Genetic engineering, including genome editing, for enhancing broad-spectrum disease resistance in crops

Xinyu Han; Shumin Li; Qingdong Zeng; Peng Sun; Dousheng Wu; Jianguo Wu; Xiao Yu; Zhibing Lai; Ricky J Milne; Zhensheng Kang; Kabin Xie; Guotian Li

doi:10.1016/j.xplc.2024.101195

. 2024 Nov 20;6(2):101195. doi: 10.1016/j.xplc.2024.101195

Genetic engineering, including genome editing, for enhancing broad-spectrum disease resistance in crops

Xinyu Han ^1,⁸, Shumin Li ^2,⁸, Qingdong Zeng ^3,⁸, Peng Sun ¹, Dousheng Wu ⁴, Jianguo Wu ⁵, Xiao Yu ⁶, Zhibing Lai ², Ricky J Milne ⁷, Zhensheng Kang ³, Kabin Xie ^2,^∗, Guotian Li ^1,^∗∗

PMCID: PMC11897464 PMID: 39568207

Abstract

Plant diseases, caused by a wide range of pathogens, severely reduce crop yield and quality, posing a significant threat to global food security. Developing broad-spectrum resistance (BSR) in crops is a key strategy for controlling crop diseases and ensuring sustainable crop production. Cloning disease-resistance (R) genes and understanding their underlying molecular mechanisms provide new genetic resources and strategies for crop breeding. Novel genetic engineering and genome editing tools have accelerated the study and engineering of BSR genes in crops, which is the primary focus of this review. We first summarize recent advances in understanding the plant immune system, followed by an examination of the molecular mechanisms underlying BSR in crops. Finally, we highlight diverse strategies employed to achieve BSR, including gene stacking to combine multiple R genes, multiplexed genome editing of susceptibility genes and promoter regions of executor R genes, editing cis-regulatory elements to fine-tune gene expression, RNA interference, saturation mutagenesis, and precise genomic insertions. The genetic studies and engineering of BSR are accelerating the breeding of disease-resistant cultivars, contributing to crop improvement and enhancing global food security.

Key words: genetic engineering, genome editing, broad-spectrum resistance, knock-in, Oryza sativa, Triticum aestivum

Genetic engineering, particularly genome editing technologies, facilitates the study and engineering of broad-spectrum disease resistance (BSR) in crops. This review summarizes recent advances in understanding the plant immune system and crop BSR mechanisms. It also highlights diverse strategies employed to achieve BSR, while discussing technological innovations and their future prospects for enhancing BSR.

Introduction

The global population is projected to increase from the current 8.0 billion to 9.7 billion by 2050, potentially peaking at nearly 10.4 billion in the mid-2080s (United Nations Population Division, 2022). As world population growth continues, it is estimated that total global crop yield must increase by 35%–56% between 2010 and 2050 to meet this rising demand (Springmann et al., 2018; van Dijk et al., 2021). However, crop yields are severely threatened by various biotic factors, including devastating diseases. Two globally distributed crop diseases, rice blast and wheat stripe rust, caused by the fungal pathogens Magnaporthe oryzae and Puccinia striiformis f. sp. tritici, respectively, lead to annual grain yield losses of 20%–30% for rice and 10%–30% for wheat (Li et al., 2019; Stukenbrock and Gurr, 2023). Developing disease-resistant crops is crucial for achieving environmentally friendly control of these diseases. However, due to the dynamic evolution of pathogen populations and the consistent emergence of new pathogen strains, crop disease resistance (R) genes can become ineffective within a few years of deployment, resulting in significant crop losses over time (Zhao et al., 2024). Therefore, broad-spectrum resistance (BSR) genes, which can confer resistance to multiple strains of the same pathogen or various pathogen species, are critical for safeguarding global food security.

Disease resistance in plants is conferred by R genes, integral components of the plant immune system. The plant immune system consists of both membrane-localized and cytoplasmic receptors that perceive pathogen invasion. Upon pathogen recognition, the plant immune system can initiate robust immune responses through pattern-triggered, effector-triggered, or atypical immune pathways (Figure 1). Researchers have utilized a variety of technologies and tools to clone and study R genes mechanistically, thereby deepening our understanding of the plant immune system. Concurrently, breeders employ techniques such as gene pyramiding and genetic engineering, including genome editing, to develop durable and broad-spectrum disease resistance in crops. Recent advancements in genome editing technologies have significantly empowered both these processes.

In this review, we briefly describe the current understanding of the plant immune system and highlight recent advances in crop BSR studies. We then provide a comprehensive summary of various strategies to achieve BSR, ranging from traditional genetic engineering to newer genome editing technologies like gene knock-in, which facilitate precise genetic and epigenetic modifications. Finally, we offer insights into technological innovations, such as R protein design, and their potential applications for BSR in crops.

The plant immune system

Pattern-triggered immunity

During their long-term coevolution with pathogens, plants have developed a dual-layered innate immune system, which includes pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) (Jones et al., 2024). PTI, often referred to as basal immunity, is activated when conserved pathogen-associated molecular patterns (PAMPs) or microbe-associated molecular patterns are recognized by plasma membrane-localized pattern recognition receptors (PRRs), such as receptor-like kinases (RLKs) and receptor-like proteins (RLPs) (DeFalco and Zipfel, 2021; Ngou et al., 2021). This recognition triggers a phosphorylation relay involving receptor-like cytoplasmic protein kinases (RLCKs), leading to a series of defense responses. These responses include Ca²⁺ influx, reactive oxygen species (ROS) burst, activation of mitogen-activated protein kinases (MAPKs), deposition of callose, and transcriptional reprogramming of defense genes, effectively combating a broad spectrum of pathogens. For instance, during bacterial PTI in Arabidopsis thaliana (hereafter referred to as Arabidopsis), the bacterial flagellin epitope flg22 is recognized by the leucine-rich repeat (LRR) receptor kinase flagellin-sensing 2 (FLS2). This recognition stimulates the formation of a receptor complex with brassinosteroid insensitive 1 (BRI1)-associated receptor kinase 1 (BAK1), thereby activating botrytis-induced kinase 1 (BIK1), an RLCK. This complex initiates downstream defense signaling pathways and responses, including MAPK cascades and ROS bursts. In response to the PAMP chitin, the rice chitin elicitor receptor kinase OsCERK1, a lysin motif RLK, perceives but does not directly bind to chitin. Instead, chitin binding triggers interaction between the chitin elicitor binding protein (OsCEBiP) dimer and OsCERK1 to form a receptor complex. This interaction leads to the homodimerization and phosphorylation of OsCERK1, subsequently activating rice immune responses (Yang et al., 2022a). In addition to detecting “non-self” PAMPs, plants can also recognize “self” danger signals known as damage-associated molecular patterns (DAMPs), which induce danger-triggered immunity (DTI) (Zhou and Zhang, 2020). DTI is analogous to PTI, leading to the activation of similar plant immune responses. In Arabidopsis, plant elicitor peptides (Peps), a family of DAMPs, are recognized by two receptors, plant endogenous peptide 1 (PEP1) receptors 1 and 2 (PEPR1/2). Following this recognition, PEPR1 and its co-receptor BAK1 interact with BIK1 and PBS1-like 1 (PBL1) to directly phosphorylate BIK1, thereby initiating immune responses through synergistic ethylene (ET) and PEPR signaling pathways (Jing et al., 2023). Arabidopsis Pep1 (AtPep1) confers BSR to bacterial speck caused by the bacterial pathogen Pseudomonas syringae pv. tomato DC3000, gray mold caused by the fungal pathogen Botrytis cinerea, and Arabidopsis late blight caused by the oomycete Phytophthora infestans (Huffaker et al., 2006). In maize, Zea mays Pep 1 (ZmPep1), a homolog of AtPep1, enhances resistance to southern leaf blight and anthracnose (Huffaker et al., 2011).

Effector-triggered immunity

In ETI, nucleotide-binding LRR receptors (NLRs) bind directly or indirectly to pathogen-secreted effectors within plant cells, marking the initiation of robust immune responses. This response is often characterized by a hypersensitive response (HR), featuring localized cell death (Remick et al., 2023). Plant NLRs are classified into three types based on their N-terminal domains: coiled-coil (CC) NLRs, Toll/interleukin-1 receptor (TIR) NLRs, and resistance to powdery mildew 8 (RPW8)-NLRs (CNLs, TNLs, and RPW8-NBS-LRR [RNLs], respectively) (Jubic et al., 2019). In Arabidopsis, the RPW8 domain, which contains a putative N-terminal transmembrane domain and a CC motif, is encoded by two dominant R genes, RPW8.1 and RPW8.2, conferring BSR to powdery mildew (Zhao et al., 2023). CNLs and TNLs, also known as sensor NLRs, recognize pathogen effectors and trigger ETI, while RNLs function as helper NLRs that operate downstream of TNLs in TNL-mediated immunity (Jacob et al., 2021). The discovery of resistosomes—structures formed by NLR proteins in vitro that trigger immune responses and cell death—has significantly advanced our understanding of plant immunity. For example, upon recognition of the effector AvrAC from the black rot bacterial pathogen Xanthomonas campestris pv. campestris, the Arabidopsis CNL ZAR1 is activated and forms a pentameric ring complex on the plant cell membrane, known as the ZAR1 resistosome (Wang et al., 2019). This resistosome functions as a Ca²⁺-permeable channel, facilitating Ca²⁺ influx and leading to cell death during HR (Bi et al., 2021). Unlike the indirect recognition of AvrAC by ZAR1, the CNL Sr35 in wheat, derived from the local variety Triticum urartu, directly recognizes the effector AvrSr35 from the stem rust fungus Puccinia graminis f. sp. tritici and assembles into a pentameric resistosome following allosteric activation. This activation occurs when the N-terminal CC domain of Sr35 interacts with its central nucleotide-binding oligomerization domain (Salcedo et al., 2017). The Sr35 resistosome also forms a Ca²⁺-permeable channel in the plasma membrane, facilitating Ca²⁺ influx and leading to localized cell death at the infection sites (Förderer et al., 2022). Similarly, the Arabidopsis CNL RPS2 recognizes the effector AvrRpt2 from P. syringae, inducing Ca²⁺ influx and triggering HR (Yuan et al., 2021). In rice, the CNL pair RGA4/RGA5 recognizes AvrPia and AvrCO39 from M. oryzae and mediates resistance to rice blast. PigmR, another CNL protein in rice, interacts with PigmR-INTERACTING and BLAST RESISTANCE PROTEIN 1 (PIBP1) through the CC domain. This interaction promotes the nuclear accumulation of PIBP1, which binds to the promoter of the defense-related (DR) genes OsWAK14 and OsPAL1, thereby inducing robust blast resistance but reducing rice yield (Zhai et al., 2019). Conversely, PigmS in rice disrupts the homodimerization of PigmR, balancing resistance and yield (Deng et al., 2017). In maize, the typical CNL protein Rp1-D confers resistance to common rust (Liu et al., 2021b). Rp1-D21, generated by recombination of two NLRs encoded by genes Rp1-dp2 and Rp1-D, triggers HR in Nicotiana benthamiana when expressed transiently alone or with its CC domain (Luan et al., 2021). MLA1 encodes a CNL that is homologous to a protein with dual functionality, conferring resistance to powdery mildew in barley and stripe rust in wheat (Jordan et al., 2011).

