Potential Pathogen Resistance in Cannabis sativa

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Potential Pathogen Resistance in Cannabis sativa

This entry is adapted from the peer-reviewed paper 10.3390/plants12152764

Cannabis (Cannabis sativa L.) is one of the earliest cultivated crops, valued for producing a broad spectrum of compounds used in medicinal products and being a source of food and fibre.

Cannabis pathogen resistance omics genome editing

1. Introduction

Cannabis (Cannabis sativa L.) is a dicotyledonous angiosperm originating from Central Asia but is cultivated across many parts of the world due to its ability to grow in a wide range of habitats and environmental conditions ^[1].

Cannabis belongs to the Cannabaceae family and is considered one of the earliest cultivated crops, being of particular interest due to its multiple uses. Cannabinoids are responsible for the pharmacological and psychoactive properties of this crop, and these therapeutic characteristics have drawn the attention of researchers from all over the world. Additionally, hemp, a Cannabis variety containing less than 0.3% of tetrahydrocannabinol (THC), is cultivated for biomass and fibre, which constitute feedstock for industrial uses. Conversely, medicinal Cannabis contains a greater amount of THC, which has been increasing in recent years, reaching 17–28% of the dry weight in some varieties ^[2], or even exceeding 30% in others ^[3].

Among the ~130 secondary metabolites identified in Cannabis ^[4], THC, along with cannabidiol (CBD), constitute the most relevant compounds produced by this crop and are the main focus of Cannabis breeding programs.

Breeding efforts to produce Cannabis with unique fragrance and flavour characteristics are also of interest. Consequently, the profile of terpenoids, which are highly abundant and largely responsible for the characteristic aroma of Cannabis, is of importance, with isoprenes, monoterpenes, and sesquiterpenes being the predominant classes ^[5]^[6].

Due to the legislation regulating Cannabis and related breeding programs, research into the cannabinoid biosynthetic pathway is underrepresented, and it has not been sufficiently characterised, especially at the molecular level ^[5]^[7]. Many other major crops have already been widely investigated from this perspective, especially after the advent of Next Generation Sequencing (NGS) technologies ^[7]. However, the recent modifications in legislation and less stringent regulations ^[8], as well as the availability of the Cannabis genomic sequence ^[9], have broadened research in this crop, with the aim also to improve its biomass quality, in the context of sustainable agriculture ^[10]^[11].

These legislative changes have also resulted in increased Cannabis production and, with it, a growth of the incidence and severity of crop pathogens, along with the detection of previously unreported diseases. Among emerging pathogens of Cannabis recently reported there are Botrytis cinerea ^[12]^[13], Fusarium spp. ^[14]^[15], Pythium ^[16]^[17] Golovinomyces spp. ^[12]^[13], and Hop latent viroid ^[18], where hop (Humulus lupulus) is a member of Cannabaceae and is closely related to Cannabis ^[19]. These pathogens can be grouped according to the tissues they infect: root and crown (Fusarium oxysporum, Fusarium proliferatum, Fusarium solani, Pythium myriotylum, Pythium dissotocum, Pythium aphanidermatum), leaves (Golovinomyces spp.), buds (Hop latent viroid) ^[12]. Botrytis cinerea is often classified as a postharvest pathogen and can attack Cannabis seeds, leaves, and stalks ^[12]. Fusarium and Pythium species are the most destructive root pathogens, especially when the infection occurs during vegetative growth. Crop losses resulting from the attack of these two pathogens can reach 30% of the total yield ^[12]. Botryis and Fusarium species also are harmful, as well as other fungi, such as Golovinomyces species, causing powdery mildew (PM, a common term for several taxa of plant pathogenic fungi), and colonizing foliar and flower tissues through the production of spores. Furthermore, extensive infection by fungi such as Fusarium can lead to mycotoxin accumulation in the tissues, potentially harmful to human health ^[20]. Hop latent viroid leads to malformation of buds and can infect other parts of the crop ^[18].

The above-reported fungi, oomycetes and the mentioned viroid have been investigated in Cannabis, as well as in several other crops, but little is known about infection within the seed, even though there are harmful pathogens, such as Alternaria, which can start their attack in developing seedlings ^[12]. The lack of significant research results on Cannabis bacteria pathogen defence mechanisms has also been underlined ^[21].

