REVIEWS

Plant immunity: towards an integrated

view of plantpathogen interactions
Peter N. Dodds* and John P. Rathjen

Abstract | Plants are engaged in a continuous co-evolutionary struggle for dominance

with their pathogens. The outcomes of these interactions are of particular importance
to human activities, as they can have dramatic effects on agricultural systems.
The recent convergence of molecular studies of plant immunity and pathogen
infection strategies is revealing an integrated picture of the plantpathogen interaction
from the perspective of both organisms. Plants have an amazing capacity to recognize
pathogens through strategies involving both conserved and variable pathogen elicitors,
and pathogens manipulate the defence response through secretion of virulence
effector molecules. These insights suggest novel biotechnological approaches to
crop protection.
Elicitors
Molecules that induce (elicit)
an immune defence response.
In the context of this Review,
this term is used to refer to
both pathogen-associated
molecular patterns (PAMPs)
and effectors.

Pathogen-associated
molecular patterns
Any of a number of
conserved, usually structural,
molecules common to
pathogen organisms.

*Commonwealth Scientific
and Industrial Research
Organisation (CSIRO),
Division of Plant Industry,
GPO BOX 1600, Canberra,
Australian Capital Territory
2601, Australia.

Research School of Biology,

Australian National
University, RN Robertson
Building, Biology Place,
Acton, Australian Capital
Territory 0200, Australia.
e-mails: [Link]@[Link];
[Link]@[Link]
doi:10.1038/nrg2812
Published online 29 June 2010

Food security has become an issue of global importance, and major price spikes for staples such as rice
and wheat have occurred in recent years. These price
spikes are partly due to the impact of plant diseases,
such as the spread of a new strain of the wheat stem
rust pathogen from East Africa into the Middle East 1.
This has sparked an increased focus on improving
approaches to crop protection. The most effective and
environmentally sensitive approach to disease prevention involves breeding crop plants for resistance. Indeed,
plant breeders have been using resistance genes to control diseases in crop plants for almost 100 years, and the
effectiveness of this strategy sparked early genetic studies that defined gene-for-gene relationships between
host resistance genes and pathogen virulence factors2.
However, only through recent molecular studies has
it become apparent that host resistance genes encode
components of the plant immune system that confer
the capacity to recognize and respond to specific pathogens. Plant immunity depends on cell-autonomous
events; these events are related to the innate immune
system in animals3 but plants have a much bigger recognition repertoire to compensate for their lack of an
adaptive immune system. Ongoing research is revealing
the recognition capacity of the plant immune system,
and concurrent studies on pathogen biology are beginning to unravel how these organisms manipulate host
immunity to cause disease. The recent convergence of
these two fields has dramatically changed our perception of plantpathogen interactions and is providing
new approaches for crop protection.

Microbial plant pathogens almost always occupy

extracellular niches. Despite this, the nutrients that
enable pathogen growth are derived from host cells, and
the host cytoplasm and organelles are important sites of
molecular interaction. Plants have evolved two strategies
to detect pathogens4,5 (FIG. 1). On the external face of the
host cell, conserved microbial elicitors called pathogenassociated molecular patterns (PAMPs) are recognized
by receptor proteins called pattern recognition receptors
(PRRs)6. PAMPs are typically essential components of
whole classes of pathogens, such as bacterial flagellin or
fungal chitin. Plants also respond to endogenous molecules released by pathogen invasion, such as cell wall
or cuticular fragments called danger-associated molecular patterns (DAMPs). Stimulation of PRRs leads to
PAMP-triggered immunity (PTI). The second class of perception involves recognition by intracellular receptors of
pathogen virulence molecules called effectors; this recognition induces effector-triggered immunity (ETI). This mode
of recognition leads to co-evolutionary dynamics between
the plant and pathogen that are quite different from PTI
as, in stark contrast to PAMPs, effectors are characteristically variable and dispensable. Extreme diversification
of ETI receptors and pathogen effectors both within and
between species is the norm, whereas some PRR functions are conserved widely across families. Generally, PTI
and ETI give rise to similar responses, although ETI is
qualitatively stronger and faster and often involves a form
of localized cell death called the hypersensitive response
(HR). PTI is generally effective against non-adapted
pathogens in a phenomenon called non-host resistance,

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REVIEWS
Pattern recognition
receptors
Plasma membrane-localized
receptors that recognize
the presence of pathogenassociated molecular
patterns (PAMPs) in the
extracellular environment.

PAMP-triggered immunity
The plant defence response
elicited by pathogenassociated molecular
pattern (PAMP) recognition.

Effectors
Proteins secreted by
pathogens into host cells
to enhance infection.
Many of these function to
suppress PAMP-triggered
immunity responses.

whereas ETI is active against adapted pathogens. However

these relationships are not exclusive and depend
on the elicitor molecules present in each infection.
Here, we provide an overview of the plant PTI and
ETI systems, highlighting recent advances and identifying key gaps in our understanding of these processes. we
consider the roles of PRRs in initial pathogen perception,
our expanding knowledge of pathogen effectors and their
roles in suppressing PTI responses, the nature of effector
recognition and the downstream responses to pathogen
perception. Finally, we discuss briefly how this knowledge
is beginning to feed back into the agricultural context
that originally spawned the study of plant immunity.

Extracellular recognition by PRRs

PRRs have been reviewed recently 7, so here we discuss
some important principles and recent findings relating to key proteins in the process of recognition of
extracellular pathogen molecules.

