Pathogen Resistance Advanced article Signalling in Plants ...msudaylab.org/wp-content/uploads/2016/11/Corrion-2015.pdf · paradigm, human inﬂuence on modern agricultural practices

Pathogen ResistanceSignalling in PlantsAlex Corrion, Department of Plant, Soil, and Microbial Sciences, Michigan State

University, East Lansing, Michigan, USA

Brad Day, Department of Plant, Soil, and Microbial Sciences, Michigan State Univer-

sity, East Lansing, Michigan, USA

Based in part on the previous version of this eLS article ‘ResistanceGenes (R Genes) in Plants’ (2007) by Kim E Hammond-Kosack andKostya Kanyuka.

Advanced article

Article Contents• Plant Disease, Pathogen Virulence,Environmental Change and Human Influence

• Plant Recognition of Pathogens

• Inheritance of Resistance

• Plant Resistance Genes

• Pathogen Avirulence and Effector Genes

• The Guard Hypothesis

• Interplay of Plant Growth and Developmentin Defence

• Plant–Pathogen Interactions and the Influenceof the Environment

• Genome-Enabled Approaches in Plant Biologyand Agriculture

• Plant Pathogens and Genome Editing

• Enhancing Crop Performance and FoodProduction

• Conclusion

• Acknowledgements

Online posting date: 15th June 2015

Within natural ecosystems, most plants are resis-tant to most pathogens. At a fundamental level,this seemingly simply truth may hold the key toour understanding of how plants have evolved tosurvive under a myriad of environmental condi-tions and their associated stresses. Indeed, in defin-ing how plants evolve, adapt and maintain broadspectrum resistance to most pathogens – typicallyreferred to as non-host resistance – we may notonly reveal the mechanisms that underpin plantresistance signalling but also the precise mannerin which plants regulate these processes undervarious environmental conditions. Herein lies thegreatest challenge and unanswered question in thefield of agriculture today: How do we feed 9 bil-lion people by the year 2050? To address this, oneof the first hurdles that must be overcome is afull understanding of the processes that regulatestress (i.e. abiotic and biotic) signalling in plants,as well as the processes that define pathogenand host specificity, including the performance ofthese processes under rapidly changing environ-mental conditions. In the case of pathogen infec-tion, plants utilise a broad suite of innate and

eLS subject area: Plant Science

How to cite:Corrion, Alex and Day, Brad (June 2015) Pathogen ResistanceSignalling in Plants. In: eLS. John Wiley & Sons, Ltd: Chichester.DOI: 10.1002/9780470015902.a0020119.pub2

inducible mechanisms to resist invasion. In largepart, these processes are governed by the activityof resistance (R) proteins, which are evolutionarilyconserved and highly evolved proteins that func-tion not only in pathogen recognition but also inthe activation of the cellular processes necessaryto defend against proliferation and the elicitationof disease. Furthermore, recent data supports thehypothesis that numerous processes, such as thebalance between growth and defence, also con-tribute to the host resistance and pathogen viru-lence.

Plant Disease, Pathogen Virulence,Environmental Change and HumanInfluence

The Green Revolution, led by the pioneering work of NormanBorlaug in the mid-1960s, yielded increases in crop productionaround the world, and as a result, saved more than a billion peoplefrom starvation. Over the past 50 years, world population growthhas more than doubled, and current estimates suggest that num-bers may reach as high as 12 billion people by the year 2100(Gerland et al., 2014). To keep pace with this increasing pop-ulation growth, it is estimated that significant improvements inagriculture are needed to meet a demand of an approximate 50%increase in food consumption. As a critical component in meet-ing this challenge, translational research in plant stress tolerancerepresents one of the primary areas of focus; this includes plant

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Pathogen Resistance Signalling in Plants

protection against pathogen infection, rising temperatures, flood-ing, drought, freezing tolerance and protection from insect pests.As each of these environmental stresses contributes to significantdecreases in crop production, losses due to biotic stress aloneare estimated to impact global crop production by 15% annu-ally (Dangl et al., 2013). These estimated impacts further supportthe need for advances in biotic stress research in plants, as wellas translational applications towards the generation of improvedbreeding lines.To understand and define what plant immunity is, and more-

over, how plant immunity functions, it is important to first iden-tify the underlying genetic basis that defines how plants andmicrobes interact. Plant disease epidemics are rare within natu-ral ecosystems; heterogeneity has a demonstrable positive impacton plant performance and survival (Pagan et al., 2012; Johnsonand Thieltges, 2010; Roscher et al., 2007). In recent decades,the impact of climate change, combined with changes in modernagricultural practices (e.g. cropping intensification and chemicalmanagement), have had significant impacts on crop production,particularly with regard to the incidence of disease severity andpathogen adaptation to biotic and abiotic stress. Indeed, whileagricultural disease epidemics are historically rare, recent diseaseoutbreaks in a number of key staple crops around the world indi-cate that a number of challenges and opportunities still remainin terms of meeting the global demands related to food produc-tion. Historically, the ‘Disease Triangle’ model has been used todescribe how plants, pathogens and the environment interact todrive resistance and susceptibility (Scholthof, 2007). Within thisbasic framework, however, are a multitude of complex interac-tions that influence host performance during pathogen infection.Modern agricultural practices, including disease managementthrough pesticide application, high-density monoculture produc-tion and the repeated use of crops containing selected R genescollectively impose a number of strong selective pressures whichultimately drive enhanced pathogen virulence. This results in a‘defeat’ in R gene efficacy, which in turn leads to increases indisease outbreaks (Figure 1).

