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PII: S1084-9521(16)30141-0
DOI: http://dx.doi.org/doi:10.1016/j.semcdb.2016.05.015
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Please cite this article as: French Elizabeth, Kim Bong-Suk, Iyer-Pascuzzi Anjali
S.Mechanisms of quantitative disease resistance in plants.Seminars in Cell and
Developmental Biology http://dx.doi.org/10.1016/j.semcdb.2016.05.015
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Mechanisms of quantitative disease resistance in plants
Elizabeth French, Bong-Suk Kim, and Anjali S. Iyer-Pascuzzi
Department of Botany and Plant Pathology, Purdue University, West Lafayette IN 47907
1
Abstract: Quantitative disease resistance (QDR) causes the reduction, but not absence, of
disease, and is a major type of disease resistance for many crop species. QDR results in a
continuous distribution of disease scores across a segregating population, and is typically due to
many genes with small effects. It may also be a source of durable resistance. The past decade has
seen significant progress in cloning genes underlying QDR. In this review, we focus on these
recently cloned genes and identify new themes of QDR emerging from these studies.
Keywords: Plant immunity, quantitative disease resistance, durable resistance, partial resistance,
spatio-temporal disease resistance, crop plants
2
1. Introduction
1.1 What is Quantitative Disease Resistance?
Plant disease resistance responses are complex and multilayered (reviewed in [1 -5]).
Historically, plant immunity has been divided broadly into two categories: incomplete resistance
provided by quantitative disease resistance (QDR) genes and complete resistance mediated by
resistance (R) proteins [1-3]. More recently, recognition of the role of microbial elicitors and
their host receptors led to the idea of microbial triggered immunity (MTI). The zig-zag model
of plant immunity accounts for the latter two categories, incorporating general pathogen elicitors,
their host receptors, and R-protein mediated resistance into a single model [4]. In this model, one
of the first lines of plant defense is recognition of microbial elicitors such as flagellin and chitin.
These Microbe Associated Molecular Patterns (MAMPs) are recognized by pattern recognition
receptors (PRR) at the cell surface that initiate a signaling cascade leading to generally weak
defense responses and MTI. Some pathogens can overcome this level of resistance by secreting
effector proteins that interfere with host metabolism and act to promote pathogen virulence.
Plants have evolved to recognize and defend themselves against such effectors; this immunity is
known as Effector-Triggered Immunity, or ETI, and typically leads to full resistance with no
disease symptoms. Plant proteins that recognize effectors are termed R proteins, and are
frequently in a class of proteins known as Nucleotide Binding Site Leucine Rich Receptors
(NBS-LRRs).
Although the zig-zag model has been extremely useful for thinking about two seemingly
separate parts of plant immunity - MTI and ETI - the model is limited largely to describing
interactions between hosts and biotrophic pathogens. It is less suitable for understanding host-
necrotrophic interactions, and does not (by design) account for the complexities of host-pathogen
interactions that lead to a wide range of host immune responses [5, 6]. The Invasion Model,
which describes plant immunity as a surveillance system that continually evolves to detect
microbial invasion, may be more useful for describing the nuanced layers of plant defense [6]. In
this model, plants recognize invasion patterns (IP) that are derived from microbes (such as
MAMPS or effectors) or endogenous elicitors that result from infection, such as Damage
Associated Molecular Patterns or DAMPs. IPs are recognized by IP triggered receptors
(IPTRs). MTI and ETI are viewed less as strictly contrasting responses and instead as continuous
immune outputs resulting from variation between different IPs and IPTRs.
Such a model accounts for Quantitative Disease Resistance (QDR). QDR has been
traditionally recognized but is less well understood than MTI or ETI [6-8]. QDR refers to host
plant resistance that leads to a reduction in disease, but not the absence of disease [1, 2, 7]. As a
quantitative trait, QDR is controlled by multiple genes that can interact with the environment and
with each other. Recent work has shown however, that the cumulative effects of pyramiding
many QDR loci can result in high levels of resistance [8-11]. Phenotypically, QDR exhibits a
continuous distribution of resistance values that do not fit Mendelian segregation ratios [1, 7].
This is in contrast to a qualitative trait, in which the variation is typically due to differences at
one locus, and the effects of different alleles at the locus are large relative to the environment.
An important point is that a resistance phenotype can vary within a population for reasons not
due to genes controlling QDR [7]. For example, varying levels of resistance within a population
could result from the effects of one gene with low heritability or low penetrance [7].
Alternatively, a host population may contain a series of R genes that each provides complete
resistance against one strain of a pathogen. However, when infected with a highly complex
3
pathogen population, such a host population may exhibit a continuous distribution of resistance
[7]. Genetic analyses must be used to determine if observed variable levels of resistance are due
to QDR. Additionally, care must be taken with the phenotyping approach used for such analyses,
as this may affect the outcome. For example, the use of a 5-point scale for disease severity could
potentially make a continuous distribution of disease severity appear to be discrete and may
result in errant conclusions.
