h ttp : / / w w w . b j m i c r o b i o l . c o m . b r /
Environmental
Microbiology
Microbial
interactions:
ecology
in
a
molecular
perspective
Raíssa
Mesquita
Braga,
Manuella
Nóbrega
Dourado,
Welington
Luiz
Araújo
∗UniversidadedeSãoPaulo,InstitutodeCiênciasBiomédicas,DepartamentodeMicrobiologia,SãoPaulo,SP,Brazil
a
r
t
i
c
l
e
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n
f
o
Articlehistory:Received23September2016
Accepted7October2016
Availableonline26October2016
AssociateEditor:MarinaBaquerizo
Keywords: Microbialinteraction Diversity Microbe–hostinteraction Molecularinteraction
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Themicroorganism–microorganismormicroorganism–hostinteractionsarethekey
strat-egytocolonizeandestablishina varietyofdifferentenvironments.Theseinteractions
involveall ecological aspects, includingphysiochemical changes, metabolite exchange,
metabolite conversion, signaling, chemotaxis and genetic exchange resulting in
geno-typeselection.Inaddition,theestablishmentintheenvironmentdependsonthespecies
diversity,sincehighfunctionalredundancyinthemicrobialcommunityincreasesthe
com-petitiveabilityofthecommunity,decreasingthepossibilityofaninvadertoestablishinthis
environment.Therefore,theseassociationsaretheresultofaco-evolutionprocessthatleads
totheadaptationandspecialization,allowingtheoccupationofdifferentniches,byreducing
bioticandabioticstressorexchanginggrowthfactorsandsignaling.Microbialinteractions
occurbythetransferenceofmolecularandgeneticinformation,andmanymechanismscan
beinvolvedinthisexchange,suchassecondarymetabolites,siderophores,quorumsensing
system,biofilmformation,andcellulartransductionsignaling,amongothers.Theultimate
unitofinteractionisthegeneexpressionofeachorganisminresponsetoanenvironmental
(bioticorabiotic)stimulus,whichisresponsiblefortheproductionofmoleculesinvolvedin
theseinteractions.Therefore,inthepresentreview,wefocusedonsomemolecular
mech-anismsinvolvedinthemicrobialinteraction,notonlyinmicrobial–hostinteraction,which
hasbeenexploitedbyotherreviews,butalsointhemolecularstrategyusedbydifferent
microorganismsintheenvironmentthatcanmodulatetheestablishmentandstructuration
ofthemicrobialcommunity.
©2016SociedadeBrasileiradeMicrobiologia.PublishedbyElsevierEditoraLtda.Thisis
anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/
licenses/by-nc-nd/4.0/).
Introduction
Microbialinteractions arecrucialforasuccessful
establish-ment and maintenance of a microbial population. These
∗ Correspondingauthorat:NAP-BIOP–LABMEM,DepartmentofMicrobiology,InstituteofBiomedicalSciences,UniversityofSãoPaulo,
Av.Prof.LineuPrestes,1374-Ed.BiomédicasII,CidadeUniversitária,05508-900SãoPaulo,SP,Brazil.
E-mail:[email protected](W.L.Araújo).
interactionsoccurbytheenvironmentalrecognitionfollowed
by transferenceof molecular and geneticinformation that
includemanymechanismsand classesofmolecules.These
mechanismsallowmicroorganismstoestablishina
commu-nity,whichdependingonthemulti-trophicinteractioncould
http://dx.doi.org/10.1016/j.bjm.2016.10.005
1517-8382/©2016SociedadeBrasileiradeMicrobiologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC
resultinhigh diversity.Theresultofthis multiple
interac-tion isfrequently relatedto pathogenic orbeneficial effect
toa host. In humans,for example,the microbial
commu-nityplaysanimportantrole inprotectionagainstdiseases,
causedbymicrobialpathogensorphysiologicaldisturbances.
Soilsmicrobialcommunitiesalsoplayamajorrolein
protec-tingplantsfromdiseasesandabioticstresses1orincreasing
nutrientuptake.
Microorganismsarerarelyencounteredassinglespecies
populations in the environment, sincestudies indifferent
habitatshas shown that anenormous richness and
abun-dance variation are usually detected in a small sample,
suggesting that microbial interactions are inherent to the
establishment of populations in the environment, which
includessoil, sediment, animal, and plants, including also
fungiand protozoacells.Themanyyears ofcoevolution of
thedifferentspeciesleadtoadaptationandspecializationand
resultedinalargevarietyofrelationshipsthatcanfacilitate
cohabitation,suchasmutualisticandendosymbiotic
relation-ships,orcompetitive,antagonistic,pathogenic,andparasitic
relationships.2
Many secondary metabolites have been reported to be
involved in the microbial interactions. These compounds
are usuallybioactiveand canperform importantfunctions
in ecological interactions. A widely studied mechanism of
microbial interaction is quorum sensing, which consists
inastimuli-response system relatedto cellular
concentra-tion.Theproductionofsignaling molecules(auto-inducers)
allows cells to communicate and respond to the
environ-ment in a coordinated way.3 During interaction with the
hostcells,microbial-associatedmolecularpatterns(PAMPor
MAMP – microbial-associated molecular pattern) are
con-served throughout different microbial taxon allowing to
increasethefitnessduringinteractionwithplantoranimal
cells4andregulatingthemicrobialinteractionswithdifferent
hosts(Table1).
Muchattention hasbeen givento researcheson
micro-bial interactions in the humanhealth field. The microbial
interactions are crucial for the successful establishment
andmaintenanceofcolonizationandinfection.Additionally,
antimicrobialhostdefensesandenvironmentalfactors also
playessentialroles.Microorganismcommunicationenables
thepopulationtocollectivelyregulatethegeneexpressionin
responsetohostandenvironmentalsignals,producedbythe
sameorevenbydifferentspecies.Thisresultsinacoordinate
responsein the microbial population, achieving successful
pathogenicoutcomesthatwouldnotbeaccomplishedby
indi-vidualcells.5–7
Consequently,knowledgeonthemechanismsinvolvedin
themicrobialinteractionscanbeakeytodevelopingspecific
agentsthatcanavoidordisturbmicroorganism
communica-tion duringinfectionand consequentlyacttodecrease the
defensiveandoffensivequalitiesofthepathogen.Thus,the
studyofthesemechanismscancontributetothe
understand-ingofthemicrobialpathogenesisandtothedevelopmentof
newantimicrobialdrugs.5,8
In addition, microbial interactions occurring in human
hostcanalsobebeneficandsomediseasesareoftenrelated
toimbalances inthe healthymicrobiota.Therefore,studies
on the healthy microbial community in the host are also
relevantasitcanleadtodiseasepredictionanditsappropriate
therapies.9–11
Microbial interactions also deserve attention from the
naturalproductsdiscoveryfield.Secondarymetabolite
clus-ters that are silent under laboratory growing conditions,
can be activated by simulating the natural habitat of the
microorganism. It has been reported that co-cultivation
with others microorganisms from the same ecosystem
can induce the activation ofotherwise silent biosynthetic
pathways leading to the production and identification of
newnaturalproducts.12–16 Furthermore,thisknowledgecan
also be applied to genetic engineering of phytopathogens
antagonists/parasites aiming to an enhanced biological
control.17
Inthisreview,wefocusedonthemolecularmechanisms
involvedinmanymicrobialinteractions,involvingintraand
interspecies microbial interactions and the microorganism
interactionwiththehost.