Plant Recognition of Pathogens

Plants rely on a suite of fundamentally complex, highly conservedmechanisms to detect changes in their environment, includingthe perception of potential pathogenic microorganisms. In manycases, the mechanisms that underpin abiotic and biotic stresssignalling share many signalling components. For example, anumber of studies have shown that plant response to droughtand pathogen infection converge at a core set of signalling path-ways (Nakashima et al., 2014); the same is true for the conver-gence of pathogen perception and response to temperature (Hua,2013), light (Sano et al., 2014) and touch (Braam, 2005). Asa first barrier to pathogen infection, and as an initial stimulusrequired for the activation of robust immune signalling, plantshave evolved mechanisms to recognise the most conserved fea-tures of a wide range of potential biotic threats. Highly con-served regions associated with a wide variety of microorgan-isms have been termed pathogen-associated molecular patterns(PAMPs). These molecules are essential to the function of the

organism and represent the most evolutionarily conserved com-ponents of the organism; as such, they are typically indispensablefor survival. Moreover, and as an illustration of their functionalspecificity, PAMPs are further defined as uniquely ‘non-self’,meaning that these molecules are not found in plants. Examplesof PAMPs include features such as the bacterial flagellum, com-ponents of the fungal cell wall and features functionally associ-ated with organismal lifestyle (Table 1). In addition to PAMPs,some molecules function as a signal of warning for surroundingcells; such is the case of damage-associated molecular patterns(DAMPs) – plant-derived compounds involved in the signallingof invading insects or wounding damage. Like PAMPs, DAMPperception initiates signalling associated with the production ofimportant hormones involved in plant defence and immune sig-nalling (Tintor et al., 2013; Zipfel, 2014). Once recognised bythe host, PAMPs/DAMPs initiate a series of general signal trans-duction cascades within the host cell to prevent proliferation ofthe invading pathogen. This first layer of plant immunity, termedpathogen-associated molecular pattern-triggered immunity (PTI;Chisholm et al., 2006), is best defined as a low-amplitudedefence response that does not result in localised cell death, butrather initiates a highly regulated response that is effective inblocking most pathogens from proliferating and causing disease(Figure 2).To further illustrate the significance and highly conserved func-

tion of PTI, it is noteworthy that a number of advances in humanpathogen and disease research were preceded by the discoveryand characterisation of PAMP receptors (e.g. pattern recognitionreceptors; PRRs) in plants (Gomez-Gomez and Boller, 2000)(Figure 3). This work, supported by the most expensive plantgenome initiative to date – The Arabidopsis Genome Initia-tive (2000) – resulted in the discovery of the largest class ofrecognisable transmembrane (TM) sensors, or PRRs, by iden-tifying more than 300 receptor-like kinases (RLKs). Generally,PRRs described to date possess an extracellular leucine-richrepeat (eLRR; Figure 3) and a cytosolic kinase domain thatfunctions in downstream signalling following elicitor binding.Of the most studied PRRs in plants is the Arabidopsis thalianareceptor-kinase protein FLS2 (FLAGELLIN SENSITIVE2,Gomez-Gomez and Boller, 2000; Zipfel et al., 2004), whichbinds a fragment of bacterial flagellin. Once bound to its lig-and, FLS2 initiates a series of signal transduction cascades,including activation of the mitogen-activated protein kinase(MAPK) pathway, concomitant changes in gene expression andthe induction of localised changes in cellular organisation, all ofwhich function to specifically counter further infection. Similarresponses have also been characterised following the activationof additional plant PRRs via PAMP perception, including theactivation of EFR (EF-Tu RECEPTOR) by the bacterial elicitorEF-Tu (Kunze et al., 2004; Zipfel et al., 2006) and the acti-vation of CEBiP (CHITIN ELICITOR BINDING PROTEIN)and OsCERK1 (CHITIN ELICITOR RECEPTOR KINASE)by fungal-derived chitin during infection of rice (Kaku et al.,2006; Shimizu et al., 2010). In all instances, ligand–receptorassociation results in the activation of functionally similar highlyconserved mechanisms whose cellular responses have evolved toprevent pathogen infection.

2 eLS © 2015, John Wiley & Sons, Ltd. www.els.net


Humaninfluence

Adapt

atio

nDisease

managem

ent

Modern

bre

eding

and monocu

lture

Selection

Disease

Performance

Environment

Host

Pathogens

Figure 1 Illustration of the interactions between plants, pathogens, humans and the environment. As an expansion of the ‘Disease Triangle’paradigm, human influence on modern agricultural practices has significantly impacted not only the performance of cropping systems as a function of bioticstress performance but also the inadvertent selection of enhanced, often hyper-virulent pathogen races. As environmental conditions and abiotic stressorsbecome more taxing on both plants and their pathogens, the influence of high temperatures, for example, has opposing effectors. For example, at hightemperatures, the growth and selection of microbes with enhanced virulence is often observed. Conversely, at high temperatures, plant performance isoften negatively affected, with plant resources and signalling processes shifted to abiotic stress tolerance/response signalling. As a result, plants are ‘forcedto choose’ between survival due to abiotic stress and to allocate signalling to support immunity and defence signalling. As a key feature of the interactionof plants with environmental and microbes, human influence on this process is also becoming more evident. As populations increase, there is also anincrease in the need to produce crops that generate higher yields, as well as perform under what are typically limiting environmental conditions (i.e. hightemperature and drought). As a result, plant breeders must often choose between a balance of phenotypic traits and genotypes to introduce lines withelite performance under one or the other conditions, including the introduction of lines with enhanced nutritional or horticultural qualities. As a functionof disease management, chemical treatment of crops with pesticides/fungicides influences not only plant performance under biotic stress conditions butcan often times have a negative – unintended – influence on the selection and propagation of hyper-virulent, pathogenic microbes. As a combination ofeach of these factors, we present an updated model of the classical ‘Disease Triangle’ to highlight the influence of humans on agricultural systems and plantperformance: the ‘Disease Diamond’. Image reproduced from Hammond-Kosack and Kanyuka (2007).

Table 1 Pathogen-associated molecular patterns (PAMPs) and plant-derived signals (damage-associated molecular patterns; DAMPs)

Elicitor Pathogen Receptor Associatedsignalling molecules

References

Flagellin (flg22) Bacteria FLS2 BIK1, BAK1,MAPK,CDPK, ROS

Gomez-Gomez and Boller(2000)

EF-Tu (elf18) Bacteria EFR BIK1, BAK1,MAPK,CDPK, ROS

Kunze et al. (2004)

Chitin Fungi CERK1, LYK5 (Arabidopsis);CEBiP, OsCERK1 (Rice)

MAPK, CDPK Kaku et al. (2006);Shimizu et al. (2010)

LPS Bacteria Unknown – Erbs et al. (2010)Coronatine P. syringae

DC3000COI1 Jasmonic acid Sherd et al. (2010)

Coat protein Virus Unknown – Gonsalves, 1998

Plant derivedPep1 – PEPR1 Ethylene Tintor et al. (2013)ATP – DORN1 WRKY, CDPK Choi et al. (2014)Oligogalacturonide – WAK1 – Zipfel (2014)