Extracellular space

PAMPs

Bacterium
Pilus

PRR

BAK1

Effector

PTI response
Haustorium

Effector
ETI response

Fungus/
oomycete

NB-LRR
Plant cell

Figure 1 | the principles of plant immunity. Bacterial plant pathogens propagate

Nature Reviews | Genetics
exclusively in the extracellular spaces of plant issues. Most fungal and oomycete
pathogens also extend their hyphae into this space, although many also form
specialized feeding structures, known as haustoria, that penetrate host cell walls but
not the plasma membrane. Other fungi extend invasive hyphae into plant cells, but
again do not breach the host membrane. Molecules released from the pathogens into
the extracellular spaces, such as lipopolysaccharides, flagellin and chitin (pathogenassociated molecular patterns (PAMPs)) are recognized by cell surface pattern
recognition receptors (PRRs) and elicit PAMP-triggered immunity (PTI). PRRs
generally consist of an extracellular leucine-rich repeat (LRR) domain (mid-blue),
and an intracellular kinase domain (red). Many PRRs interact with the related protein
BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED KINASE 1 (BAK1) to initiate the PTI
signalling pathway. Bacterial pathogens deliver effector proteins into the host cell
by a type-III secretion pilus, whereas fungi and oomycetes deliver effectors from
haustoria or other intracellular structures by an unknown mechanism. These
intracellular effectors often act to suppress PTI. However, many are recognized
by intracellular nucleotide-binding (NB)-LRR receptors, which induces effectortriggered immunity (ETI). NB-LRR proteins consist of a carboxyl-terminal LRR domain
(light blue), a central NB domain (orange crescent) that binds ATP or ADP (yellow oval),
and an amino-terminal Toll, interleukin-1 receptor, resistance protein (TIR) or
coiled-coil (CC) domain (purple oval).

Pattern recognition receptors. Known PRRs fall into

one of two receptor classes: transmembrane receptor
kinases and transmembrane receptor-like proteins,
the latter of which lack any apparent internal signalling domain7. Recent work has shown that endoplasmic
reticulum quality-control mechanisms are crucial for
PRR biogenesis (BOX 1). The receptor kinase gene family
has undergone huge expansion in plants: for example, about 610 members are present in the Arabidopsis
thaliana genome, and many of these are responsive
to biotic stresses8. The receptor-like protein class has
57 members in A. thaliana 9. The expansion of these
families is in contrast to the situation in animals, which
possess 12 Toll-like receptors that fulfil an equivalent
role to PRRs in plants10.
The PAMPs recognized by plants are multifarious
and include proteins, carbohydrates, lipids and small
molecules, such as ATP6. Recognition of PAMPs is
best understood in the case of the A. thaliana receptor kinase FlAGEllIn SEnSInG 2 (FlS2), which
binds bacterial flagellin directly and then assembles
an active signalling complex. Although the PAMP
concept encompasses the idea that all PAMPs should
be recognized by all species, this has been found to
not always be the case, as perception of the bacterial
elongation factor EF-Tu is apparently restricted to the
Brassicaceae11. Similarly, the Xa21 receptor in rice provides race-specific resistance to the bacterial pathogen
Xanthomonas oryzae, and was recently shown to act as
a PRR for a novel sulphonated bacterial protein termed
Ax21 (ReF. 12).
BAK1, a central regulator of PAMP-triggered immunity. Most known PRRs require the leucine-rich
repeat (lRR) receptor kinase BRASSInOSTEROID
InSEnSITIvE 1-ASSOCIATED KInASE 1 (BAK1) for
function13,14 (FIG. 2). An exception is the fungal chitin
receptor CHITIn ElICITOR RECEPTOR KInASE 1
(CERK1)15,16, which also responds to an unknown bacterial PAMP17. BAK1 is part of a family of five somatic
embryogenesis receptor kinase (SERK) members and
is also known as SERK3. It is not yet known whether
other SERK family members have redundant roles in
immune signalling. BAK1 does not have a direct role
in elicitor perception, but FlS2 rapidly forms a complex
with BAK1 after elicitation. This interaction results in
phosphorylation of both proteins, which peaks 3060
seconds after elicitor treatment 18. BAK1 also has a
role in the perception of other elicitors, probably
also through heterodimerization with PRRs in the
lRR-receptor kinase family.
As such, BAK1 is a central regulator of plant immunity and consequently the target of several pathogen
virulence effector molecules 19 (see below). Despite
this, A. thaliana plants containing a null mutation in the bak1 gene are actually marginally more
resistant to biotrophic pathogens, although they are
slightly more susceptible to necrotrophic pathogens20.
These phenotypes may be related to a deregulated
cell death phenotype that has been described in the
bak1 mutants20,21.

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Box 1 | Pattern recognition receptor biogenesis
Most eukaryotic membrane proteins undergo quality control during folding and
maturation in the endoplasmic reticulum (ER), a process termed ERQC114.
A number of recent studies show that the biogenesis of a pattern recognition
receptor (PRR), the EFTu receptor (EFR), is regulated by this mechanism115119.
After secretion into the ER, proteins are modified at glycosylable Asn residues by
an oligosaccharyltransferase complex, which covalently attaches a complex
polysaccharide containing three terminal glucose residues. The glucose moieties
are subsequently trimmed by glucosidases I and II. A single glucose residue is
added back by UDPglucose:glycoprotein glucosyltransferase (UGGT) near regions
of protein disorder. Monoglucosylated proteins interact with the lectins calnexin
(CNX) or calreticulin (CRT) to retain misfolded substrates in the ER. In this way,
UGGT acts as a folding sensor, and glycosylation is intimately related to protein
maturation. Terminally misfolded proteins are degraded.
Another ER folding pathway is based on the chaperone BiP (a form of heat shock
protein 70 (Hsp70)). Unfolded proteins undergo cycles of BiP binding and release,
which is regulated by Hsp40 cochaperones containing J domains (for example, the
ERdj protein). Forward genetic screens showed that Arabidopsis thaliana genes
encoding glucosidase II, UGGT, CRT3, ERdj3B and ERD2b are required for EFR
function and accumulation. In addition, STT3A, a subunit of the oligosaccharyl
transferase complex, was necessary for EFR biogenesis. Finally, STROMAL
DERIVED FACTOR 2 (SDF2) resides in a protein complex with ERdj3B and BiP, and
was also required for EFR maturation. Plants with mutations in these genes are
generally more susceptible to pathogens, indicating that EFR is not the only
immune protein that is governed by ERQC. However, neither FLAGELLIN SENSING 2
(FLS2) nor CHITIN ELICITOR RECEPTOR KINASE 1 (CERK1) function is significantly
affected in these mutants.