On the other hand, research into the characterization and use of biocontrol agents has consistently improved in recent years ^[22]. The use of synthetic fungicides to control fungal diseases has limitations due to toxicological risks, and it is necessary to replace them with safer means, for human health and with reduced environmental risks. Omics methods and their applications in the biocontrol field were recently reviewed by Massart et al. ^[23]. A better understanding of the molecular mechanisms underlying pathogen plant resistance can only have positive effects in this field of research.

Many of the above-reported pathogens have been identified using methods based on Polymerase Chain Reaction (PCR) of parts of rDNA, such as Internal Transcribed Spacer (ITS) and Inter Generic Spacer (IGS) regions ^[24]. However, for Golovinomyces and Botrytis, additional molecular markers were necessary to differentiate between species ^[25]^[26].

Abbreviations used throughout the manuscript are listed in Table 1.

Table 1. List of abbreviations used in this entry.

Abbreviations	Definition
ABA	abscisic acid
BR	Brassinosteroids
CBD	Cannabidiol
CRISPR/Cas9	Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-Associated Protein
ERF	Ethylene Response Factor
ET	Ethylene
ETI	Effector-Triggered Immunity
IGS	Inter Generic Spacer
ITS	Internal Transcribed Spacer
JA	Jasmonic Acid
JAZ	JA-Zim
LRR	Leucine-Rich Repeat
MAPK	Mitogen-Activated Protein Kinase
NBS	Nucleotide Binding Site
NGS	Next Generation Sequencing
NHR	Non Host Resistance
NO	Nitric Oxide
PAL	Phenylalanine Ammonia-Lyase
PAMPs	Pathogen-Associated Molecular Patterns
PM	Powdery Mildew
PR	Pathogenesis-Related protein
PRRs	Pattern Recognition Receptors
PTI	PAMP-Triggered Immunity
PCR	Polymerase Chain Reaction
PCWDEs	Plant Cell Wall Degrading Enzymes
R genes	Resistance genes
RLK	Receptor-Like Kinases
ROS	Reactive Oxygen Species
S genes	Susceptibility genes
SA	Salicylic Acid
SNP	Single Nucleotide Polymorphism
THC	Tetrahydrocannabinol
TLP	Thaumatin-Like Protein

2. Overview of Cannabis Resistance Genes to Pathogens

Cannabis includes genotypes whose origins are geographically very different ^[27], and this genetic diversity leads us to believe the existence of naturally occurring genotypes characterised by resistance to specific pathogens. Indeed, among 12 Cannabis genotypes evaluated, it was found that seven displayed partial or complete resistance to PM ^[28]. Furthermore, a recent study provided insight on the variability of Cannabis cultivars on disease resistance and cannabinoid accumulation over the course of crop maturation ^[29]. Here, PM resistance was shown for ‘FL 58’ cultivar, on which PM was never observed, as well as ‘RN13a’, ‘Otto II’, and ‘AC/DC’, cultivars, showing very low levels of PM disease.

Studies on other crop species have investigated the molecular mechanisms of resistance to Fusarium and PM ^[30]^[31], providing insights for further research on disease resistance responses in Cannabis. Conversely, the search for Cannabis resistance traits to viral pathogens did not yield answers so quickly ^[32].

Several studies focused on non-host resistance (NHR), a resistance of plant species against all non-adapted pathogens, which is considered the most durable and efficient immune system of plants, as described in the review by Oh and Choi ^[33]. Most non-adapted pathogen attacks are stopped by an innate defence response based on the recognition of pathogen-associated molecular patterns (PAMPs) by the plant pattern recognition receptors (PRRs), which activates PAMP-triggered immunity (PTI), also induced by reactive oxygen species (ROS) production and mitogen-activated protein kinase (MAPK) ^[34]. Specific PAMPs, harpin and flg22, were analyzed to study the response to Pythium in Cannabis ^[35]. Results showed that harpin-enhanced hemp seedlings resistant to Pythium aphanidermatum, while flg22 did not contribute to the defence mechanism against P. aphanidermatum. The lack of comprehensive experimental evidence supporting the recognition of PAMPs in Cannabis opens a field of future research.