P. syringae P. syringae

Oomycete/fungus

Haust

oriu

mCC

-NB

-LR

R

MAPKKK

Callose

PAMP-triggeredimmunity

(PTI)

Effector-triggeredimmunity

(ETI)

Chloroplast

TIR-NB-LRR

MAPKK

MAPK

MITOCHONDRIA

NUCLEUS

Defencegenes

FRK1

WRKY

Pla

sm

a m

em

bra

ne

Figure 2 Plants recognise a myriad of biotic conditions, pathogens and stresses and respond using complex, highly specific immunesignalling cascades. The recognition of pathogenic organisms by plants is typically initiated through the perception of evolutionarily conserved featuresby pattern recognition receptors, and co-receptors (represented by the blue and red transmembrane proteins, respectively), present on the cell surface ofthe invading organisms; in short, these molecules are perceived as ‘non-self’ by the host plant. This form of immune signalling, termed pathogen-associatedmolecular pattern (PAMP)-triggered immunity (PTI) results in the activation of a broad, non-specific, defence signalling response that initiates a number ofconserved and highly effective pathogen resistance mechanisms, including mitogen-activated protein kinase (MAPK) signalling, the deposition of callose andthe induction of defence-responsive genes. As a more robust, sustained immune response, following the perception of pathogen-secreted effector proteins[represented by black circles (bacterial effectors) and orange stars (oomycete effectors)], plants initiate a second, amplified, defence response, termedeffector-triggered immunity (ETI). This form of immune signalling relies on the specific interaction – either direct or indirect – between plant resistance (R)proteins and pathogen-derived avirulence (Avr) proteins – broadly referred to as effectors. Similar to the activation of PTI, ETI initiates a series of similar, shared,signalling cascades whose outcome results in localised cell death responses, termed the hypersensitive response, which is similar in function to apoptosis.The outcome of this process is the abrogation of pathogen growth, and in most cases, the survival of the host. Image reproduced from Hammond-Kosackand Kanyuka (2007).

As with most ligand–receptor interactions, additional sig-nalling components have been shown to be required for their fullactivity. In large part, these signalling components function notonly in the activation of resistance but through association withother cellular processes and pathways function to attenuate antag-onistic interactions that may impede full immune activation. Ofthese, a receptor-like cytoplasmic kinase, BOTRYTIS-INDUCEDKINASE1 (BIK1) and BRI-ASSOCIATED KINASE1 (BAK1)have been shown to associate with PAMP receptor complexesinvolving FLS2 and EFR, respectively. Once associated, thesecomplexes initiate downstream signalling cascades, in MAPKand calcium-dependent protein kinase (CDPK) signalling(Figure 3; Macho and Zipfel, 2014). In total, the initiation ofthese processes leads to numerous defence-associated processes,including transcriptional reprogramming, reactive oxygenspecies (ROS) production and cellular changes resulting indefence against pathogens (Figure 3).

Of direct relevance to crop sustainability and agricultural out-put, an understanding of the molecular-genetic and biochemicalprocesses described above can have significant, demonstrableimpact. For example, translation of fundamental research defin-ing the activity and function of the Arabidopsis PAMP receptorEFR has shown promise in improving resistance of tomato plantsto the bacterial pathogen Ralstonia solanacearum, the causalagent of bacterial wilt. In brief, when susceptible tomato plantsare genetically modified (GM) to express the EFR gene fromArabidopsis, these plants, when infected with R. solanacearum,showed reduced bacterial populations and a significant reductionin disease symptoms (Lacombe et al., 2009). Additional studieshave demonstrated the broad utility of similar approaches show-ing that the kinase domain of Xa21, a PRR from rice, is ableto functionally complement the Arabidopsis PRR EFR (Holtonet al., 2014), providing further evidence in support of the need toexploit the conservation of immune signalling in plants as a tool



IRAK4IRAK2

TRAF6IRAK1

TiR

AP

TR

IF

Plants Humans

MKK3 orMKK6

MKK4 orMKK7

E. coli

Callose

PR1, WRKY, FRK1

BIK1BIK1BIK1BIK1

RP

S2

Activation ofresistance

MAPK

ROS

CDPK

AvrRpt2

RIN4

4NI

R

BA

K1

BA

K1

TL

R5

TL

R4

MyO

88

MyO

88

TAB3 TAB2

TAK1

NucleusF

LS

2CREB

AP1

RIN4

RI

4

N

Flagellin Flagellin LPS

Nucleus

TR

AM

PTI ETI

P. syringae

Ef-Tu

EF

R

Figure 3 Immune signalling in plants and animals share a number of functionally similar pathogen perception and host signallingprocesses. The perception of pathogens in both plants and animals uses similar signalling mechanisms to induce changes in gene expression and cellularresponse to biotic stress. As a first response to pathogen invasion, plants and animals utilise a highly conserved immune signalling process – PTI – to initiatebroad, non-specific defence signalling cascades, including the generation of reactive oxygen species (ROS), activation of MAPK signalling and changes ingene expression associated with host defence. In plants, the induction of a second, amplified response – ETI – is initiated in response to the perception ofsecreted pathogen avirulence/effector proteins, which are recognised by host-specific R proteins. Image reproduced from Hammond-Kosack and Kanyuka(2007).

to identify new sources of pathogen resistance. It is also notewor-thy that the perception of evolutionarily distant pathogens canlead to the resistance of the host plant by pre-activation of thePTI immune response. For example, a recent study shows thatthe perception of bacterial flagellin by FLS2 can prime immu-nity, resulting in a reduction of growth of the necrotrophic fungalpathogen, Botrytis cinerea, when plants are first subjected to the22 amino-acid flagellin peptide elicitor, flg22 (Laluk et al., 2011).Taken together, this work suggests that the activation of PTI issufficient for broad-based immune responses to a diversity ofplant pathogens.

