 67, 2013 Contents

Fifty Years Fused to LacJonathan Beckwith � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

3′ Cap-Independent Translation Enhancers of Plant VirusesAnne E. Simon and W. Allen Miller � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �21

Acyl-Homoserine Lactone Quorum Sensing: From Evolutionto ApplicationMartin Schuster, D. Joseph Sexton, Stephen P. Diggle, and E. Peter Greenberg � � � � � � � � �43

Mechanisms of Acid Resistance in Escherichia coliUsheer Kanjee and Walid A. Houry � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �65

The Biology of the PmrA/PmrB Two-Component System: The MajorRegulator of Lipopolysaccharide ModificationsH. Deborah Chen and Eduardo A. Groisman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �83

Transcription Regulation at the Core: Similarities Among Bacterial,Archaeal, and Eukaryotic RNA PolymerasesKimberly B. Decker and Deborah M. Hinton � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 113

Bacterial Responses to Reactive Chlorine SpeciesMichael J. Gray, Wei-Yun Wholey, and Ursula Jakob � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 141

It Takes a Village: Ecological and Fitness Impactsof Multipartite MutualismElizabeth A. Hussa and Heidi Goodrich-Blair � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 161

Electrophysiology of BacteriaAnne H. Delcour � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 179

Microbial Contributions to Phosphorus Cycling in Eutrophic Lakesand WastewaterKatherine D. McMahon and Emily K. Read � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 199

Structure and Operation of Bacterial Tripartite PumpsPhilip Hinchliffe, Martyn F. Symmons, Colin Hughes, and Vassilis Koronakis � � � � � � � � � 221

Plasmodium Nesting: Remaking the Erythrocyte from the Inside OutJustin A. Boddey and Alan F. Cowman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 243

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The Algal Past and Parasite Present of the ApicoplastGiel G. van Dooren and Boris Striepen � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 271

Hypoxia and Gene Expression in Eukaryotic MicrobesGeraldine Butler � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 291

Wall Teichoic Acids of Gram-Positive BacteriaStephanie Brown, John P. Santa Maria Jr., and Suzanne Walker � � � � � � � � � � � � � � � � � � � � � � 313

Archaeal Biofilms: The Great UnexploredAlvaro Orell, Sabrina Frols, and Sonja-Verena Albers � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 337

An Inquiry into the Molecular Basis of HSV Latency and ReactivationBernard Roizman and Richard J. Whitley � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 355

Molecular Bacteria-Fungi Interactions: Effects on Environment, Food,and MedicineKirstin Scherlach, Katharina Graupner, and Christian Hertweck � � � � � � � � � � � � � � � � � � � � � � � 375

Fusarium PathogenomicsLi-Jun Ma, David M. Geiser, Robert H. Proctor, Alejandro P. Rooney,

Kerry O’Donnell, Frances Trail, Donald M. Gardiner, John M. Manners,and Kemal Kazan � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 399

Biological Consequences and Advantages of AsymmetricBacterial GrowthDavid T. Kysela, Pamela J.B. Brown, Kerwyn Casey Huang, and Yves V. Brun � � � � � � � 417

Archaea in Biogeochemical CyclesPierre Offre, Anja Spang, and Christa Schleper � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 437

Experimental Approaches for Defining Functional Roles of Microbesin the Human GutGautam Dantas, Morten O.A. Sommer, Patrick H. Degnan,

and Andrew L. Goodman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 459

Plant Cell Wall Deconstruction by Ascomycete FungiN. Louise Glass, Monika Schmoll, Jamie H.D. Cate, and Samuel Coradetti � � � � � � � � � � � � 477

Cnidarian-Microbe Interactions and the Origin of InnateImmunity in MetazoansThomas C.G. Bosch � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 499

On the Biological Success of VirusesBrian R. Wasik and Paul E. Turner � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 519

Prions and the Potential Transmissibility of ProteinMisfolding DiseasesAllison Kraus, Bradley R. Groveman, and Byron Caughey � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 543

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The Wonderful World of Archaeal VirusesDavid Prangishvili � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 565

Tip Growth in Filamentous Fungi: A Road Trip to the ApexMeritxell Riquelme � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 587

A Paradigm for Endosymbiotic Life: Cell Differentiation of RhizobiumBacteria Provoked by Host Plant FactorsEva Kondorosi, Peter Mergaert, and Attila Kereszt � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 611

Neutrophils Versus Staphylococcus aureus: A Biological Tug of WarAndras N. Spaan, Bas G.J. Surewaard, Reindert Nijland,

and Jos A.G. van Strijp � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 629

Index

Cumulative Index of Contributing Authors, Volumes 63–67 � � � � � � � � � � � � � � � � � � � � � � � � � � � 651

Errata

An online log of corrections to Annual Review of Microbiology articles may be found athttp://micro.annualreviews.org/

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molecular bacteria-fungi interactions: effects on

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