Compared to CNLs, the N-terminal TIR domain of TNLs exhibits nicotinamide adenine dinucleotide (NAD) hydrolase activity (Ma et al., 2020; Jia et al., 2022). TIR domain proteins catalyze the ADP ribosylation of ATP and adenosine diphosphate ribose (ADPR) to activate two distinct immune signaling pathways: enhanced disease susceptibility 1 (EDS1) - phytoalexin deficient 4 (PAD4) in conjunction with helper NLR-activated disease resistance 1 (ADR1) and EDS1 - senescence-associated gene 101 (SAG101) alongside another helper NLR N requirement gene, 1 (NRG1). Upon activation, NRG1, similar to CNL resistosomes, oligomerizes into Ca²⁺-permeable channels, leading to cell death (Huang et al., 2022). In Arabidopsis, the TNL RPP1 directly binds to the effector ATR1 of the downy mildew pathogen Hyaloperonospora arabidopsidis, forming a tetrameric resistosome. This assembly significantly enhances the nicotinamide adenine dinucleotide hydrolysis activity of RPP1. The nucleotide-binding oligomerization domain of RPP1 binds to ADP, triggering EDS1-dependent ETI (Martin et al., 2020; Duxbury et al., 2021). Additionally, TIR-only proteins, which lack the C-terminal effector-sensing domains, employ conserved signaling pathways similar to those of TNLs. For example, the transient expression of TIR-only proteins in Nicotiana benthamiana triggers nicotinamide adenine dinucleotide glycohydrolase-dependent cell death (Song et al., 2024). In Arabidopsis, the TIR-only protein RBA1 recognizes the effector HopBA1 from Pseudomonas fluorescens to induce EDS1-dependent ETI (Nishimura et al., 2017). Structural analyses of these R proteins and their biochemical mechanisms provide novel insights into the engineering of R proteins. However, the complete molecular events activated by these signaling molecules remain to be fully elucidated.

Atypical R genes

Atypical R genes are defined as immunity genes that do not encode traditional immune receptors but often exhibit durable BSR (Sun et al., 2024b). The first class of atypical R genes includes executor and executor-like R genes, which are direct targets of transcription activator-like (TAL) effectors. These effectors, a class of type III effectors predominantly secreted by Xanthomonas, trigger HR through TAL effector-dependent transcriptional activation of executor R genes (Boch and Bonas, 2010). For example, Xa23, an executor R gene cloned from wild rice (Oryza rufipogon), is activated by AvrXa23 of Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of rice bacterial blight, conferring robust BSR to bacterial blight (Wang et al., 2015). Similar transcriptional activation-mediated resistance has been observed in other executor-like R genes. WeiTsing is specifically induced in the pericycle upon infection by the protist Plasmodiophora brassicae and mediates the formation of a pentameric ion channel that releases Ca²⁺ from the endoplasmic reticulum (ER) into the cytoplasm, activating a series of immune responses and conferring clubroot resistance in Brassica napus (Wang et al., 2023). The barley executor-like R gene Rph3 is induced by Rph3-avirulent Puccinia hordei strains and confers resistance to leaf rust (Dinh et al., 2022). The pepper executor R gene Bs3, a flavin monooxygenase, is involved in the flavin adenine dinucleotide- and nicotinamide adenine dinucleotide phosphate-dependent oxidation reaction that confers resistance to bacterial spot disease (Romer et al., 2007). These atypical R gene-mediated signaling pathways are associated with both PTI and ETI, featuring reactions such as ROS burst, Ca²⁺ influx, and HR. However, some atypical R genes are involved in cellular processes that do not clearly align with PTI or ETI. For example, mycotoxin-degrading enzymes confer resistance to fungal pathogens. Notably, Fhb7 in wheat encodes a glutathione S-transferase that catalyzes the breakdown of the mycotoxin (deoxynivalenol), resulting in resistance to Fusarium head blight (Wang et al., 2020a). Atypical R genes also encompass mutations in disease-susceptibility (S) genes or DNA elements. Arguably the most well-known atypical R gene, MLO, is a pleiotropic gene that affects both plant senescence and yield while functioning as a susceptibility factor to powdery mildew (Buschges et al., 1997). Initially cloned in barley, mlo orthologs have been identified in various crops, including wheat, rice, tomato, pea, cucumber, and grape, enhancing resistance to powdery mildew (Appiano et al., 2015; Kusch and Panstruga, 2017). Finally, TAL effectors from Xoo bind to effector binding elements (EBEs) in the promoter of some S genes, such as SWEETs, facilitating pathogen infection. When an EBE is mutated, TAL effectors cannot bind to these mutated EBEs, and the plant lines harboring these mutated EBEs exhibit BSR to bacterial blight (Nowack et al., 2022).

Unified plant immunity

Despite the distinct pathogen recognition mechanisms and immune signaling pathways of PTI and ETI, these systems synergistically enhance plant immunity. In Arabidopsis, Yuan et al. (2021) observed that ETI enhances the transcription and protein levels of RBOHD, while PTI specifically activates its phosphorylation. Additionally, Ngou et al. (2021) revealed that ETI can respond to PTI by robustly activating and prolonging the phosphorylation of key immune proteins, including BIK1, RBOHD, and MPK3. In rice, Zhai et al. (2022) demonstrated the critical role of the deubiquitinase PigmR-interacting and chitin-induced protein 1 (PICI1) in both PTI and ETI. Pathogen-secreted toxic effectors directly target and degrade PICI1, suppressing PTI. Conversely, PigmR competitively inhibits the interaction between pathogen effectors and PICI1, stabilizing PICI1 by reducing the ubiquitination level of methionine synthase, which activates the ET pathway and thus stimulates robust ETI (Zhai et al., 2022). Furthermore, signals from PTI, DTI, and ETI interact with one another (Saijo et al., 2018; Ge et al., 2022). The LRR-RLK protein BAK TO LIFE 2 (BTL2) interacts with the DAMP receptors PEPR1/2 and male discoverer 1-interacting RLK2 (MIK2) upon the perception of Peps and serine-rich endogenous peptides, respectively. This interaction hyperactivates DTI when sensing BAK1 damage, initiating robust immune responses through the EDS1-PAD4-ADR1 signaling pathway, leading to cell death and compensating for compromised PTI (Yu et al., 2023). This unified view of plant immunity provides unique insights into BSR and facilitates the development of novel BSR engineering strategies.

Phytohormones

Phytohormones are small endogenous signaling molecules, some of which play crucial roles in plant defense responses, such as salicylic acid (SA), ET, and jasmonate (JA) (Fabregas and Fernie, 2021). SA is known to trigger systemic acquired resistance (SAR) in Arabidopsis, with NPR1 acting as a master regulator of SA-induced defense responses. A recent discovery shows that the mobile signal hydrogen peroxide (H₂O₂) sulfenylates the transcription factor CHE, which then binds to the promoter of the SA-biosynthesis gene ICS1, thereby promoting SAR (Cao et al., 2024). Loss of function mutations in ICS causes increased susceptibility to Fusarium head blight in wheat by reducing SA accumulation (Zhang et al., 2024c). JA, a lipid-derived phytohormone, positively regulates plant immunity against necrotrophic pathogens (Kumar et al., 2024). For example, GausRVE2, a Myb-like transcription factor, enhances resistance to Verticillium wilt in cotton by promoting the JA signaling pathway (Liu et al., 2023). In sweet potato, the overexpression of the B-box (BBX) transcription factor IbBBX24 enhances resistance to Fusarium wilt by boosting JA signaling (Zhang et al., 2020). ET, a gaseous phytohormone, often acts synergistically with JA to enhance resistance to pathogen invasions. For instance, OsEIL1, a master regulator of the ET signaling pathway in rice, binds directly to the promoters of the nicotinamide adenine dinucleotide phosphate oxidase gene OsRBOH and the JA biosynthesis gene OsOPR4, activating their expression. This activation facilitates the accumulation of ROS and phytoalexins, thereby enhancing disease resistance to rice blast (Yang et al., 2017a). Overexpression of the transcription factor NF-YC15 improves resistance to cassava bacterial blight via the ET-mediated immunity pathway (Zheng et al., 2024). The interaction among SA, JA, and ET forms a complex network that mediates resistance to various plant pathogens. Typically, SA and ET/JA-mediated responses antagonistically contribute to resistance against pathogens. In Arabidopsis, infection with the biotrophic pathogen P. syringae induces an SA-mediated immune response, which increases susceptibility to the necrotrophic pathogen Alternaria brassicae by inhibiting the JA/ET signaling pathway (Spoel et al., 2007). In rice, Meng et al. (2020) identified a nucleus-localized basic-helix-loop-helix transcription activator, OsbHLH6, which decreases rice blast disease resistance by activating JA signaling and suppressing the SA signaling pathway in the early stages of infection (before 24 h). However, at later infection stages (after 24 h), OsNPR1-induced export of OsbHLH6 from the nucleus to the cytosol substantially suppresses OsbHLH6-mediated activation of JA signaling but activates SA signaling, thereby conferring resistance to rice blast (Meng et al., 2020). Despite the well-established mutual inhibition between SA and JA, their relationship is not always antagonistic. OsEIL2, a positive regulator of the rice ET signaling pathway, regulates SA- and JA-mediated synergistic pathways. When induced by necrotrophs, OsEIL2 enhances resistance to Rhizoctonia solani through the accumulation of SA and JA. Conversely, during infections by the hemibiotroph M. oryzae and the biotroph Xoo, induced OsEIL2 reduces resistance to these pathogens by decreasing SA and JA levels (Zhao et al., 2024). Additionally, Wang et al. (2024a) demonstrated that introducing two healthy rhizosphere biomarkers, Sphingomonas azotifigens and Rhizobium deserti, into the rhizosphere confers resistance to wheat yellow mosaic virus (WYMV) by simultaneously activating SA and JA signaling pathways during infection. Furthermore, Li et al. (2023a) developed dual-inducible promoters by combining SA- and JA-responsive ciselements to drive the expression of antimicrobial peptides, enhancing BSR against powdery mildew in tobacco, early blight in tomato, and Verticillium wilt and Fusarium wilt in cotton.