Inheritance of Resistance

In the 1940s, seminal research by Harold H. Flor established thefoundation for modern molecular plant pathology, formulatingwhat is referred to as the ‘Gene-for-Gene’ hypothesis (Figure 4).Using the interaction between flax (Linum usitatissimum) and therust pathogen Melampsora lini, Flor demonstrated that the out-come of this host–pathogen interaction could be defined through

a tractable, yet simple genetic relationship. In brief, Flor demon-strated that the inheritance of resistance in the host and the abilityof the pathogen to cause disease are defined by the reciprocalrelationship. and presence of ‘matching’ gene pairs. In the plant,this gene is defined as a ‘resistance (R) gene’, and in the pathogen,the complementary gene is called the ‘avirulence (Avr) gene’(Flor, 1955). Subsequent work has shown that an alteration in thefunction, or a complete loss of either the R or Avr gene, resultsin the onset of disease in infected plants. This initial discoveryhas had a significant impact on plant breeding, and has usheredin a new era in modern agriculture; for the first time, the geneticbasis of resistance was defined in a manner that gave researchersa means to track the ‘genotype × phenotype’ relationship. Moreimportantly, this work provided a blueprint fromwhich additionalwork in this area can explore the potential of conferring broadpathogen resistance in plants through the expression of dominant,conserved R genes.In most cases, the primary tenets of the ‘Gene-for-Gene’

hypothesis are still widely used, and as noted above, provide thebasis for the formulation of numerous hypotheses aimed at defin-ing the genetic interactions between plants and microbes. While



Host genotypeR r

Avr

avr

Resistance

Disease Disease

Disease

Pat

ho

gen

gen

oty

pe

Figure 4 Classical illustration of the genetic foundation for the ‘Gene-for-Gene’ interaction. Proposed by Flor in the 1940s, this foundationalhypothesis describing the inheritance of resistance in plants and the maintenance of virulence in pathogens posits that for every gene in a plant that confersresistance, there is a corresponding, host-recognised, gene in the pathogen that confers avirulence. In the presence of both genes (i.e. R + Avr), plants areresistance. When either gene is lacking (i.e. r + avr), plants are susceptible. This basic process has been used to define a number of R/Avr interactions inplants in the 70+ years since it was first discovered, and moreover, it provided a tractable mechanism to guide a number of plant breeding outcomes aimedat the generation and selection of plants with broad pathogen resistance. Image reproduced from Hammond-Kosack and Kanyuka (2007).

not broadly applicable to all host–pathogen interactions, much ofour understanding of the activation of immune signalling in plantsrelies on the fundamentals described by Flor almost 75 yearsago. As is discussed below, plant breeders often use the inher-itance of dominant resistance (i.e. R) gene as a tool to developand introduce new resistance traits from wild relatives into com-monly grown crop species. In some cases, this results in stable,durable outcomes. Such is the case of Rxo1/AvrRxo1, which hasbeen demonstrated to confer resistance in rice to many bacterialpathogens, further supporting the utility of genetic modificationof important crop species for the improvement of disease resis-tance traits (Liu et al., 2014).

Plant Resistance Genes

By the early 1990s, advanced tools in molecular biology andgenetics had opened new avenues of research in plant pathol-ogy, giving rise to the cloning of the first avirulence genes inplant pathogens (Staskawicz et al., 1984), the identification andcloning of the first plant resistance genes (Mindrinos et al., 1994;Bent et al., 1994) and the sequencing of the first plant genome(Arabidopsis Genome Initiative, 2000). With these new tools,researchers were armed with the resources to not only explorethe mechanisms of resistance in plants and the virulence of theirassociated pathogens but also apply fundamental research andknowledge to a broad range of crop species. As shown inTable 1,work in this area has not only improved our understanding of thebasis of plant immune signalling but also generated a wealth ofknowledge, specific to disease resistance, which can be used to

address additional challenges affecting crop production and foodsecurity.As noted above, research over the past 20 years has ushered in

significant advances in our understanding of the genetic basis ofpathogen resistance signalling in plants. During this time, withparallel advances in genomics and bioinformatics, the number ofresistance genes identified and characterised from a multitude ofplant species has grown significantly, and in many regards, thisnew information reminds us that we are still in the infancy of ourunderstanding and the deployment of this knowledge (Table 3).Indeed, since the identification and isolation of the first plant Rgenes almost 25 years ago, additional other R genes – and genesassociated with their function – have been cloned from importantstaple crops, including barley, potato, tomato, rice and wheat(Dangl et al., 2013).Using a combination of functional genomics and bioinformat-

ics, coupled to lab-based molecular-genetic approaches, researchover the past 20 years has revealed that most of the R pro-teins identified can be classified into just a few categories; thisclassification is based largely on predicted structural motifs (i.e.coiled-coil domains). For a thorough overview of the modularstructures of plant R proteins, refer to the review by Dangl andJones (2001); Figure 5). Among the plant R proteins describedthus far, the largest group is represented by those containinga nucleotide-binding (NB) site and leucine-rich repeat (LRR)domain (i.e. NB-LRR); this family is further segregated basedon the presence of a leucine-zipper (LZ) or coiled-coil (CC)sequence at the amino terminus. Interestingly, NB-LRR resis-tance proteins from plants possess high sequence homology tothe Toll and Interleukin 1 receptor (TIR) proteins associated with



RaceSpecificR proteins

Race non-SpecificR proteins

LRR

LRRLRR

Cell wall

Plasma membrane

Cytoplasm

Kinase

KinaseKinase

KinaseECS

PEST

LRD

CC

CC

NBNB

TIR

Kinase

CC

Ve1, Ve2Cf-2, 4, 5, 9

Xa21 Pi-d2

RFO1

Pto,PBS1

BS2 Pi-taMla10,RPM1,RPS2

N,L6,RPP5

RRS1 Xa27

RPW8

RPG1

NLS

WRKY

6

5

7

7

1

2

3

4

Figure 5 R protein classes and their cellular location. The predicted domains of R proteins which confer either race-specific or race-non-specific resistanceare presented schematically: CC, coiled-coil domain; TIR, Toll and Interleukin 1 receptor-like motif; NB, nucleotide binding site; LRD, leucine-rich domain;LRR, leucine-rich repeat; NLS, nuclear localisation signal; ECS, endocytosis signal; PEST, Pro-Glu-Ser-Ther-like sequence; WRKY, motif characteristic of someplant transcription factors; 1, 2, 3, 4 – novel domains that lack significant homology to known proteins; 5, domain with homology to a B-lectin; 6, structurewith a weak similarity to a PAN domain; 7, structure with homology to epidermal growth factor (EGF)-like domain; Cf-2, Cf-4 and Cf-5 confer resistanceto Cladosporium fulvum races expressing, respectively, Avr2, Avr4 and Avr5; L6 flax rust resistance 6; Mla10, resistance to Blumeria graminis f. sp. hordeiexpressing Avra10; RPM1, resistance to P. syringae pv. maculicola expressing AvrRpm1 or AvrB; RPP5, resistance to Hyaloperonospora parasitica expressingATR5. Image reproduced from Hammond-Kosack and Kanyuka (2007).