The salicylic acid (SA) or the jasmonic acid (JA)/ethylene (ET) signalling pathways, which are known to have an antagonistic interaction ^[36], are also involved in the activation of disease resistance mechanisms. SA is involved in several key components of plant defence through complex networks, generally activated by biotrophic pathogens, and JA/ET signalling pathways are usually required for the activation of plant defence against necrotrophic pathogens ^[36].

However, specialised pathogens can suppress PTI responses through effector proteins, which can, in turn, activate subsequent defence responses called effector-triggered immunity (ETI) in plants with immunity to a specialised pathogen. ETI is also activated by SA or JA/ET pathway ^[37]. An ETI response is generally able to control specific pathogen attacks ^[38]. The majority of disease resistance genes in plants encode the conserved nucleotide binding site-leucine-rich repeat (NBS-LRR) disease resistance proteins ^[39]^[40], which can identify specific effectors to trigger ETI ^[37]^[41].

Studies on Wall-Associated receptor Kinases (WAKs) and WAK-like (WAKLs) genes have underlined their role in pathogen resistance across a wide range of plants ^[42]. The Arabidopsis WAKL22 gene is the homolog of Cannabis WAK7 and was shown to be responsible for dominant resistance against several Fusarium strains ^[43]. The cotton WAK18 and WAK29 (homolog of CsWAK4 and CsWAK7, respectively), specifically expressed in flowers, showed pathogen resistance characteristics ^[44]. The Juglans regia WAK9, the homolog of CsWAK1, has been demonstrated to be involved in pathogen response ^[45]. A recent analysis of the WAK gene family in Cannabis sativa investigated some CsWAKs/CsWAKLs (CsWAK1, CsWAK4, CsWAK7, CsWAKL1, and CsWAKL7) in leaf tissues, showing how their expression differs from their homologs in other plants ^[46]. Furthermore, the hemp WAK1 gene is highly expressed under drought stress conditions, and its expression can be induced by phytohormones like salicylic acid, methyl jasmonate, and ethylene ^[47]. These findings put the bases for future research on the potential roles of CsWAK/CsWAKLs in response to hormone treatments and abiotic/biotic stresses, including pathogen attacks.

Biosynthesis of specific terpenes may affect biotic and abiotic stress plant response and disease resistance ^[48]. For instance, few studies showed that while phytoanticipins terpenes are constitutively secreted in the absence of plant pathogen infection, phytoalexins are produced in response to pathogenic microbes ^[48]^[49]. A whole genome resequencing data across diverse samples of feral and domesticated lineages of C. sativa, aimed to examine their population structure, also allowed the identification of 6 loci related to stress response and 1 gene potentially involved in disease resistance ^[50]. This gene was annotated as mevalonate kinase (MEV kinase) and is involved in sesquiterpenes biosynthesis via the mevalonic acid pathway, with sesquiterpenes known for their antifungal properties ^[51]. Despite successful breeding efforts to modify terpene profiles, plant pathogens still constitute a significant cause of crop loss in Cannabis production ^[52].

3. Genome Editing to Generate Disease-Resistant Cannabis Varieties

Omics approaches are comprehensive methods for investigating defence response pathways and have been used broadly in medicinal plants ^[53]^[54]. Furthermore, by identifying candidate resistance genes and yielding an in-depth knowledge of the underlying molecular mechanism, they provide a strong basis for genome editing studies to generate disease-resistant Cannabis varieties ^[54].

The use of genetic engineering methods in Cannabis to enhance its resistance to pathogens and to improve desirable traits is a subject of investigation in several research projects ^[55]. However, it is challenging to regenerate fully developed Cannabis transgenic plants ^[56], and, despite some candidate genes involved in pathogen resistance having been identified, functions of these genes are not yet fully validated, and only a few studies report stable transformation for Cannabis tissues ^[43].

The first edited Cannabis line was developed by Agrobacterium-mediated transformation ^[57], in which overexpressing the Cannabis developmental regulator chimera in the embryo hypocotyls of unripe grains increased the regeneration efficiency. By applying this method, the development of transgenic callus from Cannabis has been achieved ^[58]. Evidence suggests that the overexpression of Non-expