Throughout history, plant pests and diseases have had a profound influence on human history, causing episodes of food insecurity and human suffering that have scarred our shared past. Devastating outbreaks, such as the Irish Potato Famine in the 19th century, have caused widespread hunger, economic turmoil, and mass migration with long-lasting historical consequences. Since the “green revolution” in the second half of the 20th century, our high-intensity food supply chain has become increasingly dependent on crop monocultures that are critically reliant on the excessive use of pesticides to protect against pests and diseases. However, this reliance is no longer deemed sustainable. In addition to concerns about non-target effects in the environment (1–4), the development of resistant pests, and concerns about the human health impacts of chemical residues in food products, the production and application of pesticides also generate a significant carbon footprint (5). Increasingly, such concerns have begun to influence agricultural policies globally. For example, the European Commission has proposed new policies with agricultural initiatives to reduce pesticides, such as the “European Green Deal” and “Farm to Fork Strategy” (6), which both propose a target of a 50% reduction in agrochemicals by 2030. Similar policies are being pursued in Japan, via the “Sustainable Food Systems Strategy MIDORI” (7), in the United States (8), and globally under the umbrella of the United Nations (9).

However, phasing out pesticides without replacing them with reliable alternatives can expose the food supply chain to risks that seriously affect regional food security and increase the volatility of the global food economy (10–13). Hence, there is an urgent need to identify and implement reliable alternatives to pesticides. One of the currently emerging crop protection practices identified by the European Commission is to harness strategies naturally employed by plants to resist pests and diseases (6). A plant’s immunity can be strengthened by stimulation with certain pathogens, pests, beneficial microbes, chemical agents, physical wounding, or herbivory (14). This phenomenon, known as induced resistance (IR), often provides broad-spectrum protection against a variety of pests and diseases (15, 16). IR allows plants to respond more quickly to biotic stressors (16) and can be combined with other crop protection strategies (15). IR is crucial for minimizing reliance on pesticides; moreover, in conjunction with our increasing knowledge of internal (immunological) and external (ecological) plant defense strategies (17), ample new opportunities exist to expand our current toolkit to ensure the sustainability of future plant health management. In turn, this contributes to achieving global food security and ensuring a sustainable food supply for a growing population.

Plants, much like all higher organisms, rely on several strategies to defend themselves against pests and pathogens ( Figure 1 ). The first line of self-defense is controlled by the plant’s innate immune system, which operates according to a genetic blueprint that enables plants to detect signals and activate their inducible defense mechanisms. The innate immunity of plants has been studied extensively over recent decades and conceptually involves two separate layers (18, 19). The default layer, known as pattern-triggered immunity (PTI), responds to microbial molecular patterns such as flagellin, elongating factors, and danger signals and involves a variety of defense genes and mechanisms. This innate immune response provides a wide range of protection against different styles of attack. However, it has the disadvantage of being relatively weak against specialized attacks that involve PTI-suppressing virulence effectors (20). As an evolutionary response, plants can defend themselves via effector-triggered immunity (ETI), which is based on resistance (R) genes. R genes encode intracellular receptors that can activate the hypersensitivity immune response upon the direct or indirect recognition of immune-suppressive virulence effectors and are critical for so-called gene-for-gene, race-specific, or vertical resistance (21, 22). Despite the highly effective response of ETI to biotrophic parasites, its range of effectiveness is typically limited to a single species or even subspecies levels, such as pathovars. Moreover, the ongoing co-evolution by ETI-resistant attackers is selective for the emergence of new virulence effectors that are no longer recognized by existing R proteins, rendering ETI ineffective.