innate immunity in drosophila and mammals (Chisholm et al.,2006). Additionalmembers of conservedR protein families, asidefrom the NB-LRR class, have also been identified and extensivelystudied in plants, including the cytoplasmically localised R pro-tein Pto, and the tomato plasma membrane-bound (Cf) proteinswhich confer resistance to the fungal pathogen Cladosporiumfulvum. These R proteins are distinguishable from the broaderCC-NB-LRR family in that they are composed of an eLRRdomain, a single TM spanning domain and a small putativelycytoplasmically localised domain. This class of R proteins isreferred to as receptor-like proteins (RLPs), and in many aspects,resembles the PTI-associated PRRs described above (Boller andFelix, 2009).

Pathogen Avirulence and EffectorGenes

The activation of PTI in response to pathogen infection is ahighly effective mechanism to restrict pathogen invasion and pro-liferation. So, how do pathogens survive and propagate in theface of a resistance mechanism that is, more often than not,sufficient to prevent infection and disease? In simplest terms,

pathogens – whether from plants or animals – evolve strate-gies to overcome host defences; in short, this is accomplishedby either evading preformed defence responses or by blockingthe activation of host processes, such as PTI. As a tractablesystem and working model to define the inheritance of resis-tance, the ‘Gene-for-Gene’ hypothesis offers a logical frameworkwithin which numerous host–pathogen interactions can be stud-ied. However, as a means to describe the virulence capacity ofa pathogen, and moreover, to define how pathogens successfullyovercome host defence signalling, the R–Avr interaction does notfully explain this process. In fact, it begs the question: Why doesa virulent pathogen make and secrete Avr proteins into their host,only to be recognised by the plant and to lead to the activation ofresistance?To address this, a number of research groups have also focused

on the identification and characterisation of virulence factorsfrom a broad range of bacterial, fungal and viral plant pathogens(Table 1). Similar to virulence strategies previously identifiedin human pathogenic microorganisms, it was discovered thatplant pathogenic bacteria (e.g. Pseudomonas syringae, Erwiniaamylovora) utilise a type-three secretion system (T3SS) to delivera suite of proteins – termed effectors – into the plant cell duringinfection. As noted above, the T3SS identified in plant pathogens



was homologous to that described in a number of well-studiedGram-negative bacterial pathogens of humans (e.g. Escherichiacoli, Salmonella; He et al., 2004). Using this system, pathogenicbacteria deliver what are termed type-three secreted effectors(T3Es), which are protein virulence factors hypothesised to haveevolved as a means to alter host physiology during the infectionprocess. As noted above, and more relevant to their role duringhost–pathogen signalling, T3Es broadly function to suppressthe activation of plant defence signalling, including processesassociated with PTI signalling. To date, at least 28 unique T3Eshave been identified as secreted proteins from the model plantpathogenic bacteria, P. syringae pv. tomato DC3000, and thecollective works from a number of groups have shown that T3Estarget a broad range of cellular processes – and their associatedregulators – during infection (Figure 2 and Table 2; Xin andHe, 2013).In addition, genome sequencing, combined with functional

studies using non-model systems, has revealed bacterialpathogens with a small amount of secreted effectors, as inthe case of E. amylovora (Triplett et al., 2010). However, thereduced number of secreted effectors does not seem to affect thevirulence of the pathogen on its host, as recent disease epidemicshave been documented in apple orchards throughout the UnitedStates over the past decade (Malnoy et al., 2012). Alternatively,other plant pathogens are predicted to have an expansive secretedeffector repertoire, as is the case of the oomycete pathogen Phy-tophthora infestans, the causal agent of the Irish Potato Famine,which has 563 predicted effector proteins, which have RNAexpression levels that are induced during early stages of infectionand contain an RXLR motif (Hass et al., 2009). Interestingly,many T3Es have been shown to target basic physiologicalprocesses within the host cell to promote its virulence duringinfection, suggesting that specifically inhibiting these basic

cellular processes are important in promoting pathogen growthand reproduction.

The Guard Hypothesis

While a number of predicted structural (i.e. domain motifs) dif-ferences exist among the various families of R proteins identifiedthus far in plants, many share a number of striking similaritieswith regard to functionality in immune signalling. With regardto specificity, it is hypothesised that the majority of R proteinsfunction to recognise pathogen effectors – either by direct asso-ciation or via the consequence of effector activity – and activateresistance in response to pathogen infection according to thebasic criteria established in the ‘Gene-for-Gene’ hypothesis. At afundamental level, we now know that recognition of pathogensby plants is mediated by the R–Avr interaction; we also knowthat this recognition can occur through direct association ofthe R–Avr pair (Jones and Dangl, 2006; Liu et al., 2014; e.g.Pita-AvrPita), or via the indirect association of these pairedgenetic determinants (Chisholm et al., 2006). In the case ofthe latter – the indirect recognition and activation of resistanceby R–Avr pairs – research has shown that the association ofplants and pathogens can be described and conceptually definedthrough an elegant series of evolutionary steps; these includerecognition of the invading pathogen, adaptation by the pathogenand the evolution of new resistances.The identification of the T3SS and their associated T3Es

opened a number of new directions in the field of molecular plantpathology. In the late 1990s, several hypotheses were proposedto define how R and Avr proteins function, and moreover, howeach specifies the activation of resistance or promotes the elici-tation of susceptibility. During this time, a number of important

Table 2 Major devastating plant pathogens

Species Kingdom Biological characteristics Predicted effectors References

Magnaporthe oryzae(Rice Blast)

Fungus Filamentous ascomycete fungus;causes 10–30% yield losses

>40 cloned and mapped Dean et al. (2012); Valentand Khang (2010)

Xanthomonas oryzaepv. oryzae

Bacteria Rod shaped gram-negative;10–50% yield losses

∼16 effectors aretranslocated into thehost cell

Furutani et al. (2009)

Pseudomonas syringaepv. tomato(Bacterial Spec)

Bacteria Yield losses of 5–75% in the field ∼28 effectors have beenshown to betranslocated to the hostcell

Xin and He (2013)