Organisms
involved
Microorganismsrarelyoccurassinglespeciespopulationsand
areencounteredinmanyhosts/environments,thusthereis
a large variety of types of microbial interactions
concern-ingtheorganismsinvolved.Bacteria–bacteria,fungus–fungus,
bacteria–fungus,fungus–plant/animal,bacteria–plant/animal
and bacteria–fungus–plant/animal interactions, including
parasitic,mutualisticinteractionsinvolvemanymechanisms
that havebeen described,allowingtodevelopstrategiesto
manipulatetheseinteractions,whichcouldresultinincreased
hostfitnessornewmetaboliteproduction.Accordingtovan
Elsas et al.,18 theestablishmentofa newspecies(invader)
inanenvironmentdependsonthecharacteristicofthelocal
microbialcommunity.Ingeneral,ecosystemsthatlostspecies
diversity present less ability to resist to an invader, since
presentmoreavailablenichethatcouldbeoccupiedby
indige-nousspecies.In addition,duringthe nicheoccupation, the
invadershouldinteractwithspeciespresentinthis
environ-ment.
The mechanisms involved in archaeal interactions are
largely unknown, althoughthey are very importantin the
archaealcommunities,productionofmethaneinlandfills,19
archaeainsoiland rhizosphereecosystems,20 thermophilic
archaea in bioleachingprocess,21 forexample. Virus
inter-actionswith its hostare alsovery importantsinceviruses
are responsible for many diseases in a variety of hosts,
and also, modulating the bacterial community by
infect-ing dominantspecies.Host-virus communicationisrelated
to RNA-based mechanisms such as microRNAs.22,23 The
microorganisms addressed in the present reviewed
com-prise fungi and bacteria, we did not focus on virus or
archaea.
Fungi and bacteria interactions are widely studied,
although themolecular mechanisms involvedin the
inter-actionsare oftennotcompletelyunderstood.Theyinteract
withawiderange ofdifferentorganisms–plants,humans
and other animals, among others – in different
envi-ronments, as we describe in this present review, and
Table1–Microbialinteractionstudies.
Organismsinvolved Typeofinteraction Compounds/mechanisms
involved
Findings References
Moniliophthoraroreriand
Trichodermaharzianum
Phytopathogen–endophyte T39butenolide,
harzianolide,sorbicillinol
Productionofthedescribed
compoundswasdependenton
thephytopathogenpresenceand
wasspatiallylocalizedinthe
interactionzone.
61
Trichodermaatrovirideand
Arabidopsissp.
Endophyte–plant Indole–aceticacid-related
indoles
Colonizationofplantrootsby endophytepromotesgrowthand enhancessystemicdisease resistanceintheplant.
71
Xylellafastidiosaand
Methylobacterium mesophilicum
Phytopathogen–endophyte Genesrelatedtogrowthwere
down-regulatedwhilegenes relatedtoenergyproduction, stress,transport,andmotility wereup-regulatedinthe phytopathogen.
74
Burkholderiagladioli,B. seminalisandorchid
Phytopathogen–endophyte– plant Extracellular polysaccharides;altering hormonemetabolism (suggested)
Theendophytestrainprobably interactswiththeplantbyusing extracellularpolysaccharides andbyalteringhormone metabolism,aswassuggestedby genomicanalysis.
75
Bradyrhizobiumdiazoefficiens
andAeschynomene afraspera
Symbiont–plant C35hopanoids C35hopanoidareessentialfor
symbioseandarerelatedto evasionofplantdefense, utilizationofhost
photosynthates,andnitrogen fixation.
86
Stachybotryselegansand
Rhizoctoniasolani
Mycoparasite–host Trichothecenesand
atranones
Themycotoxinsproducedbythe mycoparasiteinduced
alterationsinR.solani
metabolism,growth,and development.Thebiosynthesis ofmanyantimicrobial compoundsbyR.solaniwere downregulated.
17
Streptomycescoelicolorand otheractinomycetes
Microbialcommunity Prodiginines,
actinorhodins, coelichelins,
acyl-desferrioxamines,
andmanyunknown
compounds
Mostofthecompounds producedineachinteraction wereunique;thestudyrevealed 227compoundsdifferentially producedintheinteractions.
92
Aspergillusnidulansand
Streptomycesrapamycinicus
Microbialcommunity Aromaticpolyketides Anintimatephysicalinteraction
betweenthemicroorganisms leadedtotheactivationoffungal secondarymetabolitegenes whichwereotherwisesilent.The actinomycetetriggered
alterationsinfungalhistone acetylation.
14,93
Pseudomonasspecies Microbialcommunity Pyoverdines(siderophore) Pyoverdinesareessentialto infectionandbiofilmformation andhavebeenreportedtoactas signalingmoleculestriggeringa cascadethatresultsinthe productionofseveralvirulence factors.
95,96
Vibriosp.anddiverse marinebacteriastrains
Microbialcommunity Exogenoussiderophores,
suchasN,N-bis
(2,3 dihydroxybenzoyl)-O-serylserine
Manymarinebacteriastrains werereportedtoproduce siderophoresandiron-regulated outermembraneproteinsonlyin thepresenceofexogenous siderophoresproducedbyother species.
Table1–(Continued)
Organismsinvolved Typeofinteraction Compounds/mechanisms
involved Findings References Burkholderiaspp.,Rhizopus spp.andrice Symbiont–phytopathogen– plant
Rhizoxin,bongkrekicacid,
andenacyloxins
Thefungusisnotcapableof
formatingsporesintheabsence
oftheendosymbiont.The
endosymbiontisresponsiblefor
theproductionofthephytotoxin
rhizoxin,thecausalagentofrice
seedlingblight.Thefungus
inducesthegrowthofthe
endosymbiont.