While PTI and ETI are important first layers of defense, plants require additional strategies to survive in hostile environments. When plants successfully repel initial assaults by pests or diseases they develop acquired or induced resistance through the activation of their own immunity. IR often involves a form of immunological stress memory referred to as “defense priming”—a phenomenon that conditions plants for enhanced stress resilience. Stress or defense response pathways are initially only weakly activated upon exposure to the priming agent but are then more strongly or rapidly induced when the plant is later challenged by an attacker (16, 23, 24). A classic example of defense priming is systemic acquired resistance (SAR), which occurs in response to localized pathogen attacks, triggering the release of long-distance defense signals that prime distal plant parts for the efficient activation of defenses upon later attacks, leading to enhanced resistance in a phenomenon similar to vaccination in humans (14). This phenomenon involves the finely tuned regulation of phytohormone signaling, elevated levels of pattern recognition receptors or dormant defense regulatory elements, and chromatin modifications (16, 25, 26). The priming effect can be long-lasting; it can even be transmitted to the next generations (27–32). There is mounting evidence that the long-term maintenance of priming is controlled by epigenetic changes, such as the reduced DNA methylation of transposons and the trimethylation of lysine 4 of histone subunit H3 (H3K4me3) at defense gene promoters, which have also been implicated in “poised” genes (genes in a “ready to be active” state) in animals [ Box 1 , (26)]. However, much remains to be discovered about the mechanisms through which stress-induced epigenetic changes prime stress-specific defense genes, how these epigenetic changes are maintained over cell division and sexual reproduction, and, ultimately, how they are erased in the absence of recurrent stress.

Plants also employ external ecological pathways to adapt to biotic stress; this is known as “indirect induced defense” or “plants crying out for help” (33). This mechanism allows plants to recruit other organisms to combat attackers. For example, the herbivore-induced emission of volatile organic compounds (VOCs) can attract predatory or parasitic insects that attack the impeding herbivore (34). Recently, similar interactions have been discovered above and below ground, where stressed plants alter their root exudation and headspace VOC chemistry to select and/or recruit a disease-suppressive microbiome. This also activates an immune response in neighboring plants, which protects the plant via a range of direct and indirect mechanisms, including induced systemic resistance (ISR) (35–37).

The current approach to crop protection still relies largely on pesticides and selective breeding for R genes, whereas strategies such as IR remain relatively underexploited. Unlike pesticides, IR is not curative and rarely provides complete protection against pests or microbial pathogens. Moreover, IR chemicals may have associated allocation fitness costs (trade-offs), such as reduced plant growth and yield or increased susceptibility to other stresses. These reasons may contribute to IR remaining underexploited. However, when applied in the correct context, IR offers numerous benefits. In addition to its broad-spectrum effectiveness, IR can help reduce pathogen loads, synergize with other management methods, and protect single R gene strategies from co-evolving pests and disease adaptations. This can help to decrease our reliance on unsustainable pesticides (38).

In this review, we explore the potential applications of IR and discuss how it can be integrated with the use of pesticides, other crop protection methods, and breeding strategies. By examining the costs and benefits of IR, we aim to establish a realistic framework for the safe exploitation of IR within current crop protection schemes.

Reports on how IR combats plant pathogens date back to the 1930s ( Figure 2 ). Initially, these reports were descriptive, presenting instances in which IR-like phenomena were observed [reviewed in Chester (39)]. In 1961, the term SAR was introduced by Frank Ross, who reported an experiment showing that inoculating a tobacco leaf with tobacco mosaic virus (TMV) led to resistance against the same virus in distal non-inoculated leaves 1 week after the first inoculation. In the 1960s, numerous studies on the biological induction of resistance were conducted in various plant species in which resistance was triggered by pathogens such as viruses, bacteria, and fungi (40).