Antimicrobial peptides and phytoalexins

Additionally, plants produce a diverse array of metabolites, including phytoalexins and antimicrobial peptides (AMPs), which play crucial roles in suppressing pathogen infections through their antimicrobial activities. In Arabidopsis, camalexin, an indolic compound derived from tryptophan metabolism, is pivotal in resistance to diseases such as gray mold (Zhou et al., 2020a). The regulation of camalexin-mediated disease resistance is synergistically influenced by ET and JA signaling pathways, facilitated by interactions between the ET response factor 1 (ERF1) and WRKY33 transcription factor in Arabidopsis (Zhou et al., 2022a). In rice, resistance to rice blast is mediated by a hydroxycinnamoylputrescine biosynthesis gene cluster, which includes a decarboxylase gene (OsODC) and two putrescine hydroxycinnamoyl acyltransferase genes (OsPHT3 and OsPHT4), leading to the accumulation of hydroxycinnamoylputrescine (Fang et al., 2021). Similarly, Shen et al. (2021) identified a hydroxycinnamoyl tyramine gene cluster that contains a pyridoxamine 5′-phosphate oxidase gene (OsPDX3), a pyridoxal phosphate-dependent tyrosine decarboxylase gene (OsTyDC1), and two duplicated hydroxycinnamoyl transferase genes (OsTHT1 and OsTHT2). The end products of this cluster enhance resistance to both rice blast and bacterial blight (Shen et al., 2021). In maize, ZmCCoAOMT2 encodes a caffeoyl-coenzyme A (CoA) O-methyltransferase that confers quantitative resistance to both southern leaf blight and gray leaf spot. This resistance is achieved through graded levels of metabolites synthesized in the phenylpropanoid and lipoxygenase pathways (Yang et al., 2017b). In oat, avenacins are antifungal metabolites biosynthesized by a gene cluster located in the subtelomeric region of the genome. These compounds are particularly effective against soil-borne diseases, such as take-all, providing significant protection (Li et al., 2021c). AMPs also play a crucial role in regulating several signaling pathways that enhance resistance to biotic stresses (Ghosh and Roychoudhury, 2024). Similar to phytoalexins, AMPs confer resistance against various plant pathogens. For example, the expression of defensin Mj-AMP1 from Mirabilis jalapa enhances resistance to early blight in tomato (Schaefer et al., 2005). Similarly, the overexpression of hevein-like proteins, antifungal peptides Pn-AMPs from seeds of morning glory, provides protection against crown and root rot in tobacco (Lee et al., 2003).

Current understanding of BSR mechanisms in crops

The development of disease-resistant crops has been a major focus of both researchers and breeders (Deng et al., 2020). Understanding the molecular mechanisms underlying BSR opens new avenues for crop improvement. Most known plant resistance genes encode race-specific NLRs, which are generally susceptible to evasion by rapidly evolving pathogens. Therefore, genes that confer BSR are particularly valuable as they often provide durable resistance against multiple pathogens. Here, crop BSR genes are classified into three categories: positive regulators of plant immunity, negative regulators of immunity represented by deletions or variants of S genes and lesion-mimic mutant (LMM) genes, and stacks of multiple R genes (Figure 2). BSR genes have been identified across a variety of crops, providing resistance to a diverse array of pathogens. A summary of notable BSR genes is presented in Table 1.

An overview of scenarios conferring BSR in crops

**(A)** A single R gene can confer broad-spectrum resistance (BSR) to multiple strains of the same pathogen or to multiple different pathogens in crops (left). In this example, the rice MYB transcription repressor (MYBS1) binds to the *bsr-d1* promoter and reduces the expression of *Bsr-d1*, which is induced by the rice blast fungus *M. oryzae*. This reduction in *Bsr-d1* expression decreases the transcription of peroxidase-encoding genes and attenuates hydrogen peroxide (H₂O₂) degradation, leading to H₂O₂ accumulation and conferring BSR to rice blast. Different alleles of R genes can sometimes confer BSR, offering insights into strategies for broadening the resistance spectrum of R genes (right). For example, in wheat, different alleles of the wheat powdery mildew R gene *Pm4* recognize various alleles of the *AVR-Rmg8* effector, and some *Pm4* alleles can confer resistance to wheat blast.

**(B)** Some plant pathogens secrete transcription activator-like (TAL) effectors into the host cell, where they bind to the effector-binding element (EBE) in the promoter of a susceptibility (S) gene, thereby inducing S gene expression and facilitating pathogen infection. A C-to-G substitution in the EBE of the rice S gene *SWEET14*, which encodes a sugar transporter hijacked by the pathogen *Xanthomonas oryzae* pv. *oryzae* (*Xoo*), disrupts the induced expression of *SWEET14*, effectively starving the pathogen and enhancing BSR to isolates targeting this EBE.

**(C)** Gene stacking involves pyramiding multiple R genes into a single crop cultivar, which can be tailored to confer BSR against multiple diseases or to increase the durability of resistance by incorporating several R genes.

Table 1.

Selected BSR genes in plants.

Gene	Host	Product	Pathogen	Reference
DMR6	Arabidopsis	2-oxoglutarate and Fe(II) oxygenase	C. higginsianum, H. arabidopsidis, H. parasitica, P. capsici, P. syringae pv. tomato DC3000	Wang et al., 2024
EFR	Arabidopsis	elongation factor TU or elf18 receptor	D. dadantii, P. atrosepticum, P. carotovorum, P. syringae pv. tomatoDC3000	Lacombe et al., 2010
FLS2	Arabidopsis	flagellin receptor	P. syringae pv. phaseolicola, P. syringae pv. tomato DC3000	Robatzek et al., 2006
PEN1	Arabidopsis	syntaxin	B. graminis f. sp. hordei, E. pisi	Johansson et al., 2014
PEN2	Arabidopsis	glycosyl hydrolase	B. graminis f. sp. hordei, E. cichoracearum, E. pisi	Parween et al., 2021
PEN3	Arabidopsis	ATP binding cassette transporter	E. cichoracearum, P. syringae pv. tomato DC3000	Parween et al., 2021
NPR1	Arabidopsis	BTB/POZ-ankyrin repeat protein	P. syringae, P. parasitica	Zavaliev et al., 2020
RPW8.1	Arabidopsis	NH2-terminal transmembrane domain and CC protein	E. cichoracearum, P. syringae	Yang et al., 2024
Mla	barley	mildew locus a	B. graminis f. sp. hordei, P. striiformis f. sp. tritici	Bettgenhaeuser et al., 2021
MLO	barley	calcium channel	B. graminis f. sp. hordei stains	Buschges et al., 1997
Rph3	barley	putative transmembrane protein	P. hordei strains	Dinh et al., 2022
GhMPK7	cotton	MAPK	C. nicotianae, potato virus Y	Shi et al., 2010
GhnsLTPsA10	cotton	non-specific lipid transfer protein	V. dahliae, F. oxysporum f. sp. vasinfectum	Chen et al., 2021
GhRVD1	cotton	intracellular immune receptor	V. dahliae strains	Zhang et al., 2023
RppK	maize	CC-NB-LRR protein	P. polysora strains	Chen et al., 2022a
ZmAuxRP1	maize	auxin-regulated protein 1	F. graminearum, F. verticillioides	Ye et al., 2019
ZmCCoAOMT2	maize	caffeoyl-CoA-O-methyltransferase	C. heterostrophus, C. zeina	Yang et al., 2017b
ZmGLK36	maize	A G2-like transcription factor	maize rough dwarf virus, rice black-streaked dwarf virus	Xu et al., 2023
ZmMM1	maize	transcription factor	C. heterostrophus, C. zeina, S. turcica	Wang et al., 2021
ELR	potato	ELR protein	Phytophthora species	Du et al., 2015
StDND1	potato	cyclic nucleotide-gated cation channel	P. infestans strains	Sun et al., 2022
BSR1	rice	receptor-like cytoplasmic kinase	B. glumae, C. miyabeanus, M. oryzae, rice stripe virus, X. oryzae pv. oryzae	Wu et al., 2022
Bsr-d1	rice	transcription factor	M. oryzae strains	Li et al., 2017
Bsr-k1	rice	TPR-domain RNA-binding protein	M. oryzae, X. oryzae pv. oryzae	Zhou et al., 2018
HDT701	rice	histone H4 deacetylase	M. oryzae, X. oryzae pv. oryzae	Ding et al., 2012
IPA1	rice	transcription factor	M. oryzae, X. oryzae pv. oryzae	Wang et al., 2018a
LML1	rice	eukaryotic release factor	M. oryzae, X. oryzae pv. oryzae	Qin et al., 2018
LMM5.1/5.4	rice	translation elongation factor 1A-like protein	M. oryzae, X. oryzae pv. oryzae	Zhao et al., 2017
OsNPR1	rice	BTB/POZ-ankyrin repeat protein	M. oryzae, X. oryzae pv. oryzae	Feng et al., 2011
OsWRKY45	rice	transcription factor	M. oryzae, X. oryzae pv. oryzae, X. oryzae pv. oryzicola	Shimono et al., 2012
RBL1	rice	CDP-DAG synthase	M. oryzae, U. virens, X. oryzae pv. oryzae	Sha et al., 2023
ROD1	rice	C2 domain Ca²⁺ sensor	M. oryzae, R. solani, X. oryzae pv. oryzae	Gao et al., 2021
SPL11	rice	U-box/ARM E3 ubiquitin ligase	M. oryzae, X. oryzae pv. oryzae	Fan et al., 2018
SPL28	rice	clathrin associated	M. oryzae, X. oryzae pv. oryzae	Qiao et al., 2010
SPL33	rice	translation elongation factor	M. oryzae, X. oryzae pv. oryzae	Wang et al., 2017
Xa5	rice	small (γ) subunit of the basal transcription factor	X. oryzae pv. oryzicola, X. oryzae pv. oryzae	Jiang et al., 2006
Xa13	rice	sugar transporter	R. solani, X. oryzae pv. oryzae	Gao et al., 2018
Xa21	rice	receptor kinase-like protein	X. oryzae pv. oryzae strains	Ercoli et al., 2022
GmMEKK1	soybean	MAPK	P. manschurica, soybean mosaic virus	Xu et al., 2018
GmMPK4	soybean	MAPK	P. manschurica, soybean mosaic virus	Liu et al., 2011
eIF4E1/eIF 4E2	tomato	translation initiation factor	tomato spotted wilt virus, alfalfa mosaic virus, cucumber mosaic virus, and TMV	Mazier et al., 2011
SlDMR6-1	tomato	2-oxoglutarate and Fe(II) oxygenase	P. syringae pv. tomato DC3000, P. capsica, X. gardneri, X. perforans	Thomazella et al., 2021
SlPUB24	tomato	U-box E3 ubiquitin ligase	X. euvesicatoria pv. euvesicatoria, X. vesicatoria, X. euvesicatoria pv. perforans, X. cynarae pv. gardneri	Liu et al., 2021
SlRIPK	tomato	receptor-like cytosolic kinase	R. solanacearum, P. carotovorum, B. cinerea, F. oxysporum	Wang et al., 2022
Sw-5b	tomato	intracellular immune receptor	tomato spotted wilt virus, groundnut ring spot virus, tomato chlorotic spot virus	Zhu et al., 2017
Fhb7	wheat	glutathione S-transferase	Fusarium species	Wang et al., 2020a
Lr34	wheat	ABC transporter	B. graminis f. sp. tritici, P. triticina, P. graminis f. sp. tritici, P. striiformis f. sp. tritici	Krattinger et al., 2019
Lr67	wheat	hexose transporter	B. graminis f. sp. tritici, P. triticina, P. graminis f. sp. tritici, P. striiformis f. sp. tritici	Milne et al., 2019
Pm21	wheat	typical CC-NBS LRR protein	B. graminis f. sp. tritici strains	He et al., 2018
Pm24/Rwt4	wheat	tandem kinase	B. graminis f. sp. tritici, Pyricularia oryzae (syn. M. oryzae)	Lu et al., 2020; Arora et al., 2023
Pm4	wheat	putative chimeric kinase-MCTP protein	B. graminis f. sp. tritici. Pyricularia oryzae (syn. M. oryzae)	Sánchez-Martín et al., 2021
Stb16q	wheat	plasma membrane cysteine-rich RLK	Z. tritici strains	Saintenac et al., 2021
Yr15	wheat	tandem kinase-pseudokinase	P. striiformis f. sp.tritici strains	Klymiuk et al., 2018
Yr27/Lr13	wheat	intracellular immune receptor	P. triticina, P. striiformis f. sp. tritici	Athiyannan et al., 2022

