Innate immune memory in plants

Seminars in Immunology 28 (2016) 319–327

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Seminars in Immunology journal homepage: www.elsevier.com/locate/ysmim

Review

Innate immune memory in plants Eva-Maria Reimer-Michalski, Uwe Conrath ∗ Department of Plant Physiology, RWTH Aachen University, Aachen 52056, Germany

a r t i c l e

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Article history: Received 11 February 2016 Received in revised form 12 May 2016 Accepted 17 May 2016 Available online 2 June 2016 Keywords: Defense priming Epigenetic memory Plant innate immunity Systemic plant immunity

a b s t r a c t The plant innate immune system comprises local and systemic immune responses. Systemic plant immunity develops after foliar infection by microbial pathogens, upon root colonization by certain microbes, or in response to physical injury. The systemic plant immune response to localized foliar infection is associated with elevated levels of pattern-recognition receptors, accumulation of dormant signaling enzymes, and alterations in chromatin state. Together, these systemic responses provide a memory to the initial infection by priming the remote leaves for enhanced defense and immunity to reinfection. The plant innate immune system thus builds immunological memory by utilizing mechanisms and components that are similar to those employed in the trained innate immune response of jawed vertebrates. Therefore, there seems to be conservation, or convergence, in the evolution of innate immune memory in plants and vertebrates. © 2016 Elsevier Ltd. All rights reserved.

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Introduction: the plant immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 1.1. Nonhost resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 1.2. MAMP- and effector-triggered immunity and their interplay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 1.3. Systemic plant immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 1.3.1. Systemic acquired resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 1.3.2. Induced systemic resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 1.3.3. Wound-induced resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 1.3.4. Chemically induced immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 1.3.5. Other types of systemic plant immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Defense priming – the innate immune memory of plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Molecular mechanisms of defense priming . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 3.1. Accumulation of PRRs and dormant signaling compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 3.2. Chromatin dynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 Inheritance of immune priming in plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 Similar innate immune priming in plants and mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

Abbreviations: Arabidopsis, Arabidopsis thaliana; Avr, avirulence; BTH, benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ester; HR, hypersensitive response; JA, jasmonic acid; NHR, nonhost resistance; NPR1, nonexpresser of PR genes 1; Pip, pipecolic acid; SA, salicylic acid; SAR, systemic acquired resistance; WIR, wound induced resistance. ∗ Corresponding author. E-mail addresses: [email protected] (E.-M. Reimer-Michalski), [email protected] (U. Conrath). http://dx.doi.org/10.1016/j.smim.2016.05.006 1044-5323/© 2016 Elsevier Ltd. All rights reserved.