98,99,101
Vibriofischeriandfishesor squids
Symbiont–fish Quorumsensing Inthesymbioticassociationwith
fishesandsquidsthe
autoinducermoleculereachesa thresholdandluminescence genesareactivated.
91,92
Rhizobiumleguminosarum
andplant
Symbiont–plant Quorumsensing Thequorumsensingsystemin
thesebacteriaisrelatedto differentfunctions:nodulation efficiency,growthinhibition, nitrogenfixationandplasmid transfer.
111
XanthomonasorXylellaand grapevinesorcitrus
Pathogen–host Quorumsensing Quorumsensingsignaling
moleculescontroltheexpression ofvirulencefactoraswellas biofilmformation.
104
PantoeastewartiiandZea mays
Pathogen–host Quorumsensing QSmutantsofP.stewartiiwere
notabletodisperseandmigrate inthevasculature,consequently decreasingthedisease.
114
Pseudomonassyringaeand
tabaccoandbean
Phytopathogen–plant Quorumsensing QSsystemallowsthisbacterium
tocontrolmotilityand exopolysaccharidesynthesis essentialonbiofilmformation andleavescolonization.
115
Candidaalbicansand
Pseudomonasaeruginosa
Microbialcommunity Quorumsensing P.aeruginosaQSsystemmay
blocktheyeast-to-hypha transitionoractivatesthe hypha-to-yeastreversionofC. albicans.FarnesolproducedbyC. albicansdownregulatetheQS systemofP.aeruginosa.
123–125
processing,bioremediation,medicine,andbiocontrol.In
addi-tion, fungal–bacterial association forms a physically and
metabolicallyinterdependentconglomeratethatpresents
dis-tinctpropertieswhicharebiotechnologyrelevant,especially
consideringthenaturalproductdiscoveryandsynthetic
biol-ogyfield.1,24
Therearemanymicrobe–hostinteractions,whichcanbe
relatedtobeneficialorpathogenicinteractionsinplantsand
animals. In these interactions, the microbial cells may be
foundinbiofilmorplanktonicstate,whichresultindifferent
geneticandphysiologicalstates.
Plant-associatedmicroorganisms(endophyticand
rhizo-sphere environment) are able to promote plant growth by
producingphytohormones,improvingbiofertilization,
biore-mediation,andreducingbiotic(disease)andabioticstress.25
Root-associated endophytes are able to produce
phytohor-monesasauxins and gibberellins promotingplant growth.
Considering biofertilization, rhizosphere bacteria are able
to fix atmospheric nitrogen, produce siderophore for iron
acquisitionandmycorrhizalfungiisabletosolubilize
phos-phorusmakingitavailabletoplanthost.26
Thecontrolofplantstressisexemplifiedbytheproduction
ofACCdeaminasethatisresponsibleforthedecreaseof
ethy-lenelevelsbycleavingitsprecursor
1-aminocyclopropane-1-carboxylate(ACC)toammoniaand2-oxobutanoate,lowering
ethylenesignalingandthiswayalleviatingplantstress.27A
BurkholderiaphytofirmansPsJNmutantintheACCdeaminase
genelossestheabilitytopromoterootelongation.28Besides
that,theinoculationofamutualisticbacteriacanalsoaffect
plantfitnessbyincreasingphotosyntheticrate,CO2
assimila-tion,andchlorophyllcontent.29,30
The presence genes related to plant growth promoting
were addressedinstudiescomparingthe genomeof
endo-phytesandpathogens,revealingthatpathogenspresentgenes
involvedindegradationand hostinvasionwhilemutualists
presentgenesrelatedtohelpinstressamelioration,encoding
nitrogenfixationproteinsandribulosebisphosphate
Microbiome
interaction
with
its
host
Human
Thehumanmicrobiomeevolvesfrombirthtoelderly,
result-inginmicrobialrichnessanddiversityshiftsoverthewhole
life,modulatingtheimmunesystemand physiologicaland
morphologicalaspectsofthehost.Althoughsomebacteria
may be found in amniotic liquid with or without disease
symptoms,31–33 thedevelopmentofthehumanmicrobiome
isstudiedfrombirthuntilthismicrobialcommunitybecomes
adult-like.Duringthewholelife,thehumanmicrobiome
suf-fersimbalancesthathavebeenassociatedwithseveralkinds
of disease, such as asthma, obesity, diabetes, cancer and
inflammatoryproblemsinmanybodysites.Themicrobiome
imbalanceisreferredasdysbiosisandmayresultinfunctional
diseaseormaybecausedbyadiseaseordiseasetreatment.For
abettercomprehensionoftheassociationbetweenintestinal
microbialdysbiosisandpediatricdiseasestheArrietaetal.,34
reviewpresentanimportantdescriptionofthemicrobial
com-positionandshiftsassociatedwiththeage.
For the development of this microbial community, the
species that will composethis microbiota must show the
ability to occupy the available niches and interact with
the established microorganism and with host tissues. For
this, microbes have to shape their environment by
secre-tion products from their metabolism in a process called
niche construction. During this process, the niche is
con-structed when the microorganisms manage the nutrient
availableandpossiblecompetitorsbyproducingextracellular
enzymes,antimicrobialcompoundsoractivatingorinhibiting
thehostimmunesystem.35Amongthismolecules,
bacterio-cin(peptidesproducedbyabacterium,thathasanimmunity
mechanisms)activeagainstotherbacteriaseemstobe
ubiq-uitousinbacteriaandarchaeadomainandassociatedwith
nicheconstruction,sincetheseribosomalpeptidesmaywork
facilitatingtheintroductionand/ordominanceofaproducer
intoanalreadyoccupiedniche,ordirectlyinhibiting
compet-ingstrainsorpathogensduringgutcolonizationofworking
assignalingpeptide(cross-talking) orsignaling thehostby
interactionwithreceptorsforimmunesystem.36
Therefore,itisbelievedthattheevolutionofamicrobial
communityinthehostmaybefurtherrelatedtoanintrinsic
characteristicofthiscommunityandtheabilityofthe
micro-bialspeciestoconstructtheirniche.Theintrinsicaspectsare
associatedtofunctional redundancyofthe native
commu-nity,reducingtheavailablenichesandthenicheconstruction
theabilityoftheinvadertomanagetheenvironment(biotic
andabioticcharacteristics)inasocialevolutionarybehavior,
resultinginashapedenvironmentthatallowsthe
establish-mentofthemicrobialcolonizerintothehost.