Effector-triggered immunity
The plant defence response
elicited by effector recognition.

Biotrophic
Biotrophic pathogens
propagate in living plant tissue
and generally do not cause
necrosis as a result of infection.
They use various means, such
as haustoria production, to
extract nutrients from host cells.

Necrotrophic
Necrotrophic pathogens
actively induce necrosis in
infected tissues, often through
the production of toxins, and
obtain nutrients from the
dead host tissue.

Type-III secretion system

A syringe-like structure
produced by many plant
and animal pathogen bacteria
that allows direct secretion
of effector proteins from
the bacterial cytoplasm into
host cells.

One potential regulator of the FlS2BAK1 complex is the cytoplasmic protein kinase BOTRYTISInDuCED KInASE 1 (BIK1). BIK1 was identified as
a potential regulator because bik1 is upregulated after
pathogen or elicitor treatment of A. thaliana leaves22.
BIK1 interacts with both FlS2 and BAK1 before elicitation and seems to dissociate from the complex after elicitation. In vitro, BAK1 phosphorylates BIK1 and BIK1
phosphorylates both FlS2 and BAK1. In vivo,
BIK1 becomes phosphorylated 510 min after treatment with flagellin 23; this phosphorylation peaks
after the FlS2BAK1 phosphorylation. Confusingly,
bik1 mutant A. thaliana plants are more resistant
to Pseudomonas syringae infection than wild-type
A. thaliana plants22 as a result of them overproducing the defence hormone salicylic acid (SA), but they
are also more susceptible to infection with the necrotrophic fungal pathogen Botrytis cinerea. Despite this,
deficiencies in FlS2-mediated immune responses
could be measured in these plants23. These contrasting results make it difficult to ascribe a clear function
to BIK1 in plant immunity, and further studies will
be required.

Virulence activities of pathogen effectors

Successful pathogens are able to suppress PTI responses
and thereby multiply and cause disease. They achieve suppression through the deployment of effector proteins.
Studies of bacterial phytopathogens have provided
most of our understanding of effector strategies
and mechanisms. Individual phytopathogen strains
encode 2030 effectors, which are highly regulated and
secreted directly into the host cytoplasm by a dedicated

needle structure, the type-III secretion system (TTSS)24.

The repertoire of individual effectors varies dramatically among closely related bacterial strains, and
effectors themselves act redundantly and are apparently interchangeable25; examples of such effectors
are discussed below. Many effectors interfere directly
with PTI responses26, and bacterial mutants that lack
the TTSS system are non-pathogenic. Interestingly,
a number of examples show that transgenic overexpression of an individual type-III effector in the host
plant restores the ability of such bacterial mutants to
grow 27,28, suggesting that bacterial pathogenicity only
requires suppression of PTI. However, contributions
of as yet undefined mechanisms to other processes,
such as nutrient acquisition, cannot be excluded.
Bacterial effector functions. Bacterial effectors have
molecular or enzymatic activities that specify both
their ability to modify host targets and their intracellular recognition by ETI receptors29 (see below). The
redundancy among effectors is illustrated by the unrelated P. syringae effectors AvrPto and AvrPtoB, which
both target the FlS2BAK1 complex. Although the
models for how suppression works conflict in molecular detail19,30,31, it is generally accepted that AvrPtoB
uses a dual strategy for kinase suppression: its aminoterminal kinase-targeting domain is sufficient to suppress flagellin responses, and its carboxy-terminal
E3 ligase domain can tag interacting kinase proteins
with ubiquitin to direct them for degradation 32,33.
AvrPtoB is known to target five host kinases of the
Pto/interleukin receptor-associated kinase (IRAK)
class32, but because this clade is hugely expanded in
plants8, there are probably many more such targets.
likewise, AvrPto suppresses multiple PRR receptor
kinases, perhaps by acting as a kinase inhibitor 19,30,34.
Overall, these effectors seem to be part of a bacterial
strategy that targets host kinases nonspecifically.
A further example of overlapping effector functions involves the host protein RPM1-InTERACTInG
PROTEIn 4 (RIn4), which is targeted by the P. syringae
effectors AvrB, AvrRPM1 and AvrRpt2 through different molecular strategies35,36. Recently, it was shown
that the P. syringae effector HopF2 may also target
RIn4 (ReF. 37). Overexpression of HopF2 prevented
degradation of RIn4 by the protease AvrRpt2 but
did not alter the interactions of RIn4 with AvrRPM1
or AvrB. Bacteria that lack HopF2 have increased
growth on lines that lack RIn4, suggesting that RIn4
could indeed be a target for virulence, but an indirect
cause for this observation was not ruled out. RIn4
is a negative regulator of both PTI and ETI28,38, and
also interacts with the plasma membrane H+-ATPases
AHA1 and AHA2 to enhance stomatal opening 39, a
key event during bacterial pathogenicity on leaves.
Thus it is not clear how targeting of RIn4 by multiple
effectors would enhance bacterial virulence, as disruption of RIn4 should actually restrict pathogenicity.
However, the number of effectors involved in this
process is consistent with RIn4 being an important
virulence target.