Recent work suggests that QDR can result from quantitative variation in the components
of either MTI or ETI [1, 2], as well as through completely different mechanisms ([1, 2] and
references in this review). This fits within the framework of the Invasion Model, and supports
the idea of plant immunity as a continuum with quantitative variation in both pathogenic elicitors
and host responses leading to a spectrum from disease to resistance [6]. Consistent with this,
tolerance the hosts ability to withstand high pathogen load with limited disease symptoms or
fitness cost appears to be a component of QDR in several pathosystems, including Arabidopsis
R. solanacearum [12], and Arabidopsis Pseudomonas syringae [13].
The potential mechanisms underlying QDR have frequently been deliberated [1-3, 7, 14].
Recent years have seen a significant increase in the genes cloned that contribute to QDR. In this
review we focus on these genes and discuss new insights into the mechanisms of QDR gained
from their functions. Although QDR may result from the pathogens ability to suppress
immunity (effector triggered susceptibility, [15]), our focus here is not on susceptibility alleles,
but on plant genes that lead to QDR. For reviews and papers that highlight more historical
concepts of QDR, the reader is directed to [1, 7, 14, 16].
4
Finally, QDR is effective against a wide range of microbe classes bacteria, fungal, viral
and nematodes and against pathogens that infect different parts or different developmental
stages of the plant [1].
Cloning loci involved in QDR has proven challenging, in part because of the small effect
of many QDR loci and the difficulty in consistently phenotyping disease traits across a variety of
environments [1, 25]. However, there has been tremendous progress in the last few years in
cloning genes underlying quantitative disease resistance (Table 1). In this review, we discuss
potential mechanisms underlying QDR revealed from these recently cloned genes. Several new
themes are becoming apparent, including spatio-temporal resistance and the importance of
resistance gene expression. Additionally, new work has highlighted the importance of weak or
variant NBS-LRRs in QDR.
5
suggest that in resistant lines, induction of ZmWAK specifically in the mesocotyl results in
resistance signaling that reduces fungal infection [27]. It is intriguing to speculate how many
other genes underlying QDR result from such tightly controlled spatiotemporal gene expression.
6
2.2 QDR results from high expression levels of genes with roles in resistance: Rhg1 and RKS1
2.3.1 The ZmWAK gene for resistance to maize head smut, is discussed above and is one
example of WAKs that underlie QDR. An additional QTL encoding a wall-associated receptor
like kinase was recently cloned from maize [40]. Htn1 encodes ZmWAK-RLK1 and provides
quantitative resistance to the hemibiotrophic fungus Exserohilum turcicum, causal agent of
7
Northern Corn Leaf Blight (NCLB). Wall-associated receptor like kinases have an extracellular
elicitor binding receptor domain, a transmembrane domain, and an intracellular kinase signaling
domain. Sequencing of the resistant allele from maize cultivar RP1Htn1 and the susceptible
allele from cultivar RP1 revealed few amino acid changes in the kinase domain of the predicted
protein, which was over 98% identical between the resistant and susceptible parents. In contrast,
the extracellular domain was extremely divergent, with 46 amino acid changes, 19 amino acid
deletions, and 2 amino acid insertions in the predicted sequence of the susceptible protein
compared to the resistant. This resulted in less than 80% sequence identity in the extracellular
domain of the resistant and susceptible predicted proteins. In maize reference line B73, the
closest homolog to Htn1 was well conserved in the kinase domain but again shared only weak
conservation with Htn1 in the extracellular domain, while the rice homolog had 83% identity in
the kinase domain but only 49% in the extracellular domain. Pathogen infection did not induce
expression of Htn1 in either the resistant or susceptible parent. These data indicate that Htn1
mediated resistance is likely due to differences in the extracellular domain of the protein [40].
2.3.2 RFO/WAKL22
In a study to find QTL for disease resistance to Fusarium oxysporum in Arabidopsis,
Ausubel and Diener (2005) [41] found six loci. The major QTL RFO1 was found to encode a
protein identical to WAKL22, a wall-associated kinase-like protein containing an RLK domain
structurally similar to other identified R proteins Xa21 and Xa26 in rice. RFO1/WAKL22
provided stronger resistance when RFO2, RFO4 or RFO6 loci were present, suggesting an
interactive effect that may result from increases in gene expression of RFO1/WAKL22.
The diversity and prevalence of wall associated receptor-like kinases in monocots,
combined with the recent findings that they underlie three resistance QTL to different fungal
pathogens (ZmWAK, Htn1, RFO) suggests the possibility that they may be a common mechanism
underlying QDR.