During establishment inthe gut, microorganisms
inter-act with the host cells expressing adhesive molecules on
theirsurface,promotinginteraction withcell receptorsand
triggeringhostresponses.Themostimportantadhesive
struc-turesarepiliandfimbrialadhesinsinGram-negativebacteria,
butothersmonomericsurfaceboundadhesiveproteinshas
beenlargelyidentified.37Althoughtheregulationofadhesins
hasbeenstudiedmainly inpathogens,isbelieved thatthe
same strategy has been used by commensal species. The
chaperone-usher pathway has been an important system
to assembly pilus adhesins of enteric pathogens, but
oth-ers such astype IVpili, trimeric autotransporteradhesins
(TAA)family,adhesiveamyloids(Curli)(Gram-negative
bacte-ria)andSortaseassembledPiliandputativehead-stalk-type
adhesin (Gram-positive bacteria) are secreted and
assem-bled bySec-dependenttransporter.37 These adhesinsallow
the physical contactbetween the bacterial cells and host.
Thisinteractionmediatedbybothpilus-associatedand
non-pilus-associated adhesins with host receptors trigger host
inflammatory responses.In addition, this attachment onto
eukaryotic cells allowsbacteria suppress the host defense
by secretionofeffector proteinsinto the hostbysecretion
systems.37Thus,thegutcolonizationbeginsrapidlyafterbirth
withthemicroorganismentrybyingestionandkeepsgoingby
shapingtheenvironmentandattachmentontothehostcells
orlivingintothegutlumen.
In addition, duringthe establishmentinto thehost, gut
microbiota maytriggertoleranceorinflammatoryresponse
in the host. Some Lactobacillus spp. have the ability to
inducerheumatoidarthritisbyactivatingTLR(Toll-like
recep-tor) 2 and TLR4 followed by increasing of TH1 and TH17
activity and decreasing TReg-cellsfunction. Theproduction
of pro-inflammatory cytokines (IL-17) and endogen TLR4
agonist mediate joint inflammation by stimulatingplasma
cellstoproducearthritogenicautoantibodies.However,some
commensal bacteria, such as Bacteroides fragilis are able
to activate pro-tolerogenic machinery, the PSA, a cell wall
component, induce activation of TReg-cells and IL-10
pro-duction and repression ofTH17-cell, avoiding uncontrolled
inflammation.38 Cell wallcomponents, suchas
peptidogly-cans(PGN)mayalsospreadintothehostandberecognized
bypatternrecognitionreceptor(PRRs).Therecognitionofthis
PGNmaytrigger,notonlyahostimmuneresponse,butalso
hostmetabolismandbehavior.39
During bacterial growth, PGN isdegraded and although
bacterialPGNrecyclingpathwaytriestoreducethe
bioavail-ability of soluble fragments (preventing detection by the
host)39fragments(muropeptides)coulddisseminate
systemi-cally,activatingreceptorsfarfromthegut.Infact,receptors
(Nod1 and Nod2) that recognize these PGN fragments are
broadly distributed into the humanand animal bodies. In
addition, inrats that present sleep deprivation, the
bacte-rialtranslocationfromtheintestinetothemesentericlymph
nodeswasobserved.40andinpreviousstudies,itwasobserved
thatmuramylpeptidesmayinduceasomnogenicresponse
afterbrainventricule41 orintravenousorinjection.42 These
resultssuggestthatsleepdeprivationcouldinducebacterial
translocation,whichcouldbeasourceofmuramylpeptides
forsleepinginduction.39Theseresultssuggestthatthehost
behaviorcouldmodulatethe interactionwiththe microbial
community, which inturn contribute to shifts inthe host
physiology.
Soilandplant
All organisms are inhabited by microorganisms
includ-ing archaea, bacteria, fungi and viruses; this microbiota
microbiomeassociatedwithplantsisconsidereditssecond
genome.Itisdeterminantsforplanthealth,growth,fitness
and consequently productivity.45 Where each environment
associatedwiththeplant:rhizosphere,endosphere,and
phyl-lospherepresentaspecificmicrobialcommunitywithspecific
functions.43
These culture-independent methods show that plant
microbiomecanreachdensitiesgreaterthanthenumberof
plantcells andalsogreater expressed genesthan the host
cells.Metagenomicsanalysisusingnext-generation
sequenc-ingtechnologies showsthat only5%ofbacteria havebeen
culturedbycurrentmethods,revealinghowmany
microor-ganismsanditsfunctionsremainsunknown.25
The first step in plant–microbe interaction is microbial
recognitionofplantexudatesinthesoil.Thereisahypothesis
thatplantsareabletorecruitmicroorganismbyplant
exu-dates,whicharecomposedofaminoacids,carbohydratesand
organicacidsthatcanvaryaccordingtotheplantanditsbiotic
orabioticconditions.46Differentplantsselectspecific
micro-bialcommunitiesasreportedbyBergetal.,43whencomparing
rhizospherecolonizationoftwomedicinalplants:chamomile
(Matricaria chamomilla) and nightshade (Solanum distichum),
despitebeingcultivated undersimilarconditions, they
pre-sented differentstructural(analyzing16S rRNA genes)and
functional(analyzingnitrogenfixing–nifHgenes)microbial
community.Moreover,plantexudateofthesameplantvaries
according to plant developmental stages selecting specific
microbialcommunities.47Researchersalreadyidentifiedsome
plantexudatecompoundsresponsibleforspecificinteractions
such as flavonoids in Legume-Rhizobia48 and
Strigolac-tone asasignalmolecule forarbuscularmycorrhizal fungi
(AMF).49
Reinhold-Hurek et al.,50 proposed a model for
microor-ganismcolonization.Inbulksoil,themicrobialcommunity
presentsagreatdiversityandisinfluencedonlybysoiltype
andenvironmentalfactors.Gettingclosertoplantroots
(rhizo-sphere),wheretherearerootexudates,therearefewerspecies
andamorespecializedcommunity.Andonlyafewspecies
areabletoenterplantrootandestablishintheplant.
Further-more,afterentering theplant, microbialcommunityvaries
amongthedifferentorgans:topleaves,fruits,bottomleaves,
flowers,stemsandroots.51
Mutualistic microorganisms can protect plants from
pathogeneitherbyinducingplantresistanceorbyantibiosis.