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a

Bacterium

Apoplast

PRR

BAK1

BAK1 PRR

P BAK1 PRR P
BIK1

Plant cell

MAPKs

CDPKs

Figure 2 | Formation of active pattern recognition receptorNature

complexes.
Reviews | Genetics
a | Infectious pathogens, such as bacteria, shed pathogen-associated molecular
patterns (PAMPs; pink, yellow and purple shapes) into the apoplast, where they are
recognized by specific pattern recognition receptors (PRRs). b | Immediately after
ligand binding, the PRR forms an active complex with BRASSINOSTEROID
INSENSITIVE 1-ASSOCIATED KINASE 1 (BAK1). c | This results in transphosphorylation
(indicated by P) of the respective kinase domains of the PRR and BAK1. Signalling via
this active complex can be mediated directly by BOTRYTIS-INDUCED KINASE 1
(BIK1), or by mitogen-activated protein kinases (MAPKs) or calcium-dependent
protein kinases (CDPKs). This is a generalized model that is based on FLAGELLIN
SENSING 2 (FLS2), the receptor for bacterial flagellin.

Haustoria
(sing. haustorium.) Specialized
structures produced by
some fungal and oomycete
pathogens. Haustoria extend
through the plant cell wall
and expand in the host cell.
They remain surrounded by
a host-derived membrane
and hence are topologically
extracellular and separated
from the host cytoplasm.

Hemibiotrophic
Hemibiotrophic pathogens
incorporate aspects of both
biotrophic and necrotrophic
infection strategies. Often
this involves an initial
biotrophic infection phase
during which the pathogen
spreads in host tissue,
followed by a necrotrophic
phase during which host
cell death is induced.

NB-LRR proteins
A class of intracellular
receptor proteins containing
nucleotide-binding (NB) and
leucine-rich repeat (LRR)
domains that recognize specific
pathogen effectors.

It is important to note that not all effectors target PTI.

One example of an alternative bacterial effector strategy
is given by the transcription activator-like (TAl) effectors of Xanthomonas spp., which are transcription factors that induce the expression of specific host genes,
some of which contribute to symptom development 40.
unlike AvrPto and AvrPtoB in Pseudomonas spp., TAl
effectors do not seem to act redundantly because several
of them are essential for virulence. They interact specifically with a site in the target gene promoters through a
central tandem repeat region that forms a DnA-binding
domain4143. Strikingly, two hypervariable amino acid
residues in each repeat specify interaction with a characteristic nucleotide in the effector recognition site. Thus,
the nucleotide sequence of the target DnA can be predicted by the amino acid sequence of the tandem repeat
domain. Biotechnologically this is significant because it
enables precise modification of gene expression in vivo,
including turning this system against Xanthomonas spp.
by engineering AvrBs3-responsive elements (known as
uPA sites), upstream of active resistance genes 44. In
nature, this strategy has been pre-empted in some plant
species: target sites for certain TAl effectors have been
incorporated upstream of the resistance genes Bs3 and
Xa27 in pepper and rice, respectively 45,46.
Eukaryotic effectors. Data on eukaryotic effectors and
their functions are sparse in comparison with data on
bacterial effectors. Both fungal and oomycete pathogens produce effectors that are secreted through the
endomembrane system and are subsequently delivered
into host cells by unknown mechanisms47,48. Oomycete
effectors characteristically contain the internal motif

Arg-X-leu-Arg (RXlR, in which X represents any

amino acid), which is required for delivery into plant
cells. Genome sequencing of Phytophthora infestans 49,
the Irish potato famine pathogen, revealed 563 RXlR
effector genes. Seventy of these genes are under diversifying selection and only 16 share orthologues in the
genomes of 2 other sequenced Phytophthora spp., which
indicates that very strong selection processes act on
these effectors. A further 196 effectors of a separate class
(known as Crinkler proteins) are encoded by P. infestans.
Such generalized identification of fungal effector genes
has been restricted by the lack of conserved motifs to
aid genome interrogation, but genome analysis of several fungal pathogens predicts that they have complex
and diversified secretomes50,51. The massive expansion
in eukaryotic effector repertoires relative to bacterial
effector repertoires may suggest a requirement for more
diverse effector functions by eukaryotic pathogens,
possibly to support their more specialized nutrient
acquisition strategies.
Some data support roles of P. infestans effectors in
suppression of immunity 52; for example, Avr3a suppresses elicitor-induced cell death through interaction with the host CMPG1 E3 ligase53, but in general
very little is known about effector functions in fungi
or oomycetes. However, many other potential roles
remain, such as establishment of the pathogenic niche
through development of the haustoria feeding structures and manipulation of host cell death during the
hemibiotrophic lifestyle.
Sedentary nematode pathogens of plants form prolonged associations with roots, in which they induce the
formation of novel host structures, such as multinucleate giant cells, from which they feed using a specialized
proboscis called a stylet. The stylet also delivers salivary
secretions into host cells; proteomic analysis of saliva
from one such species, Meloidogyne incognita, identified 486 potential effector proteins54. Ongoing genomics analyses of such species will identify many more and
help in elucidating the pathogenic strategies of these fascinating organisms. In addition, viral pathogens encode
specific suppressors of the small RnA pathway to prevent degradation of their genomes and/or abrogation of
viral gene expression55.
Overall, our understanding of effector proteins and
their host targets is at a very early stage. Sophisticated
biochemical screens for host protein targets that interact
with the diverse suites of pathogen effectors are likely to
lead to the identification of important components of
host defence mechanisms and teach us more about host
immune pathways and pathogenicity strategies.