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1. Introduction: the plant immune system Plants are a rich source of nutrients and that is why they host a diversity of microbes on their shoot (stem, leaves, and reproductive structures) and root. They are protected from microbial infection by a waxy cuticle atop their shoot or, in case of perennials, by a protective periderm that mainly consists of dead cork cells. Would-be pathogens overcoming these barriers encounter a multilayered immune system comprising constitutive and inducible defenses. In contrast to jawed vertebrates, plants did not evolve mobile immune cells nor did they develop an adaptive immune system. Nonetheless, plants are capable of deploying various innate immune responses to ward off pathogens and remember previous infection. 1.1. Nonhost resistance Nonhost resistance (NHR) is the most prevalent form of plant immunity. NHR enables a plant species to ward off microbes and viruses that cause infectious diseases on other species of plant [1,2]. NHR is extraordinarily powerful and utilizes both constitutive and inducible defenses [3,4]. The former comprise, for example, the waxy cuticle and suberized cork cells, whereas the latter encompass the accumulation of antimicrobial secondary metabolites, such as the so-called phytoalexins (Greek for ‘plant defender’) [5]. Inducible defenses are being activated, e.g. upon recognition of microbeassociated molecular patterns (MAMPs) by pattern recognition receptors (PRRs) at the plant cell surface [6] and downstream cellular signaling. In contrast to mammals [7], plants do not seem to possess intracellular PRRs [8]. NHR is thought to result from multiple defense mechanisms that are supposedly regulated by even more defense-related genes [9,10]. Presently known key players of NHR to nonadapted fungi in the reference plant thale cress (Arabidopsis thaliana, hereafter called Arabidopsis) are plasma membrane-localized ATP-binding cassette (ABC) transporter PENETRATION (PEN) 3 (also called PDR8 or ABCG36) and myrosinase PEN2. The two proteins cooperate while activating, and presumably exporting, one or more antimicrobial plant secondary metabolite(s), such as glucosinolates [11–13]. In Arabidopsis, loss of PEN3 results in susceptibility to some nonadapted microbial pathogens, alters susceptibility to adapted infectious bacteria, and attenuates the hypersensitive response (HR, a programmed cell death response in plants) and fungal race-specific disease resistance [12,14–17]. Upon inoculation, PEN3 focally accumulates at sites of attempted fungal penetration, underneath papillae (appositions to the plant cell wall that serve as structural penetration barriers), and in extracellular encasements surrounding fungal feeding organs – so-called haustoria [12,18,19]. Focal PEN3-GFP accumulation was also seen after inoculation of transgenic Arabidopsis plants with adapted (infectious) bacteria or upon treatment with flg22, a MAMP in bacterial flagellin (see below) [16,19]. Upon Arabidopsis challenge with flg22, fungal xylanase, or the peptide RALF, PEN3 is being phosphorylated [20,21], possibly by Ca2+ -dependent protein kinase 10 [22]. Although it is unclear whether PEN3 phosphorylation is important to PEN3 function, it is suggestive of a kinase-dependent signaling pathway regulating PEN3 activity in the Arabidopsis immune response [20]. A recent study disclosed the Ca2+ -interacting protein calmodulin 7 as a PEN3 interactor crucial to Arabidopsis NHR [23] also suggesting a role of Ca2+ -dependent protein kinases in NHR. 1.2. MAMP- and effector-triggered immunity and their interplay The activation of inducible plant defense responses is triggered, for example, upon activation of cell surface-localized PRRs by evo-

lutionary conserved MAMPs. This induced plant disease resistance is referred to as MAMP-triggered immunity (MTI) or, less accurate, pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI). Probably the most prominent example of MAMP/PRR interaction is the activation of the leucine-rich repeat receptor kinase (LRR-RK) FLAGELLIN-SENSING2 (FLS2) by bacterial flagellin [24,25]. FLS2 recognizes a N-terminal, immunogenic epitope of 22 amino acids in flagellin, referred to as flg22 [24,25]. Flg22 binding to FLS2 induces immediate recruitment of BAK1, a LRR-RK acting as a coreceptor for flg22, that is required to fully activate flg22-triggered immunity [26]. Other prominent MAMP/PRR pairs with a role in plant defense are the bacterial elongation factor Tu (EF-Tu)/EFR (another LRR-RK duo), the fungal chitin/CERK1 (Arabidopsis) and chitin/CEBiP (rice) pairs [26,27]. MTI typically wards off multiple microbes, no matter whether infectious or not, likely because of the conserved nature of MAMPs across diverse species, genera, families, orders, or even classes of pathogens [28,29]. Thus, to no one’s surprise MTI is a likely key component of NHR [29–31]. Consistent with its broad spectrum of activity, MTI is associated with complex downstream signaling and excessive transcriptional reprogramming [8,31–33]. Recent studies suggested that endogenous danger/damage-associated molecular patterns (DAMPs) help amplifying MTI to establish a robust systemic plant immune response [34–38]. Bacterial pathogens that during evolution adapted to a given plant species suppress MTI by secreting, via their type III secretion system, effector molecules that impair MTI signaling [39–41]. This then causes so-called effector-triggered susceptibility (ETS) in the plant [6,42–46]. Different from bacteria, pathogenic oomycetes and fungi seem to secrete effector proteins from their haustorium [47–49]. Another component of plant defense is based on the direct or indirect recognition of pathogen effectors, previously called avirulence (Avr) proteins, by appropriate plant resistance (R) proteins. The direct interaction of effectors with R proteins leads to socalled gene-for-gene immunity [50,51]. In the indirect recognition of pathogen effectors, watchdog R proteins guard the integrity of cellular proteins, and when they sense modification or degradation of these proteins by appropriate effectors, they will initiate plant defense. This scenario has conceptually been described in the so-called guard hypothesis [6,52–56]. Independent of whether pathogen effectors are recognized directly or indirectly, their perception causes intense and highly robust effector-triggered immunity (ETI). In plants, ETI is often, although not always associated with HR [57–59], a localized programmed cell death response supposed to avoid spread of biotroph pathogens to the healthy tissue of plant. Both, MTI and ETI are associated with complex defense signaling which includes reactive oxygen species release, mitogenactivated protein kinase (MPK) activation, plant hormone synthesis and signaling, metabolic changes, excessive transcriptional reprogramming, and the synthesis and accumulation of phytoalexins and other secondary metabolites [6,60–62]. MTI and ETI trigger very similar transcriptional reprogramming in the plant, independent of the origin of the MAMP or effector [27,63]. However, the transcriptional ETI response usually is faster, stronger, and/or more prolonged than MTI-associated gene expression [60,62–64]. Thus, although quantitatively different, MTI and ETI seem to act in concert when conferring plant immunity [6]. Very recent studies suggested strong similarity of defense responses associated with MTI and ETI in both animals and plants. While in the latter ETI is known since many years, research in the animal field just recently provided some mechanistic insight into ETI [51,65–70]. Despite many similarities in the defense responses associated with MTI and ETI in animals and plants, the latter do not possess adaptive immunity. The absence of an adaptive immune response likely forced plants to evolve a multiplicity of PRRs, whereas

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animals elaborated only few PRRs for recognizing very highly conserved MAMPs [26,65]. 1.3. Systemic plant immunity 1.3.1. Systemic acquired resistance In plants, localized pathogen attack, whether inducing an HR or moderate symptoms of disease, often elicits broad-spectrum immunity to reinfection throughout the whole body. This type of systemic plant immunity is called systemic acquired resistance (SAR) [71–75]. SAR wards off diverse biotroph pathogens, lasts from few days to the lifetime of plant, and can be inherited [54]. SAR was extensively studied in the early 1960s [75] but only almost thirty years later it was disclosed that in tobacco and cucumber, SAR is associated with the accumulation of the plant hormone salicylic acid (SA) [76,77]. Later it turned out that SA is indispensable for SAR, at least in tobacco and Arabidopsis [78–80]. Recent work by Zeier and coworkers [81] disclosed another essential metabolite in SAR, that is the lysine catabolite pipecolic acid (Pip). Both SA and Pip activate overlapping, but distinct sets of defense-related genes when activating the SAR response [82]. The identity of the suggested molecule that moves from the site of initial pathogen attack to the healthy tissues to signal SAR is still under much debate [83,84]. It seems that a set of signals, rather than a single molecule, signals SAR to the plant. The set of signals seems to contain SA, methyl-SA (MeSA), Pip, dehydroabietinal, methyljasmonic acid (MeJA), glycerol 3-phosphate (G3P) or a glycerol 3phosphate derivative, and/or azelaic acid (AzA) [84–86]. 1.3.2. Induced systemic resistance Plants host a diversity of bacteria and fungi on or in their shoot and root [87]. Some of these are infectious, while others do not harm the plant. Certain root-colonizing bacteria and fungi even promote growth and yield, and provoke immunity in the host [88,89]. Most prominent examples for such beneficial microorganisms are certain Pseudomonas fluorescens strains [86], some species of the Trichoderma genus of fungi [90], the fungal endophyte Piriformospora indica [91], and some mycorrhizal fungi. ‘Mycorrhiza’ (Greek for ‘fungal root’) refers to the symbiotic association of fungi and the root of vascular plants. In fact, more than 80% of vascular plant species are associated with mycorrhizal fungi. The plant immune response that is activated by root-colonizing, growth/yield-promoting bacteria and fungi is called induced systemic resistance (ISR) [92]. In Arabidopsis, the ISR response that is activated by Pseudomonas fluorescens fends off multiple necrotizing microbes. It does not require SA for activation but rather depends on sensitivity to the plant hormones jasmonate (JA) and ethylene (ET) [92]. Because SAR and ISR engage different signaling pathways, activation of both these systemic immune responses can result in additive effects [93]. However, negative crosstalk of the SA and JA/ET signaling pathways was also reported [94–96]. SAR and ISR hold great promise for sustainable agriculture because both these plant immune responses have broad-spectrum activity, last for days till months, and do not considerably affect plant fitness (see below). 1.3.3. Wound-induced resistance Insect feeding and egg deposition [97,98], or physical injury [99] can induce a systemic plant immune response that repels insect pests and/or microbial pathogens. This response is called woundinduced resistance (WIR). WIR is frequently accompanied by the accumulation of protease inhibitors. These proteins can inactivate proteases important to either etiopathogenesis or the digestion of plant tissue in the insect gut [100,101]. Genetic studies revealed that several compounds of the octadecanoid pathway (e.g. JA) can mediate wound-induced systemic defense gene activation, WIR,

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and repellence of herbivorous insects from the systemic tissue [102]. However, not all wound-induced genes are activated via JA [103], indicating complexity of wound-induced defense signaling in plants. 1.3.4. Chemically induced immunity Besides pathogens, microbial endophytes, and physical injury, many different chemical compounds can induce plant immunity [104,105]. These compounds include plant immunity-associated signals such as SA, Pip, (Me)JA, and AzA. ß-aminobutyric acid is another well-known chemical inducer of plant immunity [106]. Probably the most prominent example for a synthetic plant immunity activator is benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ester (BTH). BTH, also referred to as acibenzolar Smethyl, is a synthetic SA mimic [107–109]. The compound is likely to activate SAR via the SA signaling pathway [110]. In 1996, BTH was introduced to the agrochemical market as a socalled ‘plant activator’ [111] with trade names Bion® , Actigard® , or Boost® . However, BTH’s moderate and strictly protective activity disappointed farmers who were used to the excellent curative performance of standard fungicides. Therefore, BTH’s economic success was limited. However, because some blockbuster agrochemicals (e.g. strobilurin fungicides, imidacloprid), in addition to being toxic to the appropriate pathogen or pest, seem to act though systemic plant immunity, SAR, ISR, and other types of systemic immunity in plants are increasingly being exploited in agriculture [104,112]. 1.3.5. Other types of systemic plant immunity In addition to the above systemic immune responses, plants are capable of establishing immunity in response to metabolic disturbances. One frequently reported immunity phenotype in plants is the so-called ‘high-sugar resistance’. This type of inducible immunity is associated with elevated levels of soluble carbohydrates due to, for example, certain alterations in primary metabolism [113]. Various studies supported the ‘high-sugar resistance’ concept. For instance, application of sugar to various plant tissues, or provoking sugar accumulation in transgenic plants, can activate genes encoding antimicrobial pathogenesis-related (PR) proteins [114–116]. Similarly, transgenic potato tubers with reduced activity of the plastid ATP/ADP transporter AATP1(St) not only have reduced starch content, but they also display altered levels of primary metabolites, such as glucose and other carbohydrates [117,118]. The alterations in primary metabolism coincide with immunity to soft-rot (Pectobacterium atrosepticum) [119] and early blight (Alternaria solani) disease in tubers, and with resistance to late blight disease (Phytophthora infestans) in leaves [120]. Thus, in plants alterations in primary metabolism can cause tissue-specific immunity to disease. 2. Defense priming – the innate immune memory of plants Exposure of living cells or tissues to a stimulus often influences response to a later stimulus. This finding is testament to a memory to the initial stimulation. Accordingly, upon recognizing MAMPs, herbivore-associated molecular patterns, DAMPs, pathogen effectors, or certain xenobiotics (e.g., some fungicides or pesticides), plants are often promoted to a primed state of enhanced defense. Defense priming establishes in the tissue exposed to the stimulus and in the systemic, unharmed, or untreated parts of the plant. When primed, plants respond to very low stimulation (e.g. faint pathogen rechallenge or mild abiotic stress) with faster and stronger defense than unprimed plants, and this frequently comes with local and systemic immunity or abiotic stress (e.g. drought) tolerance. Defense priming, sometimes also called sensitization [121] or trained immunity [122,123], was first postulated