Theinducedsystemicresistance(ISR)inplantsleadstohigh
tolerancetopathogens.Therearesoilsthatevenifthereis
thepathogenthediseasedoesnotoccur,themechanismsof
thesedisease-suppressivearestillbeinginvestigated.Inthis
way,Mendesetal.,52analyzedthemicrobiomeofasoil
sup-pressivetothefungalpathogenRhizoctoniasolanithatcauses
dampingoffinseveralagriculturalcrops.Using a16SrDNA
oligonucleotidemicroarray(PhyloChip)theywereableto
iden-tifymorethan33,000bacterialandarchaealtaxainthesugar
beetseedlingsrhizospheregrowninsuppressivesoilandin
conductivesoils.Theseanalysesrevealedthebacterialgroups
present onlyin the suppressive soil. Theauthors reported
that␥-Proteobacteria,especiallyPseudomonadaceae,wereall
moreabundant insuppressive soil than in conducivesoil,
focusingtherebyinthisbacterialgroup.Usingrandom
trans-posonmutagenesistechnicinPseudomonassp.theywereable
toidentifiedgenesresponsibleforthebiosynthesisofan
anti-fungal:nine-aminoacidchlorinatedlipopeptideproducedby
Pseudomonassp.andcontrolsthepathogen.
From the same PhyloChip diversity analysis, Cordovez
et al.,53 identified other antifungal, this time produced by
rhizosphere-associatedstreptomycetes. Theses Streptomyces
isolates were able to produce chemically diverse volatile
organiccompounds(VOCs)withanantifungalactivityaswell
asplantgrowth-promotingproperties.Showingthatdifferent
bacteriagroupscanhavesimilarrolesinthesame
environ-ment.AnotherexamplewasreportedbyArdanovetal.,54who
showedthattheinoculationofMethylobacteriumstrainsalso
protectedplantsagainstpathogenattackandaffected
endo-phytecommunities.Therefore,usingthisconcept,researchers
startedinoculatingplantswithapoolofmicroorganismwith
complementary traits, for example with different
mecha-nismsofcontrol,however,itisachallengetofindtheright
playerstobeinoculated.25
Inordertodefinewhichmicroorganismsshouldbe
inocu-latedseveralapproacheswereused.Thefirstapproachseeks
todefineacoremicrobiomeofahealthyhost,orunderstand
thefunctionofmicrobiomesbysequencingapproach,thatcan
befollowedbyexperimentsongnotobiotichostmanipulating
themicrobiomewithaselectionfactor (forexample
antibi-otics, salinity, and U.V. light) or transferring microbiomes
betweenhosts.55
Inthisway,researchersarestartingtostudy“microbiome
engineering”,modulatingmicrobialcommunity.This
modula-tioncanoccureitherbyperformingplantbreedingprograms
selectingabeneficialinteractionbetweenplantlinesand
rhi-zospheremicrobiomeorbyredirectrhizospheremicrobiome
bystimulatingorintroducingbeneficialmicroorganisms.25,55
The microbiomeengineering can occur byaltering
ecolog-ical processes suchas modulation in community diversity
and structure changing microbe–interaction networks and
byalteringtheevolutionaryprocesseswhichinclude
extinc-tion of microbial species in the microbiome, horizontal
genetransfer,andmutationsthatcanrestructuremicrobial
genomes.55
Summarizing, plant phenotype is the sum of plant
responsetotheenvironmentandtothepresentmicrobiome
(includingendophytesandpathogens),thismicrobiomealso
respondstotheenvironmentandinteractswitheachother.26
MendesandRaaijmakers44suggestasimilaritybetweengut
and plant rhizosphere microbiomes. They are both open
systems, witha gradient ofoxygen, water, and pH
result-ing in alarge number and diversityofmicroorganism due
to the different existing conditions. There are differences
betweengutandplantrhizospheremicrobiomecomposition,
thereforetherearesomesimilaritiesrelatedtonutrient
acqui-sition, immune system modulation and protectionagainst
infections.Bergetal.,56pointseventhesimilaritiesbetween
host-associatedmicrobiomeecology,amongthem:different
abioticconditionsshapethestructureofmicrobial
commu-nities;hostanditsmicrobiomeco-evolute;coremicrobiome
canbetransmittedvertically;duringlifecyclethemicrobiome
structurevaries;host-associatedmicrobiomesarecomposed
ofbacteria, archaea, and eukaryotic microorganisms;
func-tionaldiversityiskeyinamicrobiome;microbialdiversityis
Secondary
metabolism
Microorganismsproducealargevarietyofcompoundsknown
assecondarymetabolitesthatdonotplayanessentialrole
in growth, development, and reproduction of the
produc-ing organism.57 Nevertheless, these metabolites are often
bioactive compounds and can perform important
func-tions in defense, competition, signaling, and ecological
interactions.58,59
Toestablishamicrobialinteractionnetwork,
microorgan-ismsusuallyrespondbymetabolicexchange,whichleadsto
complexregulatoryresponsesinvolving thebiosynthesisof
secondarymetabolites. Theseinteractions can beparasitic,
antagonistic,orcompetitiveandthemetabolitesinvolvedand
theirfunctionshavebeenspeciallystudiedrecentlyasaresult
oftheadventoftoolssuchasmetabolomicsandimagingmass
spectrometry(IMS)technology.17,60,61
Siderophores are related to competitive and
coopera-tive microbial interactions and can also play other roles,
such assignaling and antibiotic activity.62 Hopanoids play
animportantrole in bacterialinteraction, conferring
toler-anceand improving theadaptation ofbacteriaindifferent
environments.63–65 In fungi, the compounds differentially
regulated in an interaction are often bioactive secondary
metabolites,suchasdiketopiperazines,trichothecenes,
atra-nones, and polyketides.14,17 Nevertheless, there is still a
lottounderstand aboutthe mechanisms involvedand the
roleofmanysecondarymetabolitesandgenesdifferentially
expressedduringtheinteraction.Inthissection,wepresent
examplesofstudiesonsecondarymetabolitesinvolvedin
dif-ferenttypesofmicrobialinteractions.