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Positive regulators of plant immunity conferring BSR

Some R genes have undergone evolutionary sequence variations that enhance BSR. In rice, the Pike locus, comprising two adjacent CNL genes, Pike-1 and Pike-2, confers BSR to rice blast. The specificity of Pike-mediated resistance is determined by Pike-1, not Pike-2, as only the CC domain of Pike-1 can interact with AvrPik-D. A novel allele at the Pik locus, Pikg, features a single amino acid substitution (D229E) in the Pike-1 CC domain, enhancing BSR against various M. oryzae strains (Meng et al., 2021). In addition, Zhou et al. (2020b) identified 13 novel Pi9 alleles with insertions or deletions (indels) in 361 blast-resistant rice varieties, with types 3/4/5/6/9/10/11 of Pi9 alleles conferring BSR to rice blast. In wheat, the Yr27 allele of the leaf rust R gene Lr13 encodes a protein sharing 1043 of 1072 amino acids with the reference protein but differs by only 2.7%, enhancing resistance to stripe rust (Athiyannan et al., 2022). The recognition of various alleles of AVR-Rmg8 by different alleles of the wheat powdery mildew R gene Pm4 enhances resistance to both leaf and panicle blast (Sánchez-Martín et al., 2021). In barley, the Mla (Mildew locus a) locus displays substantial structural and copy number variability, with Mla8 showing 97.4% identity to Mla1. Despite being a single-copy gene, Mla8 exhibits polymorphisms exclusively in the LRR region and provides dual resistance to barley powdery mildew and wheat stripe rust (Bettgenhaeuser et al., 2021). These natural allelic BSR variants provide valuable resources for identifying additional BSR genes and developing new targets for genome editing and R protein engineering. In wheat, two durable BSR genes derived from naturally occurring membrane transporter variants have been particularly notable. The first gene, Lr34, encodes an ABC transporter variant that confers durable BSR against diseases such as rust and powdery mildew (Krattinger et al., 2019). Notably, stable transgenic expression of Lr34 in various crops has conferred resistance to diseases adapted to those crops, including powdery mildew in barley, rice blast in rice, anthracnose and rust in sorghum, and leaf blight and rust in maize (Schnippenkoetter et al., 2017). Similarly, the second gene, Lr67, encodes a hexose transporter variant that confers resistance to the same wheat diseases as Lr34 and exhibits cross-species functionality as a transgene (Milne et al., 2019). Specific mutations, G144R and V387L, underlie the resistant allele of Lr67, with the G144R mutation alone demonstrated to confer rust resistance when introduced into the barley ortholog of Lr67 (HvSTP13). This finding suggests potential for modifying orthologous genes for disease resistance across diverse crops via base or prime editing, given the conservation of the G144 residue and the STP13 family across species (Gupta et al., 2021; Skoppek et al., 2022). The wheat stripe rust BSR gene Yr36 encodes a protein with a serine/threonine kinase and a putative steroidogenic acute regulatory protein-related lipid transfer lipid-binding domain. Yr36 confers resistance to multiple stripe rust races by phosphorylating thylakoid ascorbate peroxidases, resulting in ROS accumulation (Gou et al., 2015). In barley and wheat, overexpression of the dominant R gene, barley stripe resistance 1 (BSR1), encoding a typical CNL protein, confers resistance to barley stripe mosaic virus (Wu et al., 2022). In rice, the MYB transcription repressor (MYBS1) binds to the bsr-d1 promoter, preventing the induction of bsr-d1 by M. oryzae. This leads to reduced expression of bsr-d1 and the accumulation of its encoded peroxidase, thereby attenuating the degradation of H₂O₂ and enhancing BSR to rice blast (Li et al., 2017). Similarly, IPA1 encodes a transcription factor that bolsters blast resistance through binding to the promoter of the immune regulatory gene WRKY45 upon M. oryzae-induced phosphorylation of IPA1 (Wang et al., 2018a). In maize, RppK, a typical R gene, confers resistance to southern corn rust caused by Puccinia polysora. Introgression of RppK into multiple maize lines has shown robust BSR against all tested P. polysora races (Chen et al., 2022a). In potato, the R protein RLP ELR (elicitin response) from the wild potato Solanum microdontum enhances BSR to potato late blight by recognizing elicitins as oomycete PAMPs (Du et al., 2015). Although the primary functions of these R genes require further investigation, their conservation in various crops highlights the potential for developing new sources of multipathogen resistance.

Loss of susceptibility and LMM genes conferring BSR

Loss-of-function mutations in S genes, often considered negative regulators of plant immunity, frequently confer BSR in crops (van Schie and Takken, 2014). In rice, TAL effectors secreted by Xoo bind to EBEs in the promoters of SWEET sucrose transporter genes, inducing their expression and hijacking these transporters to siphon nutrients, which results in disease susceptibility. Counteracting Xoo-mediated SWEET induction is a strategy to achieve disease resistance. Natural variations in the EBEs of the SWEET13 and SWEET14 genes have been identified. A 2-bp deletion and a substitution in the EBE of OsSWEET13 effectively inhibit infection by the Xoo PXO339 strain carrying the TAL effector PthXo2. Similarly, a single-nucleotide substitution in the EBE of OsSWEET14 prevents invasion by the Xoo strain PXO86 that carries AvrXa7 (Zaka et al., 2018). A single substitution in the promoter of OsSWEET11 prevents recognition by the Xoo strain PXO99, which carries PthXo1, leading to enhanced BSR in rice (Römer et al., 2010). For multipathogen resistance in rice, ROD1 encodes a Ca²⁺ sensor protein, a disease-susceptibility factor, where a natural variant of ROD1 caused by a single-nucleotide deletion exhibits robust BSR to rice blast, bacterial blight, and sheath blight. In maize, loss of function of ZmROD1 shows enhanced resistance to maize sheath blight, demonstrating that ROD1 is a candidate gene for trans-crop applications (Gao et al., 2021a). In soybean, GmMPK4 acts as a negative immune regulator. GmMPK4-silenced lines show increased resistance to downy mildew and soybean mosaic virus due to the accumulation of SA and H₂O₂ (Rui and Wang, 2024). In addition to the loss of susceptibility factors, LMM genes also confer BSR in various crops. In maize, Zhang et al. identified a teosinte-derived allele of a resistance gene, ZmMM1, which encodes a transcription repressor with an MYB-DNA binding domain. ZmMM1 confers BSR to northern leaf blight, gray leaf spot, and southern corn rust by binding to the promoter region of the long non-coding RNA gene ZmMT3, thereby suppressing its transcription and promoting ROS accumulation (Wang et al., 2021). A dominant disease lesion mimic mutant, Les8, shows enhanced resistance to both Curvularia leaf spot and southern leaf blight through the accumulation of JA and lignin (Li et al., 2023). The LMM gene LLS1/LES30, encoding pheophorbide a oxidase involved in chlorophyll degradation, confers BSR to Curvularia leaf spot, common rust, southern leaf blight, and anthracnose in maize (Li et al., 2022a). Similarly, Liu et al. (2017) cloned the LMM gene OsCUL3a, encoding a negative regulator of plant immunity. Early termination of the OsCUL3a protein in the LMM mutant oscul3a confers BSR to rice blast and bacterial blight (Liu et al., 2017). These S genes and LMM genes that negatively regulate plant immunity represent important targets for genetic engineering, including genome editing, to improve plant disease resistance. They provide new genetic resources for breeding disease-resistant crop varieties (Lapin and Van den Ackerveken, 2013).

Gene stacking of R genes for BSR using a traditional breeding strategy

Gene stacking is an effective strategy for integrating multiple desirable traits into crops (Crété et al., 2020), particularly for enhancing disease resistance. This approach often involves combining multiple R genes, typically encoding NLR and executor R proteins, to confer BSR against various crop diseases. Zheng et al. (2020) developed wheat lines with enhanced BSR and improved grain quality by stacking the stripe rust R gene Yr26 and the powdery mildew R gene ML91260 into elite wheat cultivars (Zheng et al., 2020). Additionally, the combination of Yr30 with a quantitative trait locus on chromosome arm 4BL (YrFDC12) demonstrated enhanced resistance to stripe rust (Zhou et al., 2022b). In maize, the ZmGLK36 and ZmGDIα-hel genes were combined in lines highly susceptible to maize rough dwarf disease, significantly improving resistance (Li et al., 2024d). In rice, extensive use of pyramiding different Pi genes has proven effective in conferring BSR to rice blast. Monogenic near-isogenic lines (NILs) NIL^Pi9, NIL^Pizt, and NIL^Pi54, which carry the Pi9, Pizt, and Pi54 genes, respectively, were developed through marker-assisted backcrossing. The polygenic pyramid lines Pi9/Pi54 and Pizt/Pi54 showed BSR to rice blast (Xiao et al., 2016). Similarly, gene combinations such as Pigm/Pi1, Pigm/Pi54, Pigm/Pi33, and Pijx/Piz-t have also conferred BSR to rice blast (Wu et al., 2019; Xiao et al., 2023). The hybrid rice line 9A/R8012, produced by multi-generation hybridization and backcrossing with several superior hybrid rice lines harboring multiple R genes, including Xa21, Xa13, Xa5, and Pi25, exhibited robust resistance to both rice blast and bacterial blight (Chukwu et al., 2019). Lines pyramided with multiple genes, such as those combining Xa7 and Xa21, Xa21, Xa4 and Xa23, and Xa5, Xa13 and Xa21, have shown BSR to bacterial blight. However, not all combinations of R genes result in additive disease resistance. For example, Xa27-mediated resistance was significantly compromised by the addition of the R gene Xa5 (Gu et al., 2009). Similarly, when the Xa5, Xa23, Xa10, and Xa27 genes were combined, the resultant lines showed reduced resistance to bacterial blight to some extent (Tian et al., 2014). While the pathogen population and pleiotropy must be considered carefully in gene stacking, this strategy remains the most effective for achieving BSR in breeding.