Intracellular effector recognition

ETI is the second pathogen-sensing mechanism in
plants and is based on intracellular recognition of effector proteins4,5. Recognition events are mostly mediated
by a class of receptor proteins that contain nucleotidebinding (nB) domains and lRRs (FIG. 1). Plant NB-LRR
proteins confer resistance to diverse pathogens, including fungi, oomycetes, bacteria, viruses and insects. nB
and lRR domains are also present in nOD-like immune

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a Direct

b Guard/decoy

c Bait

Figure 3 | Models of direct and indirect recognition. Plant nucleotide-binding

Nature
Reviews |by
Genetics
(NB)-leucine-rich repeat (LRR) receptors can recognize pathogen
effectors
either direct or indirect mechanisms. a | In direct recognition, the effector (green)
triggers immune signalling by physically binding to the receptor (purple, orange,
yellow and blue; see FIG. 1 for a description of the receptor). b | In the guard and
decoy models, the effector modifies an accessory protein (red), which may be its
virulence target (guard model) or a structural mimic of such a target (decoy model).
The modified accessory protein is recognized by the NB-LRR receptor. c | Under the
bait model, interaction of an effector with an accessory protein facilitates direct
recognition by the NB-LRR receptor.

receptors (nlRs), which are involved in PAMP induction

of innate immunity responses in animals3,56, and in the
animal apoptotic factors apoptotic protease-activating
factor 1 (APAF1) and cell death protein 4 (CED4). Many
plant nB-lRR proteins also contain an n-terminal TIR
(Toll, interleukin-1 receptor, resistance protein) domain
related to the intracellular signalling domain of animal
Toll-like receptors10. A second common class of nB-lRR
proteins contain an n-terminal domain with a coiledcoil (CC) domain, whereas others have no conserved
n-terminal region.
Direct and indirect recognition. nB-lRR proteins can
recognize pathogen effectors either directly by physical
association or indirectly through an accessory protein
that is part of an nB-lRR protein complex (FIG. 3). In
general, direct recognition has been demonstrated by
yeast two-hybrid (Y2H) assays, in some cases supported
by in vitro protein interaction assays. For example, the
rice CC-nB-lRR Pi-ta protein binds to the Magnaporthe
grisea effector AvrPita both in vitro and in Y2H assays57.
The flax TIR-nB-lRR l and M proteins also interact
in Y2H assays with the Melampsora lini fungal effectors Avrl567 and AvrM, respectively 5861. These pairs of
receptor and effector proteins show evidence of strong
diversifying selection and are characterized by high
levels of sequence polymorphism between alleles in
the host and pathogen populations, respectively, with
these variants showing different recognition specificities. This is likely to be the result of antagonistic coevolution between the interacting components in the
host and pathogen.
Indirect effector recognition has been observed in
a number of cases. In the best-described models, the
effector interaction is mediated by an accessory protein
that is a pathogen virulence target or a structural mimic
of one. The effector induces a change in the accessory
protein that enables the accessory to be recognized by
the nB-lRR protein62. This strategy neatly sidesteps the
evolutionary advantage of the faster evolving pathogen,
as the host takes advantage of the pathogens virulence
strategy to drive the recognition. Three conceptual

models have been proposed to describe these mechanisms (FIG. 3). The guard model postulates that nB-lRR
proteins guard an accessory protein (or guardee) that
is targeted and modified by pathogen effectors63. This
model is exemplified by the A. thaliana RIn4 protein.
RIn4 forms exclusive complexes with the nB-lRR proteins RPM1 and RESISTAnCE TO PSEuDOMOnAS
SYRInGAE 2 (RPS2)36,64. Degradation of RIn4 by the
protease effector AvrRpt2 de-represses RPS2, whereas
AvrB or AvrRPM1-mediated phosphorylation of
RIn4 activates RPM1 (ReFS 35,36). Thus, modification
of RIn4 by the effectors explains how an individual
nB-lRR (in this case, RPM1) can recognize more than
one effector.
However, the guard model postulates that RIn4 is a
virulence target of the effectors, which is as yet unproven
(see also above). Also, this model creates an evolutionary
problem: RIn4 should evolve to avoid binding to the
effector proteins in the absence of RPS2 and RPM1, but
in their presence, selection will favour effector binding to
promote recognition5. To solve this problem, the decoy
model was proposed62, in which duplication of the
effector target gene or independent evolution of a target
mimic could relax evolutionary constraints and allow the
accessory protein to participate solely in effector perception. This situation is exemplified by the tomato nB-lRR
protein Prf, which forms a complex with the accessory
protein Pto kinase65. Pto kinase is closely related to the
kinase domains of FlS2 and CERK1, which are targets of
AvrPto and AvrPtoB32,66. Thus, Pto provides the recognition capability for Prf, and this drives diversification of
the Pto family to broaden the spectrum of recognition
capability 67. In the decoy model, the accessory protein
specializes in perception of the effector by the nB-lRR
protein but has no other function. This fails to explain
the requirement for Pto kinase activity in Prf activation68
and the clear role of RIn4 in defence responses. A further modification of the decoy concept is the bait-andswitch model69, which envisages a two-step recognition
event. First, an effector interacts with the accessory
bait protein associated with an nB-lRR, and then a
subsequent recognition event occurs between the effector and nB-lRR protein to trigger signalling. That
is, the nB-lRR protein interacts with an effector target
(the bait) to facilitate direct recognition of the pathogen
effector, rather than recognizing the modified target as
envisaged in the guard model.
It is important to remember that these models are
generalizations based on limited specific examples, none
of which is yet fully understood. Thus, although they are
useful conceptual tools, they are unlikely to adequately
describe all effector recognition events and can be
restrictive. For instance, in addition to providing effector recognition, Pto seems to participate actively with
Prf in a highly evolved co-regulatory relationship65,68.
The massive diversity in effector and receptor biology suggests that many variations on these themes,
and probably other novel recognition events, are likely
to occur. For example, the Pto kinase phosphorylates
the effector AvrPtoB, leading to inactivation of its
intrinsic E3 ligase activity 70; this is an intriguing and