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in 1933 when Chester proposed the presence of inducible immunity in plants [74]. However, the priming phenomenon did not receive much attention until in the 1970s, when the Kuc´ lab provided experimental evidence for the presence of defense priming in various types of inducible plant immunity [124]. But, these early studies were mainly descriptive. That’s probably why the relevance of defense priming to the (inducible) plant immune response remained unclear. Only since the 1990s defense priming is an appreciated part of MTI, ETI, and essentially all types of inducible plant immunity [81,112,125–127]. Defense priming accompanies SAR, ISR, WIR, and chemically-induced immunity in plants [127]. Consistently, plant defense priming can be activated by treatment with SA, Pip, (Me)JA, AzA, and certain xenobiotics [104]. Arabidopsis mutants mpk3 and hsfB1 have defects in the immunity-associated mitogen-activated protein kinase (MPK) 3 gene or heat shock-responsive transcription factor locus HSFB1 [128,129]. Because both mpk3 and hsfb1 are defective in defense priming and SAR, but not the systemic accumulation of defensive PR proteins [128,129], priming seems to be more crucial to (inducible) plant immunity than the accumulation of enzymes or compounds with antimicrobial activity. Consistently, direct activation of antimicrobial defenses in plants frequently causes dwarfism probably because of high fitness cost [130]. By contrast, defense priming only marginally impairs fitness in stress-free situations but benefits the plant in times of stress [131–133]. A key question in plant immunity asks why plants in the wild, despite permanent presence of pathogens, are not constitutively primed at all times. Field studies revealed that many plants in the wild exhibit constitutively high defense, yet others can be primed for enhanced defense upon treatment with natural or synthetic immune stimulants [134–136]. The ability for inducible (primed) immunity also depended on the life cycle of plant. Perennials, that is plants that live for more than two years, show better capacity for inducible immunity than do annual plants which complete their life cycle, from seed germination to seed set, within a year [136–138]. 3. Molecular mechanisms of defense priming 3.1. Accumulation of PRRs and dormant signaling compounds Although defense priming has been known for many years, its molecular mechanisms remained elusive. A recent study demonstrated that treatment of Arabidopsis with BTH increased the level of FLS2 and its coreceptor BAK1 in microsomal preparations associated with enhanced responsiveness of the primed plants to flg22. The BTH-primed plants also had higher levels of the chitin receptor and peptidoglycan coreceptor kinase CERK1 [139,140]. These findings provide a possible explanation for why primed plants express enhanced defense upon perceiving diverse MAMPs and DAMPs associated with systemic broad-spectrum immunity. Consistently, the priming-deficient ald1 mutant of Arabidopsis has lower FLS2 and BAK1 levels and is more prone to Pseudomonas infection than wild type, probably because it lacks the Pip synthesis gene [81]. Thus, inducible plant immunity is associated with enhanced PRR and coreceptor levels, whereas PRR and coreceptor reduction attenuates plant immunity. A previous hypothesis proposed that defense priming involves accumulation of dormant enzymes important to cellular signal amplification [112,141]. In Arabidopsis, flg22 binding to FLS2 activates a hierarchical MPK cascade presumably composed of the enzymes MEKK1, MKK4/5, and MPK3/6 [142–146]. Because the cascade serves to amplify the flg22 signal, MPK3/6 and other components of the MPK cascade represent excellent candidates for cellular signaling enzymes that mediate defense priming. In 2009, Conrath and associates [128] demonstrated that in Arabidopsis defense priming, whether induced by local Pseudomonas infection