Botrytis cinerea (GreyMold)

Fungus Necrotrophic fungus, infectsmore than 200 plant species

∼880 predicted bygenome sequencing

Amselem et al. (2011)

Pseudoperonosporacubensis (CucurbitDowny Mildew)

Oomycete Obligate biotroph; causes yieldlosses up to 100%

125 predicted RXLReffectors from genomesequencing

Burkhardt et al. (2015)

Erwinia amylovora(Fire Blight)

Bacteria Gram-negative; outbreaks causedevastating losses up to 100%

∼5 secreted Triplett et al. (2010)

Phytophthora infestans Oomycete Hemibiotroph; causal agent ofthe Irish Potato Famine

563 predicted RXLReffectors from genomesequencing

Hass et al. (2009)



Table3Listo

fsequencedplantg

enom

es

Com

mon

name

Genom

esize

Major

pathogens

Num

berof

NB-LRRgenes

Yearof

sequence

References

Arabido

psis,

ThaleCress

128Mb

Pseud

omon

assyring

ae,

Hyaloperonospora

arab

idop

sidis,Botrytiscinerea

136

2000

ArabidopsisGenom

eInitiative(200

0)

Hum

an2.91

Gb

Mycobacterium

tuberculosis,

Escherichia

coliO157:H7

Not

applicable

2001

Venteretal.(2001)

Rice

389Mb

Xan

thom

onas

oryzae,

Magna

porthe

oryzae

600

2002

and2005

Yuetal.(2002);Goffetal.

(2002);Internatio

nalR

ice

Genom

eSequencing

Project(2005)

Poplar

485Mb

Marsson

inapo

puli,M

elam

psora

medusae

398

2006

Tuskanetal.(2006)

Papaya

372Mb

Papa

yaring

spot

virus(PRSV

)55

2008

Mingetal.(2008)

Cucum

ber

367Mb

Pseud

operon

ospo

racubensis,

Phytophthoracapsici

612009

and2011

Huang

etal.(20

09);

Woycickieta

l.(2011)

Sorghu

m73

0Mb

Fusariummon

iliforme,Puccinia

purpurea

211

2009

Paterson

etal.(2009)

App

le74

2Mb

Erw

inia

amylovora

799

2010

Velasco

etal.(2010)

Soybean

1.1Gb

Fusariumvirguliforme,

Pseud

omon

assyring

aepv.

glycinea

Not

analysed

2010

Schm

utzetal.(2010)

Coffee

710Mb

Hem

ileiavastatrix(CoffeeRust)

561

2014

Denoeud

etal.(2014)

Loblolly

Pine

22Gb

Fusariumcircinatum

Not

analysed

2014

Zim

inetal.(2014)



discoveries were made, including the formulation of the basis forwhat has now become the leading paradigm in the field of molec-ular plant pathology: the ‘Guard Hypothesis’. During the earlystages of research aimed at defining the molecular and biochem-ical basis of gene-for-gene-mediated resistance, the hypothesisthat the interaction of R andAvr proteins functioned as a ‘lock andkey’ mechanism remained the most logical explanation to definehow plants and pathogens communicate (Staskawicz et al., 1984).At the same time, it did little to explain how plants and pathogensevolve to overcome the seemingly ‘back-and-forth’ evolutionof resistance and susceptibility. In 1998, a review by Van DerBiezen and Jones proposed what has now known as the ‘GuardHypothesis’:

Conceivably, one particular Avr product could correspondto one specific pathogenicity target, which, in turn, couldbe safeguarded by one matching R protein. In order toadapt rapidly to pathogen Avr modification or loss, novelrecognition specificities in R proteins are created throughthe generation of sequence variation in the 𝛽-sheet of theLRR domain.

Since this time, overwhelming evidence from a number ofplant–pathogen interactions, including those from plants inter-acting with bacteria, fungi and oomycetes, have dissected themolecular and biochemical mechanisms underpinning pathogenrecognition and immune signalling in plants. Of these, one ofthe best-characterised examples is that from the A. thaliana–P.syringae interaction, whereby the activation of multiple R pro-teins is ‘guarded’ by the plant protein RIN4. As illustrated inFigure 3, RIN4 association with the R proteins RPS2 and RPM1functions to negatively regulate resistance activation. Upon deliv-ery of the T3EsAvrRpt2, AvrRpm1 and/or AvrB into the host cell,RIN4 is targeted by the activity of the effectors, and this processleads to release of the negative regulation of these R proteins andimmune signalling is activated. Thus, through this indirect mech-anism, plants have evolved a means to recognise pathogens by‘guarding’ the activation of resistance through the utilisation of aconserved pathogen target (Chisholm et al., 2006).

Interplay of Plant Growthand Development in Defence

Above, we described how resistance is activated by specificpathogen-triggered responses, which in turn leads to the ampli-fication of host signalling pathways required for robust immunesignalling. As an illustration of the complexity of defence acti-vation and attenuation, recent work has shown that many of thebasal immune signalling pathways in plants are associated withprocesses that regulate host physiology (e.g. growth and devel-opment and circadian response), as well as response to environ-mental change and abiotic stress (Hua, 2013; Huot et al., 2014).From these collective works, a complex, often-interlinked regu-latory network has been deciphered.During its life cycle, any given plant may come into contact

with a multitude of biotic and abiotic pressures; during this,plants must balance signalling between growth, development and

survival. As an illustration of the convergence between plantgrowth and immune signalling, recent work has shown that thebasal immune signalling responses – that require the functionof PTI-associated receptor complexes – also play essential rolesin host signalling processes associated with environment (Huotet al., 2014). As detailed above, the identification and charac-terisation of FLS2 and EFR opened the door to a multitude ofstudies aimed at defining the primary immune signalling pro-cesses required for pathogen perception and the activation ofplant immunity. From this work, a complex web of interactionswas uncovered, leading to the identification of additional sig-nalling molecules required for the activation – and regulation – ofimmunity in response to the basal recognition of pathogens.Among these, the identification of BIK1 and BAK1 has led to anincreased understanding of the balancing relationships betweenimmunity, host physiology and environmental response. BIK1was identified as being required for resistance activation in Ara-bidopsis in response to the necrotrophic fungal pathogens B.cinerea andAlternaria brassicicola; interestingly, however, BIK1is not required, but instead blocks immune signalling in responseto infection by the bacterial pathogen P. syringae (Macho andZipfel, 2014). As an immune regulator, BIK1 is required for theactivation of PTI-associated processes, a process mediated in partby its physical association with key RLKs (e.g. FLS2). As a keyregulator of host physiology, and in the absence of pathogens,BIK1 is known to be required for plant response(s) associatedwith ethylene perception and signalling, processes that functionantagonistically to the key immune-associated hormone (e.g. jas-monic acid and salicylic acid) response pathways (Macho andZipfel, 2014).Similar to BIK1, another signalling component associated with