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so far unique example of the host taking the bacterias
virulence strategy for its own. Interestingly, several
examples have been described recently in which two
different nB-lRR genes are required for recognition
of specific effector proteins7175, providing a further
challenge for recognition models. The A. thaliana TIRnB-lRR genes RPS4 and RESISTANT TO RALSTONIA
SOLANACEARUM 1 (RRS1) are arranged in divergent
tandem configuration within the major recognition
gene complex MRC-J on chromosome 5 (ReF. 76). RPS4
confers immunity to P. syringae through recognition of
the effector AvrRps4, and RRS1 recognizes the Ralstonia
solanacearum effector PopP2; new data show that both
of these genes need to be expressed together for recognition of these effectors and for resistance to the fungus
Colletotrichum higginsianum 71. Genetic data suggest
that the encoded proteins act in the same pathway,
potentially as members of a protein heterocomplex.
There are nine other examples of coordinate nB-lRR
gene arrangement in the A. thaliana genome, and
numerous other examples of nB-lRR genes working
together have been described in various species. How
these proteins function together remains unknown.
NB-LRR activation. One of the remaining challenges
is to understand how effector recognition leads to
nB-lRR activation, and whether the activation mechanisms are the same for different recognition systems.
Broadly, the nB-lRR is a conserved multidomain
switch that translates diverse direct or indirect pathogen
signals into a general immune response69. numerous
genetic studies have shown that the lRR domain often
controls recognition specificity 7780, with the implication that the lRR mediates effector interaction in these
systems. However, these studies have necessarily been
conducted on nB-lRRs that belong to diversified families, including some that are known to directly interact
with their cognate effectors. By contrast, lRR domains
of nB-lRRs that participate in indirect recognition are
often conserved, and it is not clear what part the lRR
domain plays in these cases. It is possible that direct and
indirect recognition mechanisms involve fundamentally
different nB-lRR activation processes.
In the absence of an effector trigger, nB-lRR proteins are maintained in a restrained conformation. In
some indirect recognition systems, negative regulation
of the nB-lRR by an accessory protein is released by
effectors, and this is sufficient for activation of ETI81.
This constitutes a simple paradigm that may occur
widely. In other cases, the nB-lRR is autoinhibited75;
that is, intramolecular interactions hold the protein in
an inactive conformation until disrupted by the presence of the effector. This may be a general feature of
direct recognition events. nucleotide binding by the
nB domain seems to be crucial for the function of all
plant nB-lRR proteins75, and signal activation may
involve an exchange of ATP and ADP in the binding site82. Biochemical analysis of nB-lRR proteins
and their complexes has proven difficult but is crucial to advance our understanding of these complex
activation events.

Animal nB-containing proteins, such as nlRs and

the apoptotic factors APAF1 and CED4, self-oligomerize
through their centrally located nB domain after activation, thereby forming an active signalling platform83.
In this state, an n-terminal interaction domain (such
as a caspase recruitment domain (CARD), pyrin
domain or baculovirus inhibitor (BIR) domain) is
made accessible for signalling adaptor proteins, which
initiate the downstream signalling pathways leading
to inflammatory response or apoptosis84. Similarly,
the tobacco n protein oligomerizes in the presence
of p50; oligomerization is dependent on a functional
nB domain and also seems to involve the n-terminal
TIR domain85. Interestingly, tomato Prf exists in an
oligomeric complex before stimulation with AvrPto
or AvrPtoB67.
Similar to the n-terminal domains of mammalian
nOD proteins, there is evidence that the TIR domain
provides the downstream signalling capability for plant
TIR-nB-lRR proteins. For instance, deletion or point
mutations of the TIR domain from the tobacco n protein block HR induction downstream of the oligomerization event 85. Furthermore, overexpression of the
isolated TIR domains of several TIR-nB-lRR proteins
is sufficient to trigger an HR86,87. The TIR domains of
Toll-like receptors are activated by dimerization triggered by extracellular PAMP recognition10, so it is possible that effector-induced R protein oligomerization
enables TIR activation through induced proximity. For
some non-TIR nB-lRRs, overexpression of the CC-nBARC fragments can trigger plant defence signalling,
whereas the CC domains alone do not 8890. In tobacco,
the n-terminal portion of the nB domain of the Rx
protein (which confers resistance to potato virus X)
is sufficient to induce cell death89.

Signalling pathways and downstream responses

A number of cellular events associated with both PTI
and ETI are known, essentially as correlative phenomena. These include a rapid influx of calcium ions from
external stores, a burst of active oxygen species, activation of mitogen-activated protein kinases (MAPKs),
reprogramming of gene expression, deposition of callosic cell wall appositions at sites of attempted infection
and, often, localized cell death (HR). There is extensive
overlap among the gene expression profiles elicited by
most PAMPs6. PTI and ETI gene expression signatures
are largely similar, suggesting that the responses are
the same overall but vary in magnitude91. One of the
big gaps in our understanding of plant immunity is
in the signalling pathways that operate immediately
downstream of PRR and nB-lRR protein activation.
Genetic screens have had very limited success in identifying signalling components, and the components of
these pathways remain mostly elusive. Several of the
partially understood pathways are described below.
Kinase signalling. One topic that has received a lot
of attention is MAPK signalling. MAPK pathways
are ubiquitous signal transduction components in
eukaryotes and transfer signals from extracellular