Traditional genetic engineering facilitates BSR

Transgenic approaches to combine R gene-mediated BSR in crops

Transgenic approaches have significantly expedited the acquisition of desired traits in plants, particularly in enhancing disease resistance. For instance, to combat wheat stem rust, a gateway recombinase cloning strategy was employed to construct a gene cassette containing five R genes: the race-specific resistance genes Sr22, Sr35, Sr45, Sr50 and the multipathogen resistance gene Sr55. This cassette was transformed into wheat at a single locus, enabling rapid gene stacking and conferring BSR against both stem rust and leaf rust (Luo et al., 2021). Similarly, four wheat R genes (Sr22, Sr33, Sr35, and Sr45) were introduced into barley, providing BSR against stem rust (Hatta et al., 2021). Additionally, Sr26 and Sr61, derived from tall wheat-grass (Thinopyrum ponticum), encode unrelated NLR proteins. Their combined expression confers resistance to multiple races of stem rust (Zhang et al., 2021). In maize, Zhu et al. (2018) employed a similar strategy to pyramid nine genes (Chi, Glu, Ace-AMP1, Tlp, Rs-AFP2, ZmPROPEP1, Pti4, Iap, and p35), resulting in a maize line with enhanced resistance to maize sheath blight and southern leaf blight. Overexpression of the polyamine oxidase (PAO) gene in soybean leads to increased production of H₂O₂, enhancing resistance to multiple Phytophthora isolates without affecting other key agronomic traits (Yang et al., 2022b). In rice, six genes (EPSPS, OsLecRK1, Bph14, Cry1C, Xa23, and Pi9) were introduced into an elite rice cultivar using a multi-gene transformation method, enhancing resistance to multiple diseases (rice blast and bacterial blight), pests (brown planthopper), and herbicides (glyphosate) (Li et al., 2024c). Transgenic approaches are crucial for rapidly transferring multiple genes into a single locus, resulting in much simpler heritability than gene stacking via conventional breeding.

Antimicrobial peptides and phytoalexins can facilitate BSR in crops

The production of proteinaceous and chemical compounds with antimicrobial activities is an important approach for achieving BSR in crops (Li et al., 2021a). During infection, pathogens secrete small effector proteins to manipulate plant immunity and facilitate successful colonization. Successful effector translocation often requires host components, including various phospholipid species, which are also integral to defense mechanisms involving AMPs. Specific proteins that bind to phosphatidylinositol 3-phosphate (PI3P) can direct AMPs to the surfaces of Phytophthora pathogens, thereby inhibiting their infection. For example, transgenic tobacco, soybean, and potato plants expressing two AMPs from the Chinese medicinal herb Gastrodia elata, GAFP1 or GAFP3, fused with a PI3P-specific binding domain, have shown enhanced BSR against Phytophthora pathogens (Zhou et al., 2021; Helliwell et al., 2022; Yang et al., 2023). This strategy utilizes the same AMPs to disrupt the infection processes of multiple pathogens, thereby achieving BSR. Like AMPs, phytoalexins exhibit biological activity against various pathogens and play an important role in disease resistance. In rice, overexpression of the selenium-binding protein homolog (SBP) gene increased resistance to rice blast and bacterial blight through the accumulation of momilactone A (Sawada et al., 2004). Additionally, overexpression of CYP71Z18 significantly enhanced blast resistance in rice by catalyzing the accumulation of the antimicrobial diterpenoid phytoalexin dolabralexin (Shen et al., 2019). Stilbene, another type of phytoalexin, inhibits fungal growth. Overexpression of the grapevine stilbene synthase gene Vst1 in common spring wheat has enhanced resistance to powdery mildew (Liang et al., 2000). Advanced techniques from medical biology for identifying useful AMPs and phytoalexins can be adapted for crop applications. For instance, a machine learning approach was employed to screen 2349 AMPs derived from the human gut microbiome, leading to the identification of 11 AMPs with high antimicrobial potency (Ma et al., 2022). Such AI-assisted methods could potentially expedite BSR studies by identifying novel AMPs. Furthermore, the application of AMP sprays, such as peceleganan, has been utilized to treat skin wound infections and has reached the clinical trial stage (Wei et al., 2023; 2024b). Similarly, the topical application of AMPs or phytoalexins could serve as a viable complementary method to genetic strategies for enhancing BSR in crops.

Epigenetic modifications conferring BSR in crops

In plant immune regulation, epigenetic modifications, such as histone methylation, acetylation, ubiquitination, and DNA methylation and demethylation, play crucial roles in R gene-mediated immunity (Xie and Duan, 2023). These processes are emerging as promising strategies to enhance BSR (Ramirez-Prado et al., 2018). In rice, JMJ704, a histone H3 lysine 4 trimethylation (H3K4me2/3) demethylase, acts as a positive regulator of immunity against bacterial blight. JMJ704 enhances resistance by suppressing the expression of negative immune regulators, such as NRR and OsWRKY62, through the removal of H3K4me2/3, maintaining their transcriptional inactivation (Hou et al., 2015). Similarly, histone acetylation is pivotal in plant immunity; in rice, the HD2 subfamily histone deacetylase HDT701 functions as a negative regulator by modulating histone H4 acetylation of DR genes against bacterial blight (Ding et al., 2012). In wheat, the histone deacetylase TaHDA6 interacts with TaHOS15 and is recruited to the promoter of R genes, including TaPR1, TaPR2, TaPR5, and TaWRKY45, fine-tuning resistance to powdery mildew (Zhi et al., 2020). Histone ubiquitination also influences plant immunity by modulating JA, SA, and ET hormone signaling pathways (Gao et al., 2022). For instance, HUB1, an E3 ligase for histone 2B monoubiquitination, is a crucial regulator of plant defense against necrotrophic pathogens. In tomato, SlHUB1 and SlHUB2 positively regulate plant defense responses to B. cinerea by modulating hormone-mediated signaling pathways (Zhang et al., 2015). Moreover, maintaining DNA methylation homeostasis is essential for R gene expression and enhancing crop disease resistance. For example, DNA methylation in the promoter of the R gene Pib regulates its induction upon M. oryzae infection, thereby enhancing resistance to rice blast (Li et al., 2011). Additionally, PigmS, a gene harboring two tandem miniature transposons in its promoter (MITE1 and MITE2), shows increased expression through the methylation of MITE1 and MITE2, thereby interfering with PigmR homodimerization and mitigating PigmR-mediated resistance to rice blast in the panicle, balancing yield and immunity (Deng et al., 2017). Epigenetic factors serve as key regulators in the transcriptional reprogramming of plant immune responses, suggesting that epigenetics-based strategies can be broadly employed to enhance plant disease resistance.

RNAi-mediated BSR

RNA interference (RNAi) has emerged as an effective approach for achieving BSR in crops (Tang et al., 2021). This method involves gene silencing mediated by double-stranded RNA (dsRNA) that specifically targets the mRNAs of homologous genes. Dicer-like proteins process these dsRNA molecules into small interfering RNAs (siRNAs) of 21–23 bp. These siRNAs then associate with Argonaute proteins and other enzymes to form the RNA-induced silencing complex, which binds to complementary mRNA and cleaves it, thereby suppressing gene expression. In plants, RNAi generates various small RNAs (sRNAs), including microRNAs (miRNAs) and siRNAs, which facilitate mRNA degradation (Rosa et al., 2018). Specifically, miR164-no apical meristem/Arabidopsis transcription activation factor/cup-shaped cotyledon (NAC) transcription factors are known to negatively regulate disease resistance against stripe rust in wheat, rice blast in rice, and Verticillium wilt in cotton caused by the fungal pathogen Verticillium dahliae (Feng et al., 2014; Wang et al., 2018b; Hu et al., 2020). For example, Osa-miR164a targets OsNAC60, reducing its expression and thereby enhancing BSR to rice blast and bacterial blight. miR160a enhances disease resistance partially by suppressing ARF8, and ARF8 protein binds directly to the promoter and suppresses the expression of WRKY45, which acts as a positive regulator of rice immunity (Feng et al., 2022). Interestingly, the insect salivary microRNA miR-7-5P, secreted into host plants during feeding, facilitates communication between insects and plants. Silencing miR-7-5P in the insect Nilaparvata lugens enhances plant resistance by upregulating the plant immune-associated basic leucine zipper transcription factor 43 (OsbZIP43) (Zhang et al., 2024). In tomato and soybean, the miR164a/OsNAC60 regulatory module enhances resistance to late blight in tomato and root rot in soybean (Wang et al., 2018b). Beyond fungal and oomycete pathogens, RNAi also proves effective against plant viruses. Viral genes must be introduced into the host and utilize its molecular machinery to replicate; thus, RNAi can silence these viral genes without requiring sRNAs to penetrate the virus itself. In rice, a hairpin RNA structure incorporating sequences from rice ragged stunt virus and rice grassy stunt virus was introduced into Indica rice through double transfer DNA transformation. The resulting marker-free rice lines demonstrated enhanced resistance to both viruses without impacting yield (Xie et al., 2024). Similarly, Li et al. (2024b) engineered hairpins that target sequences from four viruses—rice black-streaked dwarf virus (RBSDV), southern RBSDV, rice stripe virus (RSV), and rice ragged stunt virus. This innovative approach produced the ZJU-4K rice line, which exhibits BSR to all four viruses, showcasing the potential for rapid development of elite crop varieties resistant to viral pathogens (Li et al., 2024b).