Endophyte–phytopathogen-plantinteraction
The metabolites and mechanisms involved in the
interac-tionsbetweenendophyteandphytopathogenandhostplant
are still very unclear and are predicted to involve many
secondarymetabolites.Endophyticfungiareknownto
pro-ducea largevarietyofbioactivesecondarymetabolites66,67
thatareprobablyrelatedtotheendophytecomplex
interac-tionswiththehostandthephytopathogensandcanperform
important ecological functions, for example, in the plant
development(as growth promoters)and in defense,acting
againstphytopathogens.68,69
This interaction has been studied in co-cultures ofthe
phytopathogenMoniliophthoraroreriandtheendophyte
Tricho-dermaharzianumthatcohabitincacaoplants.61T.harzianum
isextensivelyusedasabiocontrolagentandhasknown
abil-ity to antagonize M. roreri. They identified four secondary
metabolites(T39 butenolide,harzianolide,sorbicillinol, and
anunknownsubstance)whichproductionwasdependenton
thephytopathogenpresenceandwasspatiallylocalizedinthe
interactionzone.61T39butenolideandharzianolidehavebeen
reportedtohaveantifungalactivity.Sorbicillinolisan
inter-mediateinthe biosynthesisofbisorbicillinoids,afamily of
secondarymetaboliteswhichpresentdiverseactivities.70
Trichoderma atroviride, commonly used as a biocontrol
agent,producesaceticacid-relatedindolescompoundsthat
maystimulateplantgrowth.ColonizationofArabidopsisroots
byT.atroviridepromotesgrowthandenhancessystemic
dis-easeresistanceconferringresistanceagainsthemibiotrophic
andnecrotrophicphytopathogens.71
Other co-culturedstudieswere performedwithbacteria.
Araújo et al.,72 isolateda greatnumberofMethylobacterium
strains from asymptomatic citrus plants (with Xylella
fas-tidiosa but without disease), then Lacava et al.,73 showed
thatMethylobacteriummesophilicumSR1.6/6andCurtobacterium
sp. ER1.6/6 isolated from health and asymptomatic plants
inhibitedthegrowthofthephytopathogenXylellafastidiosa,
the causal agent of citrus variegated chlorosis. Moreover,
transcriptionalprofileofXylellafastidiosawasevaluated
dur-ing invitroco-cultivationwithacitrusendophyticstrainof
Methylobacteriummesophilicum.Itwasshownthatgenesrelated
to growth, suchas genes involved in DNA replication and
proteinsynthesis,weredown-regulated.Whilegenesrelated
toenergyproduction,stress,transport,andmotility,suchas
fumaratehydratase,dihydrolipoamidedehydrogenase(Krebs
cycle), pilYtransporter,clpP peptidase,acriflavinresistance,
andtoluenetolerancegenes,wereup-regulated.74
Another approach to study
endophyte-phytopathogen-plant interaction is based on the genome sequencing and
transposonmutagenesisofanendophytestrainofBurkholderia
seminalis,whichsuppressorchidleafnecrosisbyBurkholderia gladioli,revealedeightlocirelatedtobiologicalcontrol.Awcb
cluster relatedtothe synthesisofextracellular
polysaccha-ridesofthe bacterialcapsulewas identified.75 Extracellular
polysaccharidesareknowntobekeyfactorsinbacterial–host
interactions.76,77Inaddition,genesclustersputativelyrelated
toindole-aceticacidandethylenebiosynthesiswereidentified
inthesequencedgenomeoftheendophytestrain,
suggest-ingthatthisstrainmightinteractwiththeplantbyaltering
hormonemetabolism.75
Hopanoid
Hopanoidscomposethecell membraneofsomebacteria,78
presenting the same function of eukaryotes cholesterol.
They are responsible for stabilization of the membrane
and regulates its fluidity and permeability.79 Experiments
that knockout biosynthesis genes such as hnpF
(squa-lene hopene cyclase-shc) gene shows that the absence of
hopanoidsdoesnotinfluencebacterialgrowth,79,80butaffects
tolerance to several stress conditions, such as extremely
acidicenvironments81;toxiccompoundsasdichloromethane
(DCM)82; it also affects the resistance to antibiotics64 and
antimicrobial lipopeptide63; playing a role in multidrug
transport83andbacterialmotility.84
Hopanoids act increasing bacteria tolerance to adverse
environments, conferring resistance to stress conditions
including extreme pH and temperature, and exposure to
detergents and antibiotics.63,64 Inthis way,hopanoids may
be involved in bacteria–plant interaction, being
responsi-bleforadaptationofbacteriainaerobicmicro-environment
and lowpHculturemedium65;aswellasinvolvedin
nitro-gen metabolism in Frankia sp.85 For example, a type of
hopanoidsproducedbythenitrogen-fixingbacteria
Bradyrhi-zobium diazoefficiens is essential for its symbiosis with the hostAeschynomeneafraspera,atropicallegume.Inthiscase,
defense, utilization of host photosynthates, and nitrogen
fixation.86
Parasiticinteraction
Thestudyofthemycoparasitic interaction between
Stachy-botryselegansandRhizoctoniasolanirevealedmanysecondary
metabolitesdifferentiallyexpressedintheinteraction.17
Dur-ing the interaction, S.elegans produces cell walldegrading
enzymesand expressgenesassociatedwithparasitism87,88
whileR.solanirespondswithanelevatedlevelofthepyridoxal
reductase-encoding gene.89 A metabolomic study showed
theprofileoftheinducedsecondarymetabolitesduringthe
interaction.Itwasshowedasignificant effectofthe
myco-parasiteon R.solanimetabolism,the biosynthesisofmany
antimicrobialcompoundsweredown-regulated, possiblyas
a result of the interaction, and only a few
diketopiper-azineswereinduced.17Diketopiperazinesareknowntohave
antimicrobialproperties,amongothersbiologicalactivities.90