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REVIEWS
receptors to cellular responses. A MAPK cascade typically consists of a modular complex consisting of a MAPK
kinase kinase (MAPKKK), which phosphorylates a
MAPK kinase (MAPKK), which phosphorylates a MAPK.
These pathways regulate the activity of various substrates,
such as transcription factors and protein kinases.
Importantly, MAPK cascades have been implicated in both PTI and ETI92. A putative MAPK cascade that acts downstream of flagellin perception has
been characterized in A. thaliana. It comprises the
MAPKKs MKK4 and MKK5 upstream of the MAPKs
MPK3 and MPK6, and leads to activation of wRKYtype transcription factors. The cascade culminates in
the expression of defence genes93. Congruently, constitutively active MKK4 and MKK5 confer resistance
to infection by P. syringae in A. thaliana. Previously,
the MAPKKK MEKK1 was thought to be part of
this cascade 93 but more recent evidence indicates
that this is unlikely, as mekk1 mutant plants are not
compromised in activation of MPK3 and MPK6 triggered by the flagellin peptide flg22 (ReF. 94). Rather,
MEKK1 seems to act at the apex of a cascade comprising MEKK1, MKK1, MKK2 and MPK4, which is
also activated by flg22 treatment. MPK3 and MPK6
are also activated by other PAMPs6. MPK6 activates
ethylene biosynthesis through phosphorylation of
1-AMInOCYClOPROPAnE-1-CARBOXYlIC ACID
SYnTHASE (ACS6) on flg22 perception95. Moreover,
ERF104, an ethylene response factor, is a known MPK6
substrate96. The MPK6ERF104 interaction is rapidly
lost in response to flg22, presumably allowing the
liberated ERF104 to access target genes and activate
ethylene signalling during PTI96.
In a recent paper, Sheen and colleagues defined an
alternative pathway based on activation of calciumdependent protein kinases (CDPKs)97. using a functional genomics approach, they defined a subclade
of A. thaliana CDPKs that are required for FlS2dependent immunity. This pathway acts mostly independently of the MAPK pathway, as judged by gene
expression assays, but antagonistic and synergistic
effects were also observed. This model is consistent with
the observation that calcium channel inhibitors abrogate
most immune responses elicited by microbe-associated
molecular patterns (MAMPs) or effectors.
Effector-triggered immunity signalling. Most of the
genes identified in genetic screens for suppressors of
ETI are either genes specific to the recognition system
used in the screen, such as recognition accessory proteins, or members of a chaperone complex required for
the function of many nB-lRR proteins98. Only a couple of genuine signalling proteins have been identified.
EnHAnCED DISEASE SuSCEPTIBIlITY 1 (EDS1)
is required for signalling of all TIR-nB-lRRs tested to
date, suggesting that it acts specifically in TIR domain
signalling 99. However, it is not clear what intermediaries
connect EDS1 and TIR-nB-lRRs. Similarly, the integral plasma membrane protein nOn-RACE-SPECIFIC
DISEASE RESISTAnCE 1 (nDR1) is required for
signalling from some CC-nB-lRRs (which are all

membrane associated), but again the connecting steps

are unknown100. The lack of success with genetic screens
for signalling components could suggest that there
are few essential elements in ETI signalling, and
there is a possibility that redundant signalling pathways
operate in parallel. Biochemical approaches for identifying signalling components interacting with activated
nB-lRR proteins will be necessary to uncover further
steps in these pathways.
Despite the difficultly in identifying components,
an interesting model for ETI signalling has been proposed recently. In this model, nB-lRRs relocate to the
nucleus on activation and interact with nuclear factors
to trigger changes in gene expression. For instance,
the tobacco n protein, barley MlA10 protein and
A. thaliana RPS4 proteins localize to both the cell
cytoplasm and nucleus, and nuclear accumulation is
required for their function101103. However, only a small
fraction of these nB-lRR proteins is present in the
plant cell nucleus. It can also be difficult to distinguish
interactions related to recognition from those related
to signalling. For example, A. thaliana RRS1-R interacts with the Ralstonia solanacearum effector PopP2
in the nucleus104,105. In addition, although a putative
nuclear localization signal is required for the function of full-length RPS4 protein, it is not present in
the constitutively active TIR domain of RPS4 (ReF. 87).
To date, no signalling partners common to different
nB-lRR proteins have been identified in the nucleus.
It will be interesting to discover the extent to which
nuclear localization explains the signalling activity of
these examples, and whether this is a general feature
of all nB-lRR receptors.
Downstream responses. Some of the downstream
responses to ETI and PTI are better understood than the
signalling pathways. The SA and jasmonic acid (JA)
ethylene (ET) hormone pathways are important regulators of defence-gene expression106. These two pathways
act antagonistically to some extent, with SA involved in
resistance to biotrophic pathogens and JAET involved
in responses to necrotrophic pathogens and chewing
insects. However, although there are substantial differences in the gene expression outputs of these pathways, and several genes act as specific markers for the
activation of either the SA or JAET pathways, there
is also considerable overlap between them. Recently,
Tsuda et al.107 found complex interactions between SA
and JAET signalling in a detailed combinatorial study
using multiple mutants blocked in different pathways.
The SA and JAET pathways seemed to act synergistically in PTI to amplify the response. This may explain
why many pathogen effectors are able to suppress PTI
by interacting with different targets; because the signal
itself is relatively weak, blocking just one component
is sufficient to substantially perturb the response.
However, the ETI response is stronger and involves
redundant activities of SA and JAET pathways107.
Thus, even in the absence of SA signalling, the JAET
response contributes to maintaining a substantial
level of pathogen resistance. These compensatory