Host-induced gene silencing (HIGS) is a cross-kingdom RNAi strategy that suppresses pathogen genes through the expression of pathogen-derived dsRNAs in host plants. This method significantly enhances plant resistance to pathogens. sRNAs can be transferred between plants and pathogens, resulting in the silencing of target genes, a process known as cross-kingdom RNAi. In the Arabidopsis-B. cinerea pathosystem, plants transfer sRNAs into B. cinerea, silencing fungal virulence genes and thereby reducing fungal infection to achieve BSR (Cai et al., 2018). In rice, the simultaneous targeting of two chitin synthase genes of Ustilaginoidea virens, UvChs2 and UvChs5, which are responsible for the synthesis of key components of fungal cell walls and are involved in U. virens infection—enhances resistance to rice false smut (Li et al., 2021b). In the stripe rust fungus of wheat, PsFUZ7, a MAPK-encoding gene, regulates fungal infection. Stable RNAi of PsFUZ7 in wheat confers robust resistance to stripe rust (Zhu et al., 2017b). For another wheat disease, Fusarium head blight, host-induced silencing of three virulence genes (FgSGE1, FgSTE12, and FgPP1) of Fusarium graminearum enhances resistance. These genes respectively encode a regulator of deoxynivalenol biosynthesis, a key transcription factor for penetration structure formation, and an essential phosphatase (Wang et al., 2020b). In maize, Aspergillus flavus, a fungal pathogen that produces mycotoxins including aflatoxins, is targeted by HIGS. Omolehin et al. (2021) transformed maize with a hairpin construct targeting the alkaline protease (alk) gene involved in aflatoxin biosynthesis in A. flavus, thereby conferring resistance to aflatoxin production. During cotton-V. dahliae interactions, VdEXG, a cell wall-degrading enzyme, is upregulated and plays a pivotal role in fungal carbon source utilization, cell wall penetration, and pathogenesis (Su et al., 2020). Utilizing the HIGS strategy, Su et al. (2024) developed transgenic cotton varieties with enhanced resistance to Verticillium wilt by specifically silencing VdEXG. In pepper, targeting the Phytophthora capsici RXLR effector genes RXLR1 or RXLR4 enhances resistance to Phytophthora blight disease (Cheng et al., 2022). RNAi gene silencing techniques are powerful tools for engineering disease-resistant crops and have the potential to significantly enhance crop resistance to multiple diseases caused by fungi, oomycetes, and viruses (Lopez-Gomollon and Baulcombe, 2022). These advancements have profound implications for agricultural production.

Genome editing for BSR

Over the past few decades, the development of genome editing tools, such as zinc-finger nucleases (ZFNs), transcription-activator-like effector nucleases (TALENs), and CRISPR-Cas systems, has significantly advanced BSR engineering in crops (Karmakar et al., 2022). Among these, the CRISPR-Cas system has emerged as one of the most advanced and precise methods for genetic manipulation due to its simplicity, high efficiency, and versatility (Gao, 2021). Various CRISPR-Cas tools have been developed for a range of genetic modifications, including targeted gene knockout, gene insertion and replacement, base editing, epigenome editing, and CRISPR-mediated transcriptional regulation (Figure 3). Additionally, a novel genome editing tool based on a transposon-associated RNA-guided endonuclease known as TnpB, considered the ancestor of Cas12, has been engineered for genome editing (Karvelis et al., 2021). Recent applications of TnpB-mediated genome editing have successfully knocked out target genes in Arabidopsis, rice, and several medicinal plants, demonstrating its efficacy (Zhang et al., 2024a; Li et al., 2024f; Karmakar et al., 2024; Lv et al., 2024). Given its smaller size (approximately 400 amino acids) compared to Cas nucleases, as well as its comparable editing efficiency to SaCas9, programmability, and extensive diversity, TnpB holds significant potential for improving BSR in crops. In contrast to conventional crop breeding approaches, which largely rely on the discovery and screening of natural genetic variations and the pyramiding of elite traits through cross-breeding, genome editing propels innovation in plant breeding. This technology facilitates the exploration and application of crop disease resistance, pushing beyond current limitations and advancing to the next generation of crop improvement strategies (Li et al., 2024a). Genome editing strategies for improving BSR in crops are summarized in Figure 4.

Diverse genome editing technologies facilitate BSR engineering

**(A)** CRISPR-Cas-mediated targeted gene knockout. Loss-of-function mutations are generated by introducing insertions or deletions (indels) into the target gene. A small TnpB protein, consisting of 400 amino acids, was used to develop hypercompact genome editors, which achieve high editing efficiency. This approach can modify a considerable number of S genes, generating novel R alleles.

**(B)** Targeted DNA segment insertion and allele replacement are achieved through DNA double-strand break (DSB)-mediated DNA repair in the presence of donor templates. For example, targeted insertion or replacement of resistant alleles can be accomplished by excision and insertion of the non-autonomous rice transposable element *mPing* by *Pong* ORF1 and ORF2. TATSI, transposase-assisted target site integration.

**(C)** The adenine base editors (ABE) and cytosine base editors (CBE) consist of a catalytically impaired Cas9 (nCas9 [D10A]) and either an adenosine deaminase or cytidine deaminase enzyme. Using base editing, a G > A mutation (M441I) was introduced into the endogenous *pi-d2* gene, restoring its resistance to rice blast. UGI, uracil DNA glycosylase inhibitor.

**(D)** Prime editing utilizes a Cas9 nickase (nCas9 [H840A]) fused to an engineered reverse transcriptase (RT) along with a prime editing guide RNA. The prime editing-mediated recombination of opportune targets (PrimeRoot) enables precise insertion of large DNA fragments. Using PrimeRoot, the R gene *PigmR*, driven by the *OsAct1* promoter, was precisely integrated into the rice genome, conferring resistance to rice blast. PBS, primer binding site.

**(E)** CRISPR activation (CRISPRa) and CRISPR interference (CRISPRi) systems use a catalytically dead Cas9 (dCas9) along with a transcriptional activation or repression domain, respectively. CRISPRa and CRISPRi can be employed to regulate gene expression, achieving BSR in crops.

**(F)** Epigenome editors consist of dCas9 and one or more enzymes that modify DNA methylation, demethylation, or histone modifications. The reversibility of epigenetic markers enables the manipulation of chromatin and epigenetic signatures, making it an appealing strategy for BSR breeding.

Strategies for BSR in crops

**(A)** Screening for R gene alleles is a common method for identifying naturally occurring mutations associated with BSR, providing targets for genetic engineering. For example, *ROD1* (SNP1^A), a SNP in the coding region of *ROD1*, enhances resistance to sheath blight in rice.

**(B)** Transferring R genes across different crops can serve as a source of BSR. For instance, *Lr34* from wheat has been shown to enhance resistance to powdery mildew in barley, rice blast in rice, anthracnose and rust in sorghum, and leaf blight and rust in maize through trans-crop applications.

**(C)** AMPs can suppress pathogen invasion and confer BSR. *Phytophthora*-derived phosphatidylinositol 3-phosphate (PI3P) has been used to guide AMPs to the surface of *Phytophthora* pathogens during infection, enhancing disease resistance.

**(D)** Silencing virulence genes via RNAi is an effective strategy for conferring BSR in crops, particularly for the control of viruses. Host-induced gene silencing (HIGS) has been successfully used to confer BSR to fungal and oomycete pathogens. dsRNA, double-stranded RNA; siRNA, small interfering RNA; AGO, Argonaute; RISC, RNA-induced silencing complex.

**(E)** Editing S genes, LMM genes and or negative regulators of plant immunity, which are exploited by pathogens, is a reliable technique for achieving BSR. For example, knockout of wheat *MLO* and rice *SWEET* genes confers BSR.

**(F)** Multiplexed genome editing enables the simultaneous editing of multiple S genes, enhancing BSR in crops.

**(G)** Precise insertion or replacement techniques are used to insert or replace R gene alleles in crops. For example, *PigmR* has been successfully applied using PrimeRoot technology.

**(H)** R gene design strategies can also mediate BSR in crops. For example, the NLR immune receptor Pikm, when fused with nanobodies that recognize fluorescent proteins, confers enhanced resistance to Potato virus X (PVX) that expresses the corresponding fluorescent proteins. Nano, nanobody.

Targeted insertions and substitutions for BSR

In genome editing, targeted DNA insertion or replacement leverages endogenous DNA double-strand break (DSB) repair mechanisms: non-homologous end joining (NHEJ) and homology-directed repair (HDR). NHEJ, which can be engineered to cut and ligate DNA fragments at the DSB site (Chang et al., 2017), often results in non-directional integrations and introduces insertions or deletions (indels) at the ends of the inserted donor fragments, making this method less precise (Suzuki et al., 2016). Conversely, HDR-mediated genome editing allows for the precise incorporation or replacement of desired sequences at specific loci in crop genomes. However, using HDR in plants is challenging due to its significantly lower efficiency compared to NHEJ in DSB repair. Recent advancements include a study in rice where introducing a 10-EBE array, responsive to TAL effectors from various Xoo and X. oryzae pv. oryzicola strains, into the commercial cultivar Nangeng 46 through genome editing conferred durable BSR to 50 Xoo strains and 30 Xanthomonas oryzae pv. oryzicola strains (Wang et al., 2024c). Additionally, Li et al. (2016) achieved gene replacements in rice by applying NHEJ-mediated site-specific replacement and insertion to confer glyphosate resistance through the modification of the endogenous gene EPSPS. In tobacco, the R gene N′ mediates resistance only against the tobacco mosaic virus (TMV) crucifer-infecting strain (TMV-Cg) but not the TMV-U1 strain. Employing the CRISPR-Cas9 system, two resistance-related regions of the N′ gene were replaced with homologous fragments of the N′alata gene, which shares high sequence identity with N′, thus conferring resistance to the TMV-U1 strain (Li et al., 2023b). Furthermore, Liu et al. (2024) developed a novel genome engineering tool, the transposase-assisted target-site integration (TATSI) system, by fusing the rice Pong transposase protein with Cas nucleases. TATSI was successfully applied for sequence-specific targeted insertion of enhancer elements, an open reading frame, and a gene expression cassette in the genomes of Arabidopsis and soybean, demonstrating its versatility and precision (Liu et al., 2024).

In addition to DSB-based gene insertion and replacement, base editors and their derived tools, which do not introduce DSBs, have been used to introduce single-nucleotide variants, contributing significantly to BSR in crops such as rice, wheat, maize, and tomato. Pi-d2, an agriculturally important R gene in rice, confers resistance to M. oryzae, the causative agent of rice blast. A single amino acid substitution (I441M) at position 441 in Pi-d2 results in the loss of resistance to M. oryzae (Chen et al., 2006). To counter this, an optimized base editor known as rBE5, which combines a mutant version of the human activation-induced cytidine deaminase cytosine deaminase with nCa9 (Cas9 nickase), was employed to introduce a G > A substitution (M441I) into the endogenous Pi-d2 gene, thereby restoring its resistance to rice blast (Ren et al., 2018). In citrus, the effector PthA4, which is transported from the pathogen to plant cells, binds to the EBE in the promoter of the S gene LOB1, activating its expression and contributing to the development of citrus canker. Jia et al. (2024) employed Cas12a/CBE co-editing technology to generate transgene-free, canker-resistant citrus plants by mutating the EBE in the LOB1 promoter. Prime editing, a precise and highly versatile editing technology that avoids DSBs, can induce all 12 types of DNA substitutions, as well as indels, at targeted sites. Prime editing technologies have advanced rapidly and are being applied in crops with increasing success. For example, an optimized prime editor engineered by modifying the Moloney murine leukemia virus reverse transcriptase—by removing its ribonuclease H domain and incorporating a viral nucleocapsid protein with nucleic acid chaperone activity—has greatly improved prime editing efficiency across a variety of target sites in rice and wheat (Zong et al., 2022). Despite its broad utility, prime editing is often limited by its inability to insert large DNA fragments. A new genome editing tool, PrimeRoot, which combines prime editing with site-specific recombinases, has been developed to precisely insert large DNA fragments of up to 11.1 kb into the rice genome. Using PrimeRoot, the rice BSR gene PigmR, driven by the OsAct1 (rice Actin1) promoter, was accurately integrated into the rice genome, conferring enhanced resistance to rice blast (Sun et al., 2024a).