A novel aspect of IR was described in a report by White (41): it showed that infiltration of the leaves of tobacco plants with salicylic acid (SA) led to SAR against TMV and induction of pathogenesis-related (PR) proteins. This is consistent with the later-described effects of endogenous SA during plant defense (42, 43). Ultimately, this discovery allowed screening programs that identified the functional analogs of SA as IR elicitors, which yielded products such as 2,6-dichloroisonicotinic acid (INA) and acibenzolar-S-methyl (ASM; an active ingredient of the commercial product Bion) (44, 45). As early as 1975, oryzimate was used as a resistance inducer in rice seedlings (46). Transgenic plants, such as SA-degrading NahG plants, which cannot accumulate SA (47), or the Nonexpressor of pathogenesis-related genes 1 (npr1) Arabidopsis mutant (48, 49), have helped to provide a deeper mechanistic understanding of IR signaling. Similarly, the discovery of jasmonic acid (JA) as an endogenous wound-inducible IR signal against insects and necrotrophic pathogens (50, 51) led to new research into the biosynthesis and response pathways of this IR-related hormone (52). Toward the end of the 2000s, researchers independently reported long-distance signals mediating systemic IR responses, such as methyl salicylate (53), azelaic acid (54), glycerol-3-phosphate (55), dehydroabietinal (56), and N-hydroxy pipecolic acid (57) for SAR, as well as electrical signals for the systemic IR response to wounding (58).

At approximately the same time, it was discovered that prolonged maintenance of IR-related defense priming involves epigenetic control (26) ( Box 1 ), offering a plausible mechanism for the long-term (and sometimes transgenerational) durability of IR. More recently, it was shown that IR-related priming can be genetically engineered by fusing the NPR1 gene to a pathogen-responsive untranslated open reading frame (59) or epigenetically induced by the introgression of meiotically stable regions of reduced DNA methylation (60).

In the early 1990s, it was shown that IR was developed upon recovery from biotic stress, such as localized disease or herbivory, as well as being triggered by the root colonization of beneficial plant growth-promoting rhizobacteria (PGPR) (61–63).

ISR typically operates independently of SA but requires NPR1 and the intact jasmonate and ethylene (ET) signaling pathways (64–66). Subsequently, IR induction by beneficial fungi such as mycorrhizae (67) and even whole microbiota (68, 69) has been amply documented ( Box 2 ).

Indirect induced defense by plants was initially described for plant–herbivore interactions, whereby the release of herbivore-induced plant volatiles (HIPVs) recruit natural enemies of the herbivore, such as predatory spider mites or parasitic wasps (94–96). The discovery of this “cry-for-help” led to follow-up studies showing that insect-derived elicitors, such as glucose oxidase and volicitin, boosted wound-induced volatiles (97) and that similar tritrophic interactions could occur below ground, allowing the recruitment of entomopathogenic nematodes (98). Based on enhanced knowledge of the genetic control of HIPVs, subsequent studies also provided proof of concept that the “cry-for-help” mechanism could be exploited in genetic strategies to improve crop protection (99, 100). In subsequent years, it became clear that both volatile and non-volatile metabolites in root exudates could recruit and/or select for disease-suppressive soil microbes (101–103). This precipitated more recent studies that have shown that the “cry-for-help” via root exudates conditions the soil for ISR-eliciting microbial consortia (104, 105). As for the internal epigenetic maintenance of IR (26), this “cry-for-help” in root exudates can protect plants across generations by conditioning the soil microbiome for disease-suppressive activity (17, 36), and it offers a plausible explanation for earlier reports about the development of disease-suppressive soils upon multiple cultivations with high disease incidence (e.g., take-all decline) (106).

Knowledge about microbe-, herbivore-, and damage-associated patterns triggering IR, such as cell wall components (e.g., oligogalacturonides from pectin; laminarin from algae; flagellin from bacteria; and Reynoutria extract, chitin, and chitosan from fungi and insects), as well as endogenous IR signals, such as β-aminobutyric acid (BABA), have allowed the development of commercial products in which microbes themselves or derived molecules constitute the active principle ( Supplementary Table 1 ). Further development of such commercial products is ongoing: for example, there is a product based on the pheromone ascaroside 18 that is secreted by plant-parasitic nematodes (107, 108). Ascaroside 18 induces resistance in a variety of plant species to a broad spectrum of pathogens by activating both the SA-mediated and JA-mediated defense pathways, and its receptor has been identified recently (109). Ascaroside 18 is expected to be placed on the market in 2026 (D. Klessig, Boyce Thompson Institute, personal communication ² ).

Over six decades of research support IR as a potentially highly promising strategy to protect crops. IR is effective in protecting plants against a broad range of pathogens and pests. Although it may not provide 100% protection under high disease-pressure conditions, it offers an alternative to ETI-based strategies when the R gene repertoire is limited or unavailable, such as against necrotrophic pathogens and chewing herbivore pests (110, 111). Its multigenic (horizontal) character allows it to overcome resistance breakdown, and it can thus be used when resistance breakdown to pesticides or gene-for-gene strategies occurs (112). In the case of emerging diseases and pests, IR can provide faster solutions than traditional breeding. IR also offers an alternative in pathosystems for which no effective pesticides are available or where their use has been (or will be) banned and no gene-for-gene strategies are available. Because of its wide spectrum of effectiveness, IR can provide immediate protection against these challenges ( Figure 3 ). Although the protection provided by IR may not necessarily be complete, it could still offer substantial benefits for farmers and protection against the devastating consequences of newly emerging pests and diseases.

Interestingly, the induction of plant defenses implies that plant secondary metabolism has been activated, which involves the biosynthesis of multiple bioactive compounds with health-promoting activities, such as polyphenols, carotenoids, flavonoids, phytoestrogens, and the activity of several antioxidant enzymes. Thus, the elicitation of IR, while stimulating plant defenses, frequently results in higher levels of these bioactive phytochemical compounds in fruits, vegetables, and herbs. Most of these metabolites have been investigated to assess their potential role in specific organoleptic properties of foods and show protective effects in human cells. Indeed, the application of biotic and abiotic elicitors and defense-related phytohormones during plant growth or the postharvest period has been used to enhance the production of secondary metabolites and produce high-quality and healthy fresh foods (113, 114). Beneficial plant symbionts triggering IR, such as mycorrhizal fungi and PGPR, can also improve the nutritional and nutraceutical value of fruits, as shown by the increased content of lycopene and beta carotene in tomato fruits, stronger anti-estrogenic activity (115–117) and higher concentrations of iridoids (oleuropein and secologanin) and flavonols in olive oil (118), and higher phenolics and anthocyanin content in berries (119).

Finally, therefore, IR in combination with low doses of chemical pesticides reduces the evolutionary pressure for pests and diseases to develop resistance against agrochemicals and may also complement R gene strategies by protecting available R genes against co-evolving pathogens (120–123). Under low- to moderate-pressure stress, IR is sufficient when stronger solutions are lacking or may function in complement or synergy with other plant protection methods. The current and emerging agri-tech solutions offer new opportunities to facilitate the incorporation of IR in common agricultural programs. In the next section, the limitations of IR, their potential solutions, and the application of IR in modern agriculture ( Table 1 ) are discussed.

The long-lasting effect of IR and its potential to be transmitted to subsequent generations is attributed to epigenetic reprogramming ( Box 1 ). The role of epigenetic regulation in the plant response to pathogens is an emerging area recently used to elucidate plant immunity mechanisms (26). One of the most remarkable pieces of evidence linking epigenetic mechanisms with plant immunity can be demonstrated through the priming of the SA-dependent defense in Arabidopsis, where transcription-promoting modifications of the histone H3 tail in the promoters of SA-inducible defense genes are found (183, 184). These modifications facilitate the formation of open chromatin to allow for faster and/or stronger induction of defense genes (185). Dynamic and transient changes in genome-wide DNA methylation have also been observed upon the elicitation of IR in plants. DNA hypomethylation appears to be an early hallmark of plant defense activation during the onset of IR.