PTI receptor activation and signalling has been identified thatpotentially links PAMP signalling with growth and hormoneresponse. In brief, the LRR receptor kinase BAK1, describedabove, was shown to bind the hormone brassinolide, a member ofthe brassinosteroid family of hormones that promotes cell divi-sion and elongation. Upon brassinolide binding, BRI1 activatesBAK1 through a series of phosphorylation cascades, from whichit is hypothesised that the recruitment and subsequent activationof BAK1 to membrane-specific signalling systems mediates thedifferential signalling of defence and growth (Macho and Zipfel,2014). At present, the function of BAK1 in innate immune sig-nalling is hypothesised to be independent of its function in hor-mone signalling.

Plant–Pathogen Interactionsand the Influence of theEnvironment

As a function of immune activation and signalling (i.e. ETI), theimpact of environment and temperature has also been demon-strated to impact the performance of plant R and pathogen Avrgenes. Indeed, substantial research in this area has shown thatchanges in temperature affect a wide range of biotic and abioticfactors, including response to light, growth and development(Hua, 2013). For example, temperature fluctuations have been



found to have significant impacts on pathogen virulence; inmammals, many pathogen virulence genes are induced at 37 ∘Cand attenuated at temperatures at or below 30 ∘C (Steen et al.,2002; Kimes et al., 2012). Similarly, in plant–pathogen inter-actions, numerous virulence factors are induced at low (i.e. c.20 ∘C) temperatures and repressed at temperatures above 30 ∘C(Hua, 2013). From this work, it has been hypothesised that acomplex trade-off exists, in part as a direct function of pathogenphysiology: at high temperatures, the activation of ETI is reducedin part due to a block in effector secretion, while at the sametime, PTI signalling is enhanced as a consequence of enhancedbacterial proliferation (Hua, 2013).The ‘Disease Triangle’ predicts that the onset and incidence of

disease is coincident with an interaction of factors unique to thehost plant, the pathogen and the environment. In short, high dis-ease pressure is observed when pathogen populations increase,which can be influenced by any number of factors, includ-ing environmental temperatures, host performance and inten-sive monoculture. When faced with these pressures, pathogensadapt – through mutation – to overcome resistance. Higher tem-peratures typically favour increased pathogen proliferation; thisis true in both mammals and plants. In addition, in plants, highertemperatures generally mean additional abiotic stresses placedon the plant, such as drought and heat stress (Nakashima et al.,2014). As a function of host performance, higher temperaturesare also hypothesised to accelerate the breakdown (or loss in per-formance) of R genes; this is predicted to be a result of increasedpathogen pressure on the host. There are, however, examples ofR genes whose performance is directly influenced by tempera-ture. For example, in wheat, the R gene Yr59 has been shown toperform ‘better’ at higher temperatures, as revealed by increasedresistance to the rust pathogen Puccinia striiformis f. sp. tritici.At low temperatures, pathogen virulence is favoured, and wheatis susceptible to infection and disease (Bryant et al., 2014). Thereare also described examples where the converse is true: the inhi-bition of R gene-mediated resistance at higher temperatures hasalso been described.

Genome-Enabled Approachesin Plant Biology and Agriculture

Over the past two decades, the elucidation of the genetic archi-tecture of numerous plant species has provided a treasure-troveof valuable resources to not only define the molecular-geneticand biochemical basis of numerous plant processes but alsoprovide a foundation to further describe the evolution of theseprocesses. This work achieved a milestone in the early 2000swith the completion of the Arabidopsis genome, and since thistime, the further development and use of new technologies haveled to a substantial increase in the number of resources andtools at our disposal (Table 3). For example, in recent years,significant advances in genome sequencing (e.g. Illumina) andtheir application to host–pathogen interactions have resulted inhigh-throughput cost-effective methods for plant genotyping andsequencing transcriptional changes during infection (Hamiltonand Buell, 2012). In total, these technologies have facilitated

countless advances in transcriptomic-based studies, facilitatingnot only a better understanding of the function and consequenceof transcriptional reprogramming during infection but also theimpact of environmental stress on the ultimate outcome of thehost–pathogen interaction (Wang et al., 2014b). Since the releaseof the Arabidopsis genome sequence in 2000, the number ofplant genome sequences elucidated continues to increase at aseemingly limitless pace (Table 3). In total, comparative anal-yses of these genomes has led to a greater understanding ofthe complexity and evolution of plants, as well as has identi-fied a number of shared commonalities related to the functionof cellular processes, including the mechanisms that underpinplant–pathogen interactions. Indeed, the enabling power of theArabidopsis genome sequence has allowed scientists to identifyimportant protein homologues in non-model species to furtherinvestigate and define the conservation and function of immunesignalling across species. In many cases, sequence-similar homo-logues have been shown to have similar functions in modeland non-model plant species. For example, the citrus orthologueof the Arabidopsis protein NDR1 (NON-SPECIFIC DISEASERESISTANCE1) has been shown to functionally complementthe Arabidopsis ndr1 mutant plants (Century et al., 1995; Knep-per et al., 2011) to restore resistance to bacterial pathogens (Luet al., 2013). Future comparative analyses between model andnon-model systems may similarly prove pivotal in defining keymechanisms required for durable, sustainable resistance in impor-tant crop species.