or SA/BTH treatment, results in enhanced accumulation of MPK3/6 mRNA transcript and protein in all leaves of plant. MPK3/6 are still kept inactive in primed cells but are ready-to-go in case of pathogen rechallenge. Upon reinfection, more MPK3/6 proteins were activated in primed than unprimed plants, associated with enhanced defense and systemic immunity. Accumulation of inactive protein monomers in leaves with systemic immunity was also reported for NONEXPRESSER OF PR GENES 1 (NPR1), a key immune regulator in plants [72,147,148]. Thus, the accumulation of dormant PRRs, MPK3/6, NPR1, and probably other proteins important to cellular signal transduction seems to provide a memory to previous infection by priming the cell for enhanced defense [128,149]. Consistent with this hypothesis, systemic immunity was reduced or absent, in the Arabidopsis mpk3, mpk6, npr1, and ald1 mutants with reduced levels of MPK3, MPK6, NPR1, or ALD1, respectively [81,128,150]. Enhanced accumulation of dormant proteins before, and activation of more of these proteins upon reinfection was also reported for several members of the WRKY family of plant transcription factors whose encoding genes are expressed upon SA/BTH treatment [151]. 3.2. Chromatin dynamics ATP-dependent chromatin remodeling and modification to, or replacement of, histones in chromatin control the transcriptional activity of genes in all eukaryotes [152–154]. In plants, these events guide, for example, flowering time and organ development [155]. Over the last few years, it has become increasingly clear that histone modification, histone replacement, and chromatin remodeling can provide a memory that influences the later transcription of genes [154,156], including those with a role in (inducible) immunity. In eukaryotes nuclear DNA is associated with core histones (H2A, H2B, H3, H4), histone H1, non-histone proteins, and RNA that together constitute chromatin. The smallest packaging unit of chromatin is the nucleosome consisting of two copies of histone H2A, H2B, H3 and H4 wrapped by 146 base pairs of DNA [157]. Access of the transcriptional machinery to DNA, amongst others, is regulated by nucleosome positioning and chromatin architecture [158]. In fact, DNA and histones can both become covalently modified. Cytosine bases in DNA can be methylated, which usually attenuates or even inhibits transcriptional activity, whereas the N-terminal histone tails can be subject to a variety of posttranslational modifications such as ubiquitination, sumoylation, crotonylation, poly-ADP-ribosylation, carbonylation, glycosylation, phosphorylation, acetylation, and methylation [156,159,160]. It is generally accepted that the pattern of different histone modifications in the promoter and coding region of a given gene and their spatial relationship defines the chromatin structure and transcriptional competence of that specific locus [161–163]. Unfortunately, the role of most histone modifications in transcriptional regulation is unclear, as is the identity of enzymes that write, read, or erase a given modification. However, it is generally accepted that acetylation of histone lysine residues slacks the interaction of nucleosome neighbors, loosens the ionic DNA-histone interaction, and provides docking sites for regulatory proteins containing bromodomains (e.g. transcription factor IID [TFIID] and the SWI/SNF chromatin remodeling complex) [164,165]. The proposed ‘histone code’ also claims that modified histones recruit regulatory enzymes to discrete loci in chromatin [166]. For example, histone acetylation seems to facilitate site-specific recruitment of the general transcription machinery, including TFIID, and the RNA polymerase II (RNAPII) complex. Accordingly, in all examined eukaryotes there is close correlation of histone H3 and H4 acetylation and gene transcription [164]. The role of histone methylation in transcriptional regulation is less clear because lysine and arginine residues can be methy-