The descendants of IR-elicited plants exhibit IAR, in which plants remain less susceptible to pathogens (30, 32, 186). However, the mediators, target regions, and physiological consequences of the intergenerational maintenance of IR remain largely unknown. Although the exposure of epigenetically heritable IR phenomena to stress tends to be variable with relatively low effect sizes (31, 151), epigenetic modifications at the level of DNA methylation can provide almost complete disease protection that is metastable over multiple generations. The proof of concept for this approach comes from recent studies of epigenetic inbred lines (epiRILs) of Arabidopsis expressing disease resistance against virulent pathogens (60, 187). These epiRILs are genetically identical but vary in DNA methylation at transposable elements (188, 189). Moreover, the epigenetic quantitative trait loci mediating stably inherited resistance to downy mildew have been shown to act through the priming of pathogen-inducible defense genes without concomitant reductions in plant growth (60). Hence, the introduction of epigenetic variation into genetically identical crop inbred lines would facilitate the selection of meiotically stable IR phenotypes. Intriguingly, the loss of function of decrease in DNA methylation 1 (DDM1), a chromatin remodeler responsible for gene body methylation, was recently shown to lead to enhanced responsiveness to suboptimal doses of BABA (190). To advance the selection of epigenetically primed plant varieties, more precise and adjustable methods are required to introduce epigenetic variation into plant genomes. For example, the recent development of “reverse epigenetics” methods, such as the clustered regularly interspaced short palindromic repeats (CRISPR)-based multimodal targeting of chromatin remodelers, allows the precise modulation of IR-regulating epi-loci (191). Recently, an artificial zinc-finger fusion construct of various proteins involved in epigenetic regulation was demonstrated to direct gene silencing of specific target genes in Arabidopsis (22). Although translation to crop plants is still required, this could be of great value for the crop protection and breeding industry. This could also act as a valuable research tool to explore the complex mechanisms by which epigenetically altered genomes prime defense genes and mediate IR. Therefore, more detailed mechanistic studies are needed, not only to decipher the pathways by which plants acquire and maintain their epigenetic stress memory of IAR but also to understand how they erase these stressful memories. Insight into these epigenetic regulatory mechanisms will help improve the spectrum, effect size, and heritability of IR.

A series of hallmark events has accompanied the development of agriculture, from its infancy 12,000 years ago with continuous selection and breeding, through the improvement in yield using fertilizer and irrigation during the green revolution, the generation of crops with new attributes through transgenesis (GMOs), and the emergence of integrated pest management and crop improvements based on CRISPR-associated protein (CRISPR-Cas) technology, to utilizing IR to pathogens and pests, as presented in this review ( Figure 4 ). IR offers a remarkable opportunity to support our agricultural system in an environment exposed to rapidly expanding challenges—not only those relating to climate change that favor the rapid spread of pests and emergence of new diseases but also in response to the rapidly changing socioeconomic environment. As scientists, we can investigate the mechanisms underlying IR, as outlined above, propose research, development, and technological advancements, and strive to obtain feedback from extension workers and farmers who are willing to try and implement IR technology.

Efforts should also be invested at the legislative level. Clear guidelines concerning the quality control and efficacy of marketed IR products must be established and harmonized across countries and continents. Implementing quality standards, for example, in terms of stability, inoculum quality in the case of microbes, efficacy, and shelf-life, is of utmost importance.

In the report, The future of crop protection in Europe (192), the European Union proposes IR as one of the options to support the sustainability of European farmers to work sustainably while securing food production, preserving biodiversity and the environment, and supporting farmers’ incomes. According to this report, the potential impacts of IR will be seen in crop yield, food security, and the competitiveness of EU farming. Similar initiatives are taking place in Asia and the United States (193).

Recently, it has also become apparent that there is a substantial added value for the application of IR technologies for improving the nutraceutical value of foods, which can confer medical or health benefits, for example, in obesity, metabolic syndrome, inflammation, diabetes, hypertension, cardiovascular diseases, and cancer, by increasing the levels of bioactive compounds in induced plants (115, 119, 194).

In summary, the elicitation of plant defenses can lead to the production of safe and high-quality food, which is an important societal issue facing high demand by both consumers and producers and, at the same time, reduce the possible negative effects of current agricultural practices on the environment.

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fsci.2024.1407410/full#supplementary-material