Plant Pathogens and GenomeEditing

As described above, recent advances in sequencing technolo-gies have resulted in the generation of a wealth of informationuseful in guiding plant breeding to address abiotic and bioticstress. In addition, previous work on fundamental questions inplant–pathogen interactions has led to the discovery and cre-ation of enabling technologies for genome editing technologyand crop improvement. One such example is the identificationof transcription activator-like (TAL) effectors, a novel class ofpathogen-derived proteins – secreted effectors – that are producedand delivered by Gram-negative bacterial pathogens and deliv-ered into the host during infection. Once delivered into the host,TAL effectors translocate into the host nucleus where they bindspecific DNA sequence targets; this binding results in transcrip-tional changes, and ultimately, regulates the expression of hostsusceptibility genes, which results in cellular changes that benefitthe pathogen to cause disease (Bogdanove et al., 2010). From thefundamental work in this area, numerous advances in our under-standing of TAL effector-targeted gene function have been made,including the identification of specific host genes that are acti-vated by TAL effectors, such as the activation of Os8N3 by theXanthomonas oryzae pv. oryzae (Xoo) effector, PthXo1 (Bog-danove et al., 2010). In short, this work found that constitutiveoverexpression of Os8N3, a gene required for pollen develop-ment in rice, resulted in plants that showed enhanced suscepti-bility to mutant Xoo strains lacking PthXo1, whereas silencing of



Os8N3 resulted in rice plants that showed enhanced resistance.Through this work, as well as numerous additional work fromother groups, methods have been developed to create targetedmutations of specific host gene sequences by fusing TAL effec-tors with an endonuclease resulting in transcription activator-likeeffector nucleases (TALENs; Bogdanove et al., 2010). As a toolfor improving agriculture, this method shows promise as a use-ful tool to modify plant genomes for trait selection. Lastly, inaddition to the use of TALEN-based methods, a quickly devel-oping alternative genome editing system, CRISPER-Cas, hasshown substantial promise as a tool that uses single guide RNAmethods to make targeted deletions within the genome; in plantresearch, this is being used to generate plants that are ‘immune’to the impact of pathogen manipulation and ultimate elicitationof disease. This technology has been demonstrated to function atextremely high specificity, thus showing promise as a rapidmeansto generate agricultural plant lines with improved environmental(abiotic) and biotic stress response (Kumar and Jain, 2014; Wanget al., 2014a).

Enhancing Crop Performanceand Food Production

To say that the acceptance of GM crops still has many hur-dles to overcome before being universally accepted and deployedis an understatement. However, one cannot ignore the poten-tial for genome-assisted selection and breeding of elite traits toaddress many of the numerous challenges facing agriculture. Forexample, a report by Jonathan Jones outlines many of the suc-cess stories since the first release of key GM crops. As noted byJones (2011), of the four major crops that are grown worldwide(corn, canola, soybean and cotton), a collective yield increaseof approximately 30 million metric tons has been recorded as adirect result of the utilisation of GM-based technologies. Indeed,one such example of fundamental knowledge generated throughthe study of plant resistance is the deployment of Bt (Bacillusthuringiensis)-toxin crops, a GM technology that has demonstra-ble success in controlling insect damage to crop plants. In addi-tion, Bt corn plants were found to have reduced levels of fungal(e.g. Fusarium) growth, which in turn led to a reduced accu-mulation of harmful mycotoxins in harvested corn (Wu, 2006).Finally, genetic modification technologies have also been effec-tive in combating plant diseases that, if left unchecked, will dec-imate entire agricultural industries. Such is the case of papayaproduction in Hawaii, whereby through the use of GM-enabledapproaches, the plant is protected from papaya ringspot virus(PRV; Gonsalves, 1998). Although there are many success sto-ries associated with the generation and deployment of GM-basedtechnologies, broad acceptance is far from guaranteed.

Conclusion

Over the past decade, numerous advances in plant breeding andgenome technologies have enabled significant improvements inthe performance and yields of staple crops around the globe. For

example, since 1950, rice yields around the world have more thandoubled. Similarly, the production of both wheat and corn hasseen significant increases in production (Tester and Langridge,2010). In parallel to increased food yields of each of these crops,traits have also been incorporated into lines to address a numberof biotic and abiotic stresses most commonly associated with per-formance and yield. These include traits associated with improve-ments in disease resistance (Dangl et al., 2013), environmentalstress response (Nakashima et al., 2014) as well as a numberof instances of traits associated with improvements in nutritionalqualities (e.g. ‘Golden Rice’; Paine et al., 2005). To date, manyof these yield increases have been realised through the utilisationof a hybrid approach, coupling traditional breeding to the imple-mentation of elite lines selected based on genotype. As a resultof combining the power of genomics with traditional methods inbreeding, the time needed to identify, characterise and incorpo-rate important traits associated with crop performance has beensignificantly reduced. Thus, while these advances can be seen asa step in the right direction in terms of meeting the demands thatpopulation and climate place on agriculture, we have only begunto scratch the surface in terms of our utilisation of research andtechnology to feed the growing population. As outlined through-out this article, current research aimed at defining the fundamen-tal processes and mechanisms associated with plant response tobiotic stress has led to significant advances in our understand-ing of the broader role that environment and human influenceplay on crop performance and durability (Figure 1). As popu-lation growth and global temperatures continue to rise, currentresearch objectives must maintain a focus on addressing the mul-titude of genetic and environmental interactions that drive plantperformance under pathogen challenge. To combat this problem,multidisciplinary approaches, including classical plant breeding,genomics, molecular biology, ecology and plant pathology, areneeded now more than ever to meet the demands of populationgrowth and the impact of human and environmental stress on agri-cultural production.

Acknowledgements

The authors would like to thank all the members of the Day Labfor their help and critical reading of the manuscript before publi-cation, specifically Alyssa Burkhardt. Research in the laboratoryof Brad Day is supported by the National Science Foundation andthe United States Department of Agriculture.

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Further Reading

Belhaj K, Chaparro-Garcia A, Kamoun S, et al. (2014) Editiong plantgenomes with CRISPR/Cas9. Current Opinion in Biotechnology29: 76–84.

Boyle PC andMartin GB (2015) Greasy tactics in the plant-pathogenmolecular arms race. Journal of Experimental Botany. DOI:10.1093/jxb/erv059[Epub ahead of print].

Weilberg A, Wang M, Lin FM, et al. (2013) Fungal small RNAssuppress plant immunity by hijacking host RNA interference path-ways. Science 342: 118–123.

Zhao H, Sun R, Albrecht U, et al. (2013) Small RNA profilingreveals phosphorus deficiency as a contributing factor in symptomexpression for citrus huanglongbing disease. Molecular Plant 6:301–310.


Documents

Pathogen Resistance Advanced article Signalling in Plants ...msudaylab.org/wp-content/uploads/2016/11/Corrion-2015.pdf · paradigm, human inﬂuence on modern agricultural practices