Saturation mutagenesis for new R genes alleles

Although natural R gene alleles are limited, they have provided valuable resources for disease resistance in crops (Deng et al., 2024). In contrast, saturation mutagenesis produces diverse variant libraries, offering a resource for identifying new R gene alleles. In saturation mutagenesis, random or targeted mutations are introduced into the protein-coding sequences or regulatory regions of genes, creating a library of mutant alleles. These alleles are then screened for those exhibiting desirable traits, such as enhanced resistance. Saturation mutagenesis is a straightforward technique for functional studies of genes and the generation of elite alleles. In rice, an elite allele named RBL1^Δ12 was generated through CRISPR--Cas9-based saturation mutagenesis, which harbors a 12-bp deletion in RBL1 and confers BSR to rice blast, rice false smut, and bacterial blight without a yield penalty (Sha et al., 2023). Additionally, the trade-off between immunity and yield—often caused by known BSR genes—can now be circumvented (Figure 5). Engineered dual-base editors have also been applied for the directed evolution of OsACC, achieving near-saturation mutagenesis and rapidly generating herbicide-resistant rice lines (Li et al., 2020). Recently, Chen et al. (2024) developed a novel platform, helicase-assisted continuous editing, which fuses helicase with deaminase to induce hypermutation in the downstream genomic sequence. This platform has the potential to serve as a powerful tool for targeted saturation mutagenesis to generate numerous candidate BSR genes (Chen et al., 2024). In addition to these advancements, saturation mutagenesis can also be used to knock down or knock up phytoalexin biosynthetic pathway genes, thereby maximizing their production and contributing to BSR. Overall, the current genome editing toolkit represents a powerful set of resources for the directed evolution of crops with enhanced BSR.

Strategies to balance growth-immunity trade-offs in crops

**(A)** Phosphorylation of IPA1 is critical for balancing immunity and yield in rice. In the *ipa1-1D* mutant, IPA1 binds to the promoter of *DEP1* to promote its expression, thereby regulating rice yield. Phosphorylated IPA1, induced by *M. oryzae* infection, preferentially binds to the promoter of *WRKY45*, a positive transcription factor of plant immunity, and enhances its expression, thereby improving disease resistance.

**(B)** *Tamlo-R32*, generated by editing the *MLO* genes, alters chromatin structure, increasing the expression of the upstream gene *TaTMT3*, which encodes tonoplast monosaccharide transporter 3. This modification mitigates the growth penalties caused by *MLO* mutations, achieving a balance between immunity and yield.

**(C)** Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂), a disease susceptibility factor in rice, is enriched in cellular structures involved in fungal effector translocation. A specific novel allele, *RBL1*^Δ12, involved in PI(4,5)P₂ biosynthesis, is generated via CRISPR-Cas9 and confers BSR without yield penalty by disrupting pathogen infection-specific structures through the reduction of PI(4,5)P₂. BIC, biotrophic interfacial complex.

**(D)** PigmR NLR forms homodimers that confer BSR but cause yield losses. In contrast, PigmS competitively suppresses the homodimerization of PigmR to inhibit resistance. Additionally, *PigmS* is epigenetically regulated and is highly expressed in rice pollen, counteracting the yield penalty associated with *PigmR*.

**(E)** Constitutive activation of NPR1, an activator of SA-mediated plant immunity, significantly inhibits plant growth. The translation of TBF1, a key immune regulator, is rapidly and transiently induced to enhance resistance upon pathogen infection in *Arabidopsis*. The upstream open reading frame (uORF) of *TBF1*-*NPR1* mediates this translational control mechanism, conferring BSR to rice blast, bacterial blight, and bacterial leaf streak without compromising plant fitness.

Editing S genes and negative regulators of resistance for BSR

SWEET sugar transporters are a family of plant susceptibility factors commonly targeted by bacterial pathogens. Loss of SWEET function or preventing the hijacking of SWEET gene expression can confer disease resistance. For example, targeted mutagenesis of the OsSWEET14 promoter confers resistance to rice bacterial blight through transcription-activator-like effector nuclease-based disruption (Zeng et al., 2020). Similarly, targeted mutation of OsSWEET13 also results in resistance to rice bacterial blight (Zhou et al., 2015). In another case, mutating OsAP47, an aspartic proteinase, enhances resistance against RBSDV and southern RBSDV (Wang et al., 2022c). Knockout of DMR6 orthologs using CRISPR-Cas9 confers resistance to a range of diseases including downy mildew in barley, bacterial leaf streak in rice, banana Xanthomonas wilt in banana, and bacterial spot and powdery mildew in tomato (Thomazella et al., 2021). Similarly, the same tool was used to knock out TaPsIPK1, a negative immune regulator in wheat, enhancing BSR to stripe rust without compromising yield (Wang et al., 2022a). The TaHRC gene encodes a histidine-rich calcium-binding protein that serves as a disease susceptibility factor for wheat Fusarium head blight. Ding et al. (2023) discovered the rice homolog, OsHRC, and mutation of OsHRC confers resistance to rice blast. The goal of multiplexed genome editing is to simultaneously target multiple loci or genes, enabling the rapid generation of genetic variants with enhanced BSR (Zhu et al., 2020). By editing multiple S genes, multiplexed genome editing can enhance disease resistance in crops to various pathogens. In rice, mutations in the promoters of three SWEET genes (SWEET11, SWEET13, and SWEET14) using CRISPR-Cas9 enhance resistance to bacterial blight (Oliva et al., 2019). The pi21-bsr-d1-xa5 triple mutant shows significantly enhanced resistance to both rice blast and bacterial blight without growth penalties (Tao et al., 2021). Similarly, mutations in Bsr-d1, Pi21, and ERF922 enhance resistance to rice blast and bacterial blight (Zhou et al., 2022b). MLO was originally identified as an S gene for powdery mildew resistance in barley and is conserved across monocots and dicots (Bai et al., 2008). In wheat, Wang et al. (2014) knocked out all three TaMLO genes simultaneously, conferring BSR to powdery mildew. A novel mlo wheat line, Tamlo-R32, shows disease resistance to powdery mildew without compromising yield due to induced chromatin structure remodeling (Li et al., 2022c). Likewise, targeted mutation of SlMLO through CRISPR-Cas9 enhances disease resistance to powdery mildew in tomato (Nekrasov et al., 2017). NPR3, a homolog of NPR1, negatively regulates SA-mediated defense responses. Mutation of NPR3 confers resistance to potato zebra chip disease by activating SA signaling (Ramasamy et al., 2024). In tomato, knockout of SlBBX20, a BBX transcription factor, confers resistance to gray mold disease by modulating JA signaling (Luo et al., 2023). In barley, simultaneous knockout of HvMORC1 and HvMORC6a confers BSR to powdery mildew and Fusarium head blight (Galli et al., 2022).

Transcriptional and translational control of R genes for BSR

The ability to regulate gene expression and protein translation to generate quantitative phenotypic changes is crucial for developing novel and desirable traits in crops, including enhanced BSR (Xue et al., 2023). Gene expression is governed by diverse regulatory elements, including promoters, 5′ upstream open reading frames (uORFs), and 5′ and 3′ untranslated regions (UTRs). In the context of crop disease resistance, these regulatory elements play a significant role in modulating resistance levels. For example, in wheat, a transposon insertion in the 3′ UTR of the R gene Pm41b reduces its expression and resistance to powdery mildew (Li et al., 2022b). In rice, 3′ UTR polymorphisms in two S genes, RNG1 and RNG3, are associated with changes in their expression levels and blast resistance (Xu et al., 2023a). Cis-regulatory element variants generally induce subtle phenotypic changes by modulating the expression levels of target genes, making the editing of these elements a promising strategy for improving agronomic traits. For example, CRISPR-Cas9-mediated mutagenesis of the SlCLV3 promoter in tomato generates novel cis-element alleles, leading to a wide range of quantitative variations in gene expression (Rodríguez-Leal et al., 2017). The CRISPR-Cas12a promoter editing (CAPE) system has been applied in rice to produce quantitative trait variation continuums for grain starch content, size, and semidwarfism by targeting OsGBSS1, OsGS3, and OsD18, respectively. This approach could be adapted for BSR engineering in crops (Zhou et al., 2023). In addition to editing cis-regulatory elements, introducing transcriptional regulatory proteins is another effective method for manipulating gene expression. CRISPR-dCas-mediated transcriptional interference (CRISPRi) and activation (CRISPRa) are used to suppress or enhance gene expression, respectively (Heidersbach et al., 2023). While altering gene expression by fusing dead Cas9 (dCas9) with transcriptional or epigenetic regulators has been widely explored in mammalian systems and model plants, its application for achieving BSR in crops is still emerging. Recently, CRISPRi has been applied to pathogens for pathogenesis studies. Zhang et al. (2023b) developed a novel CRISPRi toolkit that employs a single guide RNA to achieve a 100-fold reduction in target gene expression. Using tRNA-gRNA strategies, they simultaneously silenced MoATG3, MoATG7, and UvPal1 in rice blast and false smut fungi, respectively, facilitating functional genomics studies of these two devastating fungal pathogens. This approach provides new targets for crop BSR engineering (Zhang et al., 2023b). Another promising approach to achieving BSR is pathogen-induced CRISPRa, which upregulates genes involved in plant immunity. For example, diacylglycerol kinase 5, which is involved in phosphatidic acid biosynthesis, contributes to resistance against both bacterial and fungal pathogens (Gong et al., 2024). In a recent study, Yao et al. (2024) introduced an in-locus activation technique to achieve efficient multiplexed gene upregulation in rice through CRISPR-Cas-mediated insertion of short transcriptional enhancers into target gene promoters (Yao et al., 2024). The ability of CRISPRi and CRISPRa to simultaneously control the expression of multiple genes makes them powerful tools for achieving BSR in crops. These techniques allow precise reprogramming of R and S genes, which could strike a balance between disease resistance and other important traits in crops. Given the potential of these methods, they are likely to become key components of crop improvement strategies aimed at enhancing disease resistance.

In addition to altering gene expression levels using the methods described above, 5′ uORFs are important alternative targets for genome editing due to their role in the regulation of protein translation (Si et al., 2020). For example, in rice, uORF_TBF1-mediated translational control of NPR1, a master regulator of SA-mediated immunity, is used to precisely regulate its protein translation, resulting in enhanced BSR to rice blast, bacterial blight, and bacterial leaf streak without affecting other agronomic traits (Xu et al., 2017). Similarly, by editing the uORF to suppress the translation efficiency of OsGS2 in rice, BSR has been achieved with minimal fitness costs (Tian et al., 2024). Base editing and prime editing technologies have also been used to generate novel uORFs or extend existing ones, enabling the fine-tuned regulation of protein translation to produce differential phenotypes. For instance, a series of rice plants with graded phenotypes was generated by editing the 5′ UTR of OsDLT, a gene involved in the brassinosteroid signaling pathway (Xue et al., 2023).