This idea is intriguing considering that another wall associated kinase, Arabidopsis
WAK1, was recently shown to be a receptor for oligogalacturonides, which are DAMPs resulting
from the breakdown of the pectin polysaccharide homogalacturonan [42]. DAMPs are
endogenous danger signals caused by damaged cells or tissues. Recognition of these
endogenous invasion patterns by host receptors leads to plant perception of self-damage, and
provokes an immune response. However, whether WAK1 or other DAMP receptors such as
DORN1, a kinase that recognizes extracellular ATP [43], are components of QDR, remains to be
established.
8
syringae secreting the effector AvrRps4 [47-49] the soil-borne pathogen Ralstonia solanacearum
secreting the effector PopP2 [47-49], and is involved in resistance to the fungal pathogen
Colletotrichum higginsianum [47]. Since RPS4 acts in tandem with RRS1, the authors tested
whether single rps4 or rrs1 mutants, or the double rps4 rrs1 mutant, showed increased
susceptibility to Xcc. All three mutants showed increased bacterial colonization and disease
lesion index after inoculation with strains of race 6 Xcc, but not other races, suggesting that the
RRS1/RPS4 gene pair may function in QDR to Xcc [46].
Interestingly, RRS1 PopP2 interaction is required for tolerance to strain BCCF402 of R.
solanacearum in ecotype Kil-0 of Arabidopsis [12]. The Kil-0 ecotype allows high levels of
pathogen colonization without bacterial wilt symptoms, consistent with the idea that pathogen
tolerance represents another facet of QDR. It is currently unclear whether RPS4 functions in
tolerance in the R. solanacearum-Kil-0 pathosystem.
Increasingly, it appears that QDR spans a wide range of mechanisms. For example, the
same gene(s) may contribute to both QDR and ETI, possibly dependent on genetic background
of both host and pathogen strain. For example, in the R. solanacearum- Arabidopsis interaction,
ETI to R. solanacearum strain GMI1000 is found in the Arabidopsis accession Nd-1, but
tolerance is observed in the Kil-0 ecotype to a different R. solanacearum strain. Although not
part of a R gene pair, the R gene RPM1 also has a role in both tolerance and ETI (Roux et al.
2010), with host genetic background and initial inoculum density influencing the defense
outcome.
2.4.2. Poly-allelic variation at R gene loci underlying QDR: Pi35 and durable resistance
The rice Magnaporthe oryzae pathosystem has provided multiple insights into
quantitative disease resistance. M. orzyae is the causal agent of rice blast, and more than 90
genes from a wide range of rice cultivars have been implicated in either qualitative, gene-for-
gene resistance or QDR. Nearly all of the race-specific, gene-for-gene blast R genes encode
NBS-LRRs, but typical for QDR, blast resistance genes underlying this phenomenon appear to
be different. The Pi35 QTL for blast resistance has been used in Japan since the early 1960s, and
has been a durable source of blast resistance [45]. Recent work by Fukuoka et al. (2014) [45]
showed that Pi35 encodes a different allele of Pish, a NBS-LRR gene that had already been
implicated in race-specific qualitative resistance to blast. Unlike Pish, which causes an HR-
induced resistance to the M. oryzae isolate Kyu77-07A, the Pi35 allele provides moderate levels
of resistance against multiple races of M. oryzae, and results in smaller lesion size, but does not
cause a HR [45]. The genomic sequences of Pish and Pi35 differ both in the NBS and LRR
domain. Chimeric proteins with the NBS and LRR domains from either Pish or Pi35 (NBS/Pish
LRR/Pi35 or NBS/Pi35-LRR/Pish), showed that much of the functional difference between Pish
and Pi35 is due to changes in the LRR region of the encoded protein. The chimeric protein
NBS/Pi35-LRR/Pish lost the QTL-mediated resistance of the wild-type Pi35 protein, and had
similar susceptibility to a virulent isolate as the wild-type Pish protein. Thus the difference
between race-specific, qualitative resistance and QTL-mediated resistance was due to differences
in two alleles at the same locus [45]. This work demonstrates that allelic differences at the same
locus can be responsible for two different types of resistance phenomena and shows the close
linkage of gene-for-gene and quantitative disease resistance.
2.4.3. The defeated or Weak R gene: Xa4 and bacterial blight of rice
9
The concept of the defeated R gene, in which the resistance provided by an R gene has
been overcome by a new strain of its respective pathogen, but the gene continues to provide a
reduced level of resistance against the pathogen, has frequently been considered as a basis for
QDR [1]. One example of a defeated R gene is the rice bacterial blight disease resistance gene
Xa4. In a study to examine the genetic components of resistance to multiple strains of
Xanthomonas oryzae pv. oryzae (Xoo), Li et al., (1999) [44] screened a RIL population in which
one of the parents contained the dominant Xa4 allele, a well-characterized R gene that had been
overcome by the CR6 Xoo strain with a mutant avrXa4 locus. The group found a number of
QDR loci against the strains studied; most interestingly that against the CR6 strain, Xa4 acts as a
recessive QDR locus. As a QTL, Xa4 provides about 50% of the level of resistance that it
provided as a major R gene. Many of the QTL discovered in this study map to similar locations
as known dominant R genes. Additional defeated R genes that may contribute to QDR include
those in the wheat powdery mildew [50] and wheat - stem rust pathosystems [51]. Together,
these results suggest that some QTL for QDR may be the same genes as major dominant R
genes, but encode a weaker allele that leads to residual resistance [44].