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lated. In addition, up to three methyl groups can attach to a same lysine residue [157,167]. The closest correlation between histone methylation and gene transcription was shown for tri-methylation of lysine 4 in histone H3 (H3K4me3) in the promoter and coding region of gene [168]. By contrast, the role of H3K4me2 and H3K4me1 is less clear [169]. In 2007, H3K4me3 was uncoupled from PR1 defense gene transcription in Arabidopsis [170]. H3K4me3 has instead been associated with a permissive state of PR1 transcription. The authors hypothesized that this was in preparation for swift changes in gene transcription in times of stress [170]. Another study revealed that in Arabidopsis priming the promoter of the defense-related transcription factor gene WRKY29 by BTH is associated with H3K4me3, H3K4me2, and acetylation of H3K9 (H3K9ac), H4K5ac, H4K8ac, and H4K12ac. Yet, these modifications did not activate WRKY29 until the plants were rechallenged [171]. Thus, specific chromatin marks that for a long time have been associated with gene activity are induced during priming before actual gene transcription [170,172]. Similar observations were made for the related defense genes WRKY6 and WRKY53 in Arabidopsis [171]. Together, the findings demonstrated that priming certain WRKY genes for enhanced transcription involves histone modifications on the gene promoter that seem to facilitate WRKY gene transcription upon rechallenge. These promoter histone modifications could either slack the interaction of nucleosome neighbors, loosen the ionic DNA-histone interaction, destabilize chromatin structure, and/or provide docking sites for transcription coactivators, chromatin remodeling factors, and other effector proteins in chromatin [165,173–175]. Together these processes could facilitate recruitment of components of the transcription pre-initiation complex and/or the general transcription machinery (e.g. the RNAPII complex, TFIID), thus supporting transcription initiation and gene transcription. In a bona fide SAR experiment localized inoculation of Arabidopsis leaves with infectious Pseudomonas in systemic leaves primed WRKY6, WRKY29, and WRKY53 for enhanced expression upon pathogen rechallenge [171]. The systemic WRKY6/29/53 priming was associated with enhanced H3K4me3 and H3K4me2 on the WRKY6/29/53 promoters and with augmented H4K5ac, H4K8ac, and H4K12ac on the promoter of WRKY29. These histone marks were induced on the WRKY gene promoters in systemic leaves after localized infection at distal leaves but before rechallenge [171]. Thus, it seems that localized bacterial infection initiates distribution of systemic signal(s) whose information is converted and stored as modifications to histones on defense gene promoters in systemic leaves. Hence, priming-associated chromatin modification seems to provide a memory for priming in the systemic plant immune response. Close correlation between WRKY29 priming and promoter H3K4me3 in various Arabidopsis mutants pointed to this particular histone mark as being important to WRKY priming and systemic immunity in this plant [171]. In a follow-up study, Singh et al. [176] showed that repetitive exposure to mild drought enhances H3K4me3, H3K9K14ac, and presence of RNAPII on MTI-associated genes thus likely causing the observed immunity to pathogen challenge. The defense priming by abiotic stress was impaired in the hac1-1 mutant with a defective histone acetyltransferase pointing to crosstalk of the primed biotic and abiotic stress response on the chromatin level [176]. 4. Inheritance of immune priming in plants Inheritance of acquired traits, also called soft inheritance, is one of the hallmarks of Lamarckism and has been under debate since the 19th century [177]. Recently, inheritance of the primed (acquired) state of enhanced defense and immunity was demonstrated from Pseudomonas-infected Arabidopsis plants to their offspring using PR1, WRKY6, and WRKY53 expression and immunity to downy

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mildew (Hyaloperonospora arabidopsidis) and chlorotic speck disease (Pseudomonas syringae) as the assays [178]. The primed state of enhanced defense was sustained over a stress-free generation and, therefore, the authors suspected an epigenetic mechanism would underlie this phenomenon [178]. In fact, H3K9ac, indicative of a permissive state of gene transcription, was enhanced on the PR1, WRKY6, and WRKY53 promoter in the offspring of infected plants. What’s more, the drm1drm2cmt3 mutant of Arabidopsis with affected non-CpG methylation mimicked the trans-generation immunity phenotype [178]. This finding points to DNA hypomethylation as a transmitter of immunity to the next generation [179]. However, the genome of several organisms with proven transgenerational memory (e.g. Drosophila genus, Caenorhabditis elegans) does not encode DNA methyltransferases and, therefore, DNA methylation/demethylation cannot provide a universal epigenetic memory. It might be restricted to plants [180]. Another study disclosed that the progeny of plants primed by ß-aminobutyric acid or localized Pseudomonas infection expressed primed defense gene activation, associated with immunity to bacterial speck and downy mildew disease [181]. The study disclosed that even the capacity for defense priming can be inherited. Progeny of primed Arabidopsis plants expressed even stronger defense priming than offspring of unprimed plants (‘primed-to-be-primed’ phenotype) [181]. 5. Similar innate immune priming in plants and mammals Biomedical textbooks strongly discriminate between innate and adaptive immunity. While the innate mammalian immune system provides a first line of defense by recognizing MAMPs and DAMPs, T and B cell-mediated adaptive immunity is characterized by extraordinary specificity and a long-lasting memory to previous infection. However, the discrimination between innate and adaptive immunity does not reflect reality because several types of cell are involved in both immune responses [122]. What’s more, different from textbook content the innate immune system of vertebrates, just like in plants, can certainly build immunological memory. For example, vaccination with various facultative parasites can protect mice from diseases unrelated to the vaccinating agent [182,183]. This cross-protection differs from adaptive immunity. For distinguishing the acquired characteristic of the innate immune system from the adaptive immune response, Netea et al. [184] introduced the term ‘trained immunity’. The term is attractive, but its introduction ignored that the memory-based enhancement of defense in mammalian innate immunity was termed ‘priming’ before [185–188]. Trained immunity in mammals corresponds to defense priming in plants and is equally characterized by an enhanced capacity for mobilizing defense which often provides immunity. Primed immunity was verified in all prototypical cells of the innate mammalian immune system, that’s natural killer (NK) cells, monocytes, and macrophages. When infected by cytomegalovirus, mouse NK cells expressing the virus-specific Ly49H receptor often are promoted to long-living memory cells [189]. In contrast to naive NK cells, the memory type of NK cells responds to activation of the Ly49H receptor by viral m157 protein with augmented synthesis of interferon-␥ (INF␥). This then stimulates nearby cells to build antiviral defense. Reminiscent to the enhanced presence of PRRs in primed Arabidopsis, the priming of memory NK cells is associated with elevated levels of the Ly49H receptor [189]. Another example of primed innate immunity in mammals is the vaccination of humans with bacille Calmette-Guérin, the live attenuated vaccine against Mycobacterium tuberculosis and some unrelated pathogens. The protection is assumed to be due to defense priming, since blood of immunized healthy volunteers after mycobacterial challenge contained elevated levels of INF␥, tumor