The mycoparasite S. elegans produced several mycotoxins,
mainly trichothecenes and atranones. They hypothesized
thatthetrichothecenesweretriggeredbyR.solaniandwere
responsibleforthealterationinitsmetabolism,growth,and
development.17 Trichothecenes are a major classof
myco-toxinsandhavebeenreportedtoinhibiteukaryoticprotein
biosynthesisandgenerateoxidativestress.91
Microbialcommunitiesinteraction
Actinomycetesare noteworthyasproducersofmany
natu-ralproductswithawiderangeofbioactivities.60Astudyon
Streptomyces coelicolor interacting with other actinomycetes
showedthatmostofthecompoundsproducedineach
inter-actionwereunique,revealingadifferentialresponseineach
case.Manyunknownmoleculesand anextendedfamily of
acyl-desferrioxaminesiderophoresneverdescribedbeforein
S.coelicolor were identified. Theyidentified 227compounds
differentially produced in interactions; half of these were
knownmetabolites:prodiginines,actinorhodins,coelichelins,
andacyl-desferrioxamines.Thus,actinomycetesinterspecies
interactionseemstobeveryspecificandcomplex.92
Ithasbeenshownthatfungal–bacterialinteractionscan
leadtotheproductionofspecificfungalsecondarymetabolites
andnotonlydiffusiblecompoundsactinthiscommunication,
butthereisalsoacontributionfromphysicalinteraction.14
Schroeckhet al.,14 demonstrated that anintimate physical
interactionbetweenAspergillusnidulansandtheactinomycete
Streptomycesrapamycinicus leadsto the activation of fungal
secondarymetabolitegenesrelatedtotheproductionof
aro-maticpolyketides,whichwereotherwisesilent.APKSgene
required for the biosynthesis of the archetypal polyketide
orsellinicacid,lecanoricacid(typicallichenmetabolite),and
thecompoundsF-9775AandF-9775B(cathepsinKinhibitors)
wasidentified.14Itwaslaterreportedthatalterationsin
fun-galhistoneacetylationviatheSaga/Adacomplexaretriggered
bytheactinomyceteleadingtotheinductionoftheotherwise
silentPKScluster.Thisresultshowsthatbacteriacantrigger
alterationsofhistoneacetylationinfungi.93
Siderophore
Theproductionandacquisitionofsiderophoresby
microor-ganisms is a crucial mechanism to obtain iron. Many
microorganismssecretesiderophoresintheenvironmentthat
whenloadedarerecognizedbycellsurfacereceptorsandthen
transportedintothemicrobialcell.94Thus,theyarerelatedto
competitiveandcooperativemicrobialinteractions.In
addi-tion,manysiderophorescanalsopresentotherfunctions,for
example,theycanfunctionassequestersofavarietyofmetals
andevenheavymetaltoxins,assignalingmolecules,asagents
inregulatingoxidativestress,andasantibiotics,whichwere
reviewedbyJohnstoneandNolan.62
In some Pseudomonas species, a group of siderophores
calledpyoverdinesisessential toinfection and biofilm
for-mation, probably helping to regulate bacterial growth.95
Pyoverdineshavebeenreportedtoactassignalingmolecules
triggeringacascadethatresultsintheproductionofseveral
virulencefactors,suchasexotoxinA,PrpLendoprotease,and
pyoverdineitself.96
Inthemarineenvironment,exogenoussiderophoresaffect
thesynthesisofinducedsiderophoresandotheriron
acqui-sition mechanismsbyothers microbial species,workingas
signaling compounds that influence the growth of marine
bacteriaunderiron-limitedconditions.Manystrainsofmarine
bacteria were reported to produce siderophores and
iron-regulatedoutermembraneproteinsonlyinthepresenceof
exogenoussiderophoresproducedbyotherspecies,suchas
N,N-bis (2,3-dihydroxybenzoyl)-O-serylserine from a Vibrio
sp.,evenunderverylowironconcentrations.97
Symbioticinteraction
Aremarkablycomplexinter-kingdominteractionisthe
symbi-oticrelationshipbetweenBurkholderia,agenusofbacteria,and
Rhizopus,agenusofphytopathogenfungithatcausescausing
rice seedling blight. The endosymbiotic bacteria
Burkholde-riaspp. isresponsibleforthe productionofthe phytotoxin
rhizoxin, the causal agent ofrice seedling blight.98 It was
reportedthatintheabsenceoftheendosymbiont,Rhizopus
isnotcapableofproducespores,indicatingthatthefungusis
dependentonfactorsproducedbythesymbionttocomplete
itslifecycle.99Thiscomplexsymbiont–pathogen–plant
inter-action is stillpoorly understood regarding the metabolites
andmechanismsinvolvedinthecommunicationand
interac-tion.Astudyonexopolysaccharide(EPS),whichusuallyplays
keyrolesininteractions,producedbyBurkholderiarhizoxinica
described apreviouslyunknownstructureofEPS.However,
thelossofEPSproductiondidnotaffecttheendosymbiotinc
interactionwithRhizopusmicrosporus,asshownbyatargeted
knockoutmutantexperiment.100Burkholderiagladioliproduces
enacyloxins(polyketideswithpotentantibioticactivity)in
co-culturewithR.microsporus.Thefungusinducesthegrowthof
B.gladioliresultinginanincreasedproductionofbongkrekic
acid,whichinhibitedthegrowthofthefungus.101
Quorum
sensing
Quorum sensing (QS)is the bacterial cell-cell
signalingmolecules(calledautoinducers) allowingbacterial
communitiestoexpressgenescollectively.102QSsystemsare
differentinGram-negativesandGram-positives,thesignaling
molecules are called acyl-homoserine-lactones (AHLs) in
proteobacteriaorcis-11-methyl-2-dodecanoicacid(alsocalled
diffusible signal factor – DSF) mainly in Xanthomonas and
Xylella,gramnegativesandgamma-butyrolactonesin Strep-tomycesandpeptidesinGrampositives.103,104
Thefirst QSsystemdescribedwasinthe1980sinVibrio
fischeri(formerlyknownasPhotobacteriumfischeri)bacterium.