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REVIEWS
Box 2 | Novel agricultural applications
Plant breeders have long recognized the importance of resistance genes for
preventing disease in crop plants. Many of these genes have now been found to
encode effectortriggered immunity (ETI) receptors, and we know that pathogens
can evolve to overcome these genes through loss or alteration of the effectors
that are recognized. The careful deployment of resistance genes in crop plants,
particularly by using multiple effective receptors in combination and by
selecting target effectors that have crucial virulence functions, should allow
more durable resistance.
Many nucleotidebinding (NB)leucinerich repeat (LRR) genes have now been
cloned, and this can facilitate their application in agriculture either through
conventional breeding approaches, in which the cloned sequences are used as
molecular markers, or through transgenic means. Widespread genome
sequencing of plant pathogens is now yielding long lists of effector proteins that
could be recognized by plant immune receptors, and these can now be screened
against wild relatives of crop plants to identify new sources of resistance. This
approach has been useful already in identifying new sources of resistance to the
potato blight pathogen Phytophthora infestans in wild potatoes120. Pathogen
associated molecular pattern (PAMP)triggered immunity (PTI) receptors are
typically not variable within species and thus have not contributed widely to
traditional breeding efforts. However, the transfer of these receptors among
species has tremendous potential to deliver durable resistance, as the recognition
components are highly conserved among pathogens. Although pathogens that
are adapted to a particular host plant may be adept at suppressing the pattern
recognition receptors (PRRs) of that host, their effectors might not recognize
PRRs from other host plants. For instance, the Arabidopsis thaliana EFTu receptor
occurs only in the Brassicaceae family, and transfer of this gene into tomato
provided good resistance against various bacterial pathogens121.

interactions may simply result from the higher signal

flux in ETI, and probably make this response more
robust against pathogen interference.
Despite, or perhaps because of, the number of gene
expression changes resulting from PTI and ETI activation, the key changes that result in prevention of
pathogen growth are not clear in any disease system.
Perhaps the many responses each have such minor
effects that individual contributions are difficult to
quantify, but it is also likely that different aspects of
the response are effective against different types
of pathogens. Some recent work is beginning to
unravel specific responses with significant effects on
pathogen invasion. For instance, the PEnETRATIOn 2
(PEn2) and PEn3 proteins of A. thaliana are involved
in preventing cellular penetration by powdery mildew
fungi108,109. PEn2 is a hydrolytic enzyme that produces a
glucosinylate compound from an inactive precursor and
PEn3 is an ABC transporter that seems to be involved
in secretion of this molecule at the site of fungal
attack110,111. Although these activities may have a direct
antimicrobial role, both proteins are also required for
the deposition of callose at the infection site and encasement of powdery mildew haustoria, suggesting a more
subtle regulatory role in blocking infection. The Lr34
gene of wheat, which has been widely used in agriculture
because it confers broad spectrum resistance against leaf
and stripe rust fungi as well as powdery mildew, was
also recently shown to encode an ABC transporter 112.
RPw8 in A. thaliana is another protein that provides
broad spectrum resistance to powdery mildew fungi. It
is targeted to a host-derived membrane that surrounds

the fungal infection structures and also acts to enhance

the callosic encasement of the fungal haustorium113.

Conclusions
The current synthesis of plantpathogen molecular
interactions provides a strong conceptual framework
for understanding how these organisms coexist. Plants
have evolved innate immune systems that recognize
the presence of potential pathogens and initiate effective defence responses, whereas successful pathogens
have evolved effector proteins that can suppress host
immune responses. Furthermore, effectors can themselves act as elicitors and can be disabled by the host.
Overall, the pathogenic niche is highly evolved and
carefully monitored by both participants.
Despite the advances in characterization of individual molecular interactions and their consequences, our
understanding of hostpathogen molecular co-evolution
is poorly developed. The dominant synthesis, as currently understood, invokes a molecular arms race.
However, this area is in fact relatively unexplored and
both hosts and pathogens have generally not evolved
rapid mechanisms to generate massive diversity in
pathogen elicitors or host receptors, respectively. It is
crucially important for the deployment of existing and
novel resistance genes in agriculture that we advance
our knowledge in this area to aid predictions of how
changes in selection parameters will affect the evolution
of pathogens, at both microscale and population levels.
This need for a better understanding of co-evolution is
particularly true for breakthrough technologies, such as
the deployment of new PAMP-recognition specificities
in crop species (BOX 2).
Moreover, there are many fundamental molecular
questions about which we are still ignorant, such as
what are the distinct and common signalling components of PTI and ETI? How are nB-lRR proteins activated by effector recognition? what are the induced
host components and compounds downstream of
pathogen perception that effect immunity? what are
the targets of effectors, and how does the deployment
of these effectors maximize the pathogenic niche? And
what are the effector delivery mechanisms of fungi
and oomycetes? widespread genome sequencing of
both host and pathogen genomes will facilitate the identification of effector proteins, the genome-wide analysis
of dynamic effector expression patterns and the identification, through proteomics and gene homology, of host
target proteins. The immediate technological impact of
next-generation sequencing will open up the study
of important non-model hostpathogen systems, such
as wheat rusts and the black sigatoka disease of banana.
One promising avenue is to exploit the diversity of
plant species to access useful pathogen receptors from
sexually incompatible host plants, which will expand
the resource of resistance genes that can be transferred
into agricultural species. However, filling in many of the
current gaps in knowledge will require the application
of biochemical, structural and cell biology approaches
to unravel the molecular events associated with receptor
activation and downstream signalling pathways.

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Acknowledgements

We apologize to those authors whose work could not be cited

owing to space limitations. J.P.R. is an Australian Research
Council Future Fellow. Work in P.N.D.s laboratory is funded
by the Australian Research Council, the US National Institutes
of Health and the Grains Research and Development
Corporation. We thank J. Ellis and B. Staskawicz for helpful
discussions.

Competing interests statement

The authors declare no competing financial interests.

DATABASES
TAIR: [Link]
RPS4 | RRS1
UniProtKB: [Link]
BAK1 | BIK1 | CERK1 | FLS2 | RIN4 | RPS2

FURTHER INFORMATION
Peter N. Dodds homepage:
[Link]
John P. Rathjens homepage:
[Link]
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