Precise control of gene expression is the goal of CRISPR-Cas-based transcriptional and translational tools. AI-guided genome editing has become an increasingly effective strategy for generating desired traits by fine-tuning the expression levels of target genes. When combined with techniques such as assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and other data providing candidate sites for promoter editing, these strategies can be used to manipulate R gene expression and enhance resistance without a growth trade-off in crops (Liu et al., 2021a; Hendelman et al., 2021; Zhou et al., 2023).

Concluding remarks and prospects

Genetic resistance to crop diseases, particularly BSR, is essential for global food security. Here, we reviewed the plant immune system, common BSR genes and their mechanisms, and genetic engineering approaches, including genome editing, for enhancing BSR. A mechanistic understanding of the plant immune system, including the mutual potentiation of PTI and ETI, along with insights into the biochemical and structural nature of R proteins, significantly advances our knowledge for BSR engineering. Some R genes have evolved to provide enhanced BSR, offering valuable insights for engineering new immune receptors with enhanced BSR. For instance, some orphan receptors have been modified to mimic the effector-binding region of Sr35, enabling them to recognize the non-corresponding effector Avr35 (Förderer et al., 2022). These findings suggest that novel elite R gene alleles can be identified and integrated into crops to rapidly improve BSR.

Moreover, the study of paired R genes presents an innovative strategy for R protein design, which can be widely applied to enhance BSR (Liu et al., 2021d; Zhang et al., 2024b). For example, fusing the NLR Pikm with a nanobody that recognizes fluorescent proteins provides resistance to potato virus X, which expresses the corresponding fluorescent proteins (Kourelis et al., 2023). In addition, newly developed AI-enabled protein design algorithms, such as Rfdiffusion, are facilitating the design of R proteins with enhanced functionality (Watson et al., 2023).

Genome editing will continue to play an increasingly important role in future BSR development. Technological advancements will make genome editing more versatile, enabling diverse strategies for improving disease resistance. Large-scale genome-edited crop populations will provide numerous genetic variants for novel R gene alleles. The recent development of the PrimeRoot genome editing tool, which allows the insertion of large fragments into crop genomes, offers a promising avenue for rapidly stacking R genes for BSR in different crops (Sun et al., 2024a). Furthermore, AI-enabled technologies will accelerate precise genome editing for BSR, advancing molecular breeding efforts. Multiplexed genome editing to target multiple S genes for BSR will also play an important role in the future of BSR engineering across various crops.

In addition to the aforementioned engineering approaches, natural and mutagenized crop populations will continue to be important sources of BSR genes. These populations have already been developed for several major crops. For instance, a whole-genome-sequenced wheat population consisting of 827 wheat lines from Watkins landraces and 3366 whole-genome-sequenced chickpea varieties has provided 1582 previously unutilized genes, representing an untapped source of new BSR genes (Varshney et al., 2021; Cheng et al., 2024). In rice, a set of 18 142 rice lines, derived from 16 parent accessions of diverse geographic origins, was used to map 1207 quantitative trait loci for 16 agronomic traits using genome-wide association studies, offering a large genetic resource for BSR in crop improvement (Wei et al., 2024a). In maize, a high-density genomic variation map based on 744 maize genomes identified over 70 million SNPs, providing another valuable resource of genetic diversity for the identification of novel BSR alleles (Chen et al., 2022b). The sequencing of multiple wheat genomes has enabled multi-genome comparisons and characterization of the wheat NLR repertoire, facilitating the identification of Sm1, a gene associated with insect resistance (Walkowiak et al., 2020). These genetic resources are expected to play a pivotal role in the rapid identification and cloning of crop BSR genes in the future.

As genome editing tools continue to advance and demonstrate success in the genetic improvement of crops, regulatory barriers to transgenic and genome-edited crops are gradually easing (Vora et al., 2023). Attitudes toward the regulation of such crops are becoming more open, facilitating the broader application of genetic engineering and genome editing to enhance BSR in various crops. In summary, the rapid advancement of genetic engineering technologies, including genome editing, combined with positive changes in regulatory policies toward transgenic and genome-edited crops, is accelerating the commercialization of genetically modified crops with substantial implications for global food security.

Glossary

ABE: adenine base editor. Composed of Escherichia coli transfer RNA adenosine deaminase and nCas9 (D10A); mediates the conversion of A⋅T to G⋅C in genomic DNA.

AMP: antimicrobial peptide. Endogenous polypeptides produced by multicellular organisms; play a crucial role in the innate immunity of the host.

BSR: broad-spectrum resistance. Plant disease resistance to most races or strains of the same pathogen species or resistance to multiple pathogen species.

CBE: cytosine base editor. Composed of cytidine deaminase fused with nCas9 (D10A) and uracil glycosylase inhibitor; converts C⋅G to T⋅A in genomic DNA.

CRISPR-Cas: Clustered regularly interspaced palindromic repeats/CRISPR-associated proteins. Targets DNA or RNA in microbes as part of the adaptive immune system and has been engineered into the canonical genome editing tool for RNA-guided genetic manipulation.

DTI: danger-triggered immunity. A process whereby plant plasma membrane receptor kinases recognize plant-derived DAMPs and subsequently initiate host immune responses.

EBE: effector binding element. A DNA sequence that TAL effectors recognize and bind. The presence of an EBE in the promoter of a gene makes the gene inducible by TALE effectors.

Effector: A protein produced by pathogens that is secreted into host cells and can disrupt the plant immune response or alter plant gene expression to facilitate infection.

ETI: effector-triggered immunity. The process by which pathogen effectors are sensed by NLR receptors to activate a strong immune response.

LMM: lesion-mimic mutant. A mutant that typically exhibits autoimmunity and HR-like cell death in the absence of biotic or abiotic stress.

NLR: nucleotide-binding LRR receptor. An immune receptor that recognizes pathogen effectors within the cell.

PAMP: pathogen-associated molecular pattern. A highly conserved molecular structure present in microorganisms, such as chitin and flagellin.

PE: prime editor. Composed of a Cas9 nickase (Cas9 H840A) fused to a reverse transcriptase, which utilizes a prime editing guide RNA to target and encode specific edits. PEs can introduce all 12 types of base substitutions and small DNA indels in a precise and targeted manner.

PrimeRoot editor: prime editing-mediated recombination of opportune targets (PrimeRoot). A tool derived from prime editors that combines a PE and site-specific recombinases. It is capable of precisely inserting large DNA fragments into plants without DSB intermediates.

PRR: pattern recognition receptor. Located on the plasma membrane, PRRs can directly recognize specific molecular structures on the surface of pathogens.

PTI: pattern-triggered immunity. A type of plant immune system mediated by cell surface-localized PRRs. PTI is triggered by the recognition of conserved molecular structures present in pathogens.

Resistosome: a large oligomeric complex formed via the direct or indirect recognition of pathogen effectors by plant NLRs. Resistosomes play a crucial role in plant innate immunity and are divided into CNL and TNL types, which mediate plant immune responses.

RLK: receptor-like kinase. A specific type of transmembrane receptor kinase comprising an extracellular LRR domain, a transmembrane domain, and an intracellular kinase domain. RLKs play a pivotal role in immune signaling.

RLP: receptor-like protein. A type of transmembrane receptor that functions in plant immune processes, lacking a cytoplasmic kinase domain.

S gene: A plant susceptibility gene that facilitates pathogen infection and contributes to host susceptibility.

TAL effector: transcriptional activator-like effector. A protein secreted by the bacterial genus Xanthomonas via the type III secretion system. It possesses a DNA binding domain that activates host gene transcription of S genes to facilitate successful host colonization.

TIR-only protein: a type of protein that lacks canonical NLR architecture. The TIR domain represents a conserved immune module in both prokaryotic and eukaryotic organisms. Signaling regulated by TIR-only proteins is also critical for plant immunity.

TnpB: a transposon-associated RNA-guided endonuclease known to be the ancestral endonuclease of Cas12. The TnpB protein consists of about 400 amino acids and possesses double-strand DNA cleavage activity guided by right-end element RNA. TnpB proteins have been used to develop hypercompact genome editors.

Acknowledgments

This work was supported by Biological Breeding-National Science and Technology Major Projects (2023ZD04070), the Key R&D Program of Hubei Province (2023BBB171), the National Key R&D Program of China (2022YFA1304402), and Fundamental Research Funds for the Central Universities (2662023PY006, AML2023A05, 2662024ZKPY001) (to G.L.). This work was also supported by the Fundamental Research Funds for the Central Universities (2662023PY006) (to K.X.). This work was also supported by the National Natural Science Foundation of China (32172373 and 32293243) (to G.L. and K.X., respectively) and Hubei Hongshan Laboratory. No conflict of interest is declared. Figures were created with BioRender.

Author contributions

G.L., K.X., Q.Z., S.L., and X.H. planned the review outline. X.H. and S.L. wrote the majority of the manuscript and prepared the figures. Q.Z., P.S., S.L., and X.H. prepared Table 1. Q.Z., D.W., J.W., X.Y., Z.L., R.J.M., Z.K., K.X., and G.L. revised the manuscript. All authors read and approved the final manuscript.

Published: November 20, 2024

Contributor Information

Kabin Xie, Email: kabinxie@mail.hzau.edu.cn.

Guotian Li, Email: leeguotian@163.com.

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PERMALINK

Genetic engineering, including genome editing, for enhancing broad-spectrum disease resistance in crops

Xinyu Han

Shumin Li

Qingdong Zeng

Peng Sun

Dousheng Wu

Jianguo Wu

Xiao Yu

Zhibing Lai

Ricky J Milne

Zhensheng Kang

Kabin Xie

Guotian Li

Abstract

Introduction

Figure 1.

The plant immune system

Pattern-triggered immunity

Effector-triggered immunity

Atypical R genes

Unified plant immunity

Phytohormones

Antimicrobial peptides and phytoalexins

Current understanding of BSR mechanisms in crops

Figure 2.

Table 1.

Positive regulators of plant immunity conferring BSR

Loss of susceptibility and LMM genes conferring BSR

Gene stacking of R genes for BSR using a traditional breeding strategy

Traditional genetic engineering facilitates BSR

Transgenic approaches to combine R gene-mediated BSR in crops

Antimicrobial peptides and phytoalexins can facilitate BSR in crops

Epigenetic modifications conferring BSR in crops

RNAi-mediated BSR

Genome editing for BSR

Figure 3.

Figure 4.

Targeted insertions and substitutions for BSR

Saturation mutagenesis for new R genes alleles

Figure 5.

Editing S genes and negative regulators of resistance for BSR

Transcriptional and translational control of R genes for BSR

Concluding remarks and prospects

Glossary

Acknowledgments

Author contributions

Contributor Information

References

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