In the sea,it isin a lowpopulation density and does not
luminesce.Therefore,whenit isinasymbioticassociation
withfishesandsquidsitluminesces.Aftertheautoinducer
moleculereachesathresholdluminescencegenes are
acti-vated.Thislightmatchesthe moonlight,making thesquid
invisibletothepredatorsbelow.105,106
In Gram-negativebacteria, twoproteins are involved in
QSsystem:thetranscriptionalregulatorR(orLuxR)andthe
autoinducer synthase I (or LuxI). In V. fischeri this system
iscalledLuxR/LuxI. Thesignaling moleculeor autoinducer
(AHL)ligatestothetranscriptionalregulatorLuxR,thisligation
isveryspecific, usedforinterspeciescommunication.107,108
Therefore,thereare severalreportsofintraspecific
commu-nication as well.109 Some bacteria present more than one
system, for example, Rhizobium leguminosarum with five R
proteins,110usedfordifferentfunctions:nodulationefficiency,
growthinhibition,nitrogenfixationandplasmidtransfer.111
Thereby,QScanhavedifferentroles:fluorescence
emis-sion(asreportedabovewithVibriofischeriexample),virulence,
sporulation, competence,antibiotic productionand biofilm
formation,102andcanactduringtheinteractionofdifferent
organism: bacteria–bacteria, fungal–bacteria, bacteria–host
(animalorplant).Itregulatesalargenumberofgenes,around
6–10%ofthemicrobialgenome.103
Ingram-positivebacteria,specificallyBacillussubtilisand
Streptococcuspneumoniaepeptide signal caninduce
sporula-tion and competencedevelopment. Thiswas evidenced by
experimentsshowingthatsporulationandcompetenceare
inefficientatlowcelldensitiesandneedsasecretedbacterial
factor.112
Concerningvirulence,pathogensareabletocontrol
viru-lencefactorsexpressionbyQSmolecule.Vascularpathogen,
suchasXanthomonasandXylellausesDSFsignalingtoexpress
virulencefactor aswell asbiofilmformation104 Xylella also
usesDSFsignalingtocolonizetheinsectvector,whichiskeyin
thediseasetransmission.113OthervascularpathogenPantoea
stewartiiusesAHLmoleculestoexpressdisease,QSmutants ofP.stewartiiwerenotabletodisperseandmigrateinthe
ves-sels,consequentlydecreasing thedisease.114 Theepiphytic
plantpathogenPseudomonassyringaealsousesAHLmolecule
invirulence.Thisbacteriumisabletocontrolmotility and
exopolysaccharidesynthesisessential onbiofilm formation
andleavecolonization.115Therefore,QSinhibitors(QSI)can
reducebiofilmformationandincreasedebacterial
suscepti-bilitytoantibiotics.Therearefourstrategiesusedtointerfere
withQSinhibitionof:1.signalgeneration;2.signal
dissemina-tion,3.Signalreceptorandsignalingresponsesystem.116,117
ReportsofAHLdegradationbyenvironmentaland clinic
bacteria, affectingAHL signaling have been described. For
example,P.aeruginosaandBurkholderiacepaciaareassociated
topneumoniaeincysticfibrosispatientsandduringthis
infec-tionthecrosstalkseemstobeanimportantstrategyforboth
bacteria.P.aeruginosaproducesAHLabletoinduceB.cepacia
genes involvedinbiofilmformation.111 Onthe otherhand,
NonAHLproducing bacteria canforecloseAHLmovement,
affectingAHL–mediatedresponses.118Thiscross-talkingcan
occurbetweenotherorganismssuchasplantsandbacteria,
which is key during plant–bacteria interaction. Plants
pro-ducecompoundsthatmimicsAHLandinterfereswithAHL
biosensors,119 for example, Medicago sativa may produce a
compoundabletoinhibitexopolysaccharidesproductionin
Sinorhizobiummeliloti.120QSalsoregulatesconjugative
trans-ferduringplant-Agrobacteriumtumefaciensinteraction,which
bacteriainducecrown-gallbytransferringT-DNA,thatcodifies
proteinsinvolvedinopinebiosynthesis,totheplant.The
con-jugationistriggedbyAHLmolecules.111Thiscross-talkingcan
alsooccurbacteria–fungusandbacteria–animal.Fungusand
animalscanproducecompoundsthatinhibitQS-controlled
genesinP.aeruginosa.116,121,122
The Candida albicans and Pseudomonas aeruginosa
inter-action is an important model that show how fungi and
bacteria canregulateeach other byQS system.Farnesol(a
sesquiterpene) and tyrosol’s produced by Candida albicans
are associated to control the physiology and virulence of
this fungi. In fact, farnesol is associated to resistance to
drugs,antimicrobialactivityandinhibitionoffilamentation
stage and biofilm formation, while tyrosol induces
oxida-tive stress resistance, a shortened lag phase of growth
and stimulatethe germ tube inyeast cells and hyphae in
the early stage of biofilm formation.123 In the host,
Can-dida albicans may share the same environment with the
bacteriumP.aeruginosa,whichbacteriummaypresenta
com-plexQSsystembasedonthesynthesisofmanymolecules,
suchas3-oxo-C12homoserine-lactones(HSL)and
2-heptyl-3-hydroxy-4-quinolone(PQS–Pseudomonasquinolonesignal).P.
aeruginosamayattachontoafilamentousformofC.albicans
and inhibit this fungus by synthesizing many molecules,
includingphenazines,pyocianyn,haemolyticphospholipase
C,124 suggesting that these molecules are associated with
niche construction duringestablishment in the host.
Dur-ing this interaction,the P. aeruginosaQS systemmay block
theyeast-to-hyphatransitionoractivatesthehypha-to-yeast
reversion,suggestingthatC.albicansmaysensethepresence
ofthebacteriumandactivates asurvivalmechanism.123 In
anotherhand,thefarnesolproducedbyC.albicans
downreg-ulatethePQSsystemofP.aeruginosa,inhibiting,inturn,the
pyocyaninproduction.125Thiscross-talkbetweenP.aeruginosa
andC.albicansandbasedonthesynthesisoffarnesol,HSLand
PQSallowthecoexistenceofthesemicrobesinthesame
envi-ronment andcontrolthe populationlevelofboth,showing
thatthissystemmayregulatethemulti-trophicinteractionin
complexcommunities.
Concluding
remarks
In the environment, microorganisms live in close contact
withmany differenthostsandwitheach otherin
commu-nities,usuallyincludingmanyspecies.Inaddition,theyare
whichinturnaffecttheinteractionamongmicroorganisms
andthehost.Thestudiesinmicrobialecology,includingthe
interaction amongmicrobial speciesand between
microor-ganism and the host has led to importantfindings in the
ecology,humanhealthyandbiotechnologicalresearches,such
asmolecularmechanismsrelatedtophysiologicalresponse
inhumansystemic diseases and antimicrobialdrug
devel-opment based on natural products, synthetic biology and
quorumsensing.
Microbialinteractionsarehighlycomplexandmany
mech-anisms and molecules are involved, enabling that some
microorganismsidentifysomespeciesand respondtoeach
otherinacomplexenvironment,includingshiftsin
physical-chemicalconditionandpresenceofdifferenthosts,manyof
themwere presentedin thisreview. However,thereisstill
alottounderstandaboutthe“molecularlanguage”usedby
microorganismsandthemoleculesandsignsrelatedto
inter-action with the host. The development and adaptation of
toolsandmethodsincludingin vitroand invivomodelsare
still highlyrequired to betterunderstand and characterize
the microbial interactions with more molecular details.In
addition, understanding the connectionbetween genomes,
geneexpression,andmoleculesincomplexenvironmentsand
communitiescompriseaverydifficultchallenge.Thewaysin
whichmicrobial speciesinteract witheach other and with
the hostare a complex issue that isonly beginning to be
understood,but recentstudies haveprovided newinsights
inmicrobialinteractionsandtheirapplicationinecologyand
humanhealthy.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgements
This work was supported by a grant from the
Founda-tion for Research Assistance, São Paulo State, Brazil (Proc.
2012/24217-6and2015/11563-1).WethankFAPESPforM.N.D.
(Proc.2013/17314-08)andCNPqforR.M.B.(Proc.141145/2012-9)
fellowships.W.L.A.receivedProductivity-in-Research
fellow-ship (Produtividade em Pesquisa – PQ) from the National
CouncilforScientificandTechnologicalDevelopment(CNPq).
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