10
allele and the recessive pi21 allele is a loss-of-function mutation. Of the 12 different haplotypes
observed at the Pi21 locus in a variety of rice cultivars, only that with a large deletion in the
proline consensus motif (PxxPxxP) was resistant. Since this motif is part of the protein-protein
interaction domain, it is tempting to speculate that perhaps the loss of this domain renders the
resistant protein unable to interact with a pathogen virulence factor, leading to resistance [19].
2.7.1 Rhg4: Supporting a role for primary metabolism in QDR, the soybean Rhg4 gene
underlying QDR to the soybean nematode (Heterodera glycines) pathogen encodes a serine
hydroxymethyltransferase (SHMT) [60]. SHMT enzymes play major roles in folate-dependent
one-carbon (C1) metabolism [61] and are well conserved across biological kingdoms [62]. C1
metabolism is crucial to organisms, as it involves the generation, interconversion and transfer of
C1 groups [62, 63]. SHMT catalyzes the reversible reaction of serine and tetrahydrofolate (THF)
to glycine and 5,10-methylene THF, and is a major entry point for folate-dependent metabolism
[62, 63]. One-carbon metabolism is important for the development of nematode feeding cells
(syncytia) in plant roots [64, 65], and thus disturbing folate metabolism may lead to detrimental
effects on nematode life cycle. Five nucleotide differences were identified in the genomic
sequences from the resistant and susceptible lines used for map-based cloning of Rhg4. Two of
these resulted in an amino acid change. The SHMT enzyme from each of the resistant and
susceptible parents was able to complement an E. coli glycine auxotroph, suggesting that both
are functional as SHMT enzymes. Although it is not clear exactly how the amino acid change
leads to resistance, kinetic studies showed that the resistant and susceptible SHMT proteins have
different kinetic properties. This may result in an altered or new function in planta that leads to
resistance [60].
In addition to Rhg4, several studies have shown that camalexin, a secondary metabolite
derived from tryptophan, has a major role in QDR against multiple pathogens in Arabidopsis [66
- 69].
11
resistance gene. Given that spatio-temporal resistance gene expression is one mechanism of
QDR, this is an interesting hypothesis for further investigation.
Recently, Fukuoka et al. 2015 [8], methodically tested the blast resistance provided by
four independent QTL in rice by introgressing different combinations of these QTL into the same
genetic background. They show that multiple, different QTL combinations within the same
genetic background provide increased levels of resistance compared to any individual QTL
alone, and that there is a positive correlation between the amount of resistance QTL in a given
genetic background and resistance levels. Rice lines containing four Blast resistance QTL allow
M. oryzae penetration into rice cells, but do not allow further fungal development. The authors
speculate that this may reduce selection pressure on the pathogen, and may ultimately lead to
longer-lasting durable resistance.
4. Conclusions
The recent cloning of several genes underlying QDR has made it clear that many different types
of genes and mechanisms lead to QDR. Indeed, QDR fits well within the idea of plant immunity
as a monitoring system to detect many different invasion patterns that can lead to a range of
defense phenotypes [6]. The cloned genes underlying QDR now offer the prospect to investigate
the relationship between QDR and other types of resistance. For example, several recently
cloned QDR loci have been effective in the field for decades, providing the opportunity to dissect
durable resistance and its relationship to QDR. Given the wide range of genes controlling QDR
among them kinases, metabolic enzymes, transporters, and altered NBS-LRRs, it is likely that as
additional genes underlying QDR are cloned, new mechanisms will become apparent. The
valuable insights gained from these studies will enhance our ability to effectively use
quantitative disease resistance in crop improvement.
Acknowledgements
Our work is supported by Purdue Universitys Center for Global Food Security, and Purdue
University start-up funds. EF is supported by a NSF Graduate Research Fellowship, grant
number DGE-1333468.
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Rhg1 copy number Heterodera cyst soybean [34]
variation for an glycines nematode
amino acid
transporter, an -
SNAP protein,
and a wound-
inducible protein
Pi35 NBS-LRR Magnaporthe rice blast rice [40]
oryzae
RPS4/RRS1 R gene pair: Xanthomonas black rot Arabidopsis [41]
NBS-LRR and campestris pv. disease
NBS-LRR- campestris
WRKY
18