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necrosis factor ␣ (TNF␣), and interleukin-1␤ (IL1␤) [190]. Similar knowledge comes from studies in which defense priming was activated by Candida albicans and its cell wall MAMP ␤-glucan [191]. Treatment with any of the two agents primed human monocytes for augmented TNF␣ and IL6 secretion and for immunity to C. albicans reinfection. The ␤-glucan-induced monocyte priming coincided with enhanced H3K4me3 on the TNF˛ and IL6 gene promoter uncovering another remarkable similarity to defense priming in plants [191]. The same study also disclosed that ␤-glucan treatment of human monocytes enhances the endogenous level of dormant p38, an equivalent to Arabidopsis MPK3, followed by phosphorylation of more p38 molecules upon Toll-like receptor 2 (TLR2) activation by the bacterial lipopeptide Pam3Cys [191]. In mammals priming not only conditions immunity upon primary infection, vaccination, or MAMP perception, but it is also important to cellular communication. For example, the biological relevance of monocyte priming by IFN␥ becomes obvious when circulating monocytes sense systemic IFN␥, move to inflammatory sites, and become primed for TLR agonist perception. Consequently, IFN␥-primed macrophages secrete more IL12 and nitric oxide upon recognizing the TLR agonist lipopolysaccharide or CpG-DNA [192]. IFN␥ priming also enhances lipopolysaccharide-induced IL12 and TNF␣ secretion by monocytes and macrophages [185,186]. The IFN␥-induced macrophage priming is a presumed consequence of elevated levels of cellular signaling components. In fact, IFN␥ enhances expression of TLRs, the TLR4 coreceptor CD14, its accessory molecule MD2, and the signaling proteins MyD88 and IRAK1, reminiscent of the enhanced level of PRRs and their coreceptors in primed Arabidopsis and memory NK cells [192]. In sum, there is striking similarity in the molecular regulation of the primed innate immune response of plants and mammals: enhanced presence of PRRs and coreceptors, enhanced levels of dormant MPKs, and transcription-permissive H3K4me3 on the promoter of defense genes. In both, plants and mammals DNA hypomethylation and H3K4me3 seem to provide a long-lasting epigenetic immune memory [123,171,174,178,193,194]. The similarities in defense priming in plants and mammals point to conservation or convergence in the evolution of the innate immune system in both biological kingdoms.

6. Conclusion Defense priming is as an important part of the innate immune system of plants and mammals. The primed state of enhanced defense provides a memory to previous infection by modifying histones (e.g. H3K4me3) and demethylating DNA in the promoter of defense genes, depositing dormant cellular signaling enzymes (e.g. MPKs), and increasing the level of PRRs in the cell membrane. By doing so, priming conditions cells for an enhanced defense response, and this often provides immunity to reinfection. In contrast to the direct activation of defense, priming shifts a cell to the alert without impairing fitness much. The more we know about the molecular mechanism(s) of defense priming, the more obvious become similarities in the primed innate immune response in plants and mammals. The emerging knowledge will increasingly translate defense priming to practice, thereby improving sustainable agriculture and molecular medicine.

Acknowledgments Research on priming in the Conrath lab is supported by German Research Foundation (DFG), the Excellence Initiative of the German federal and state governments, and Bayer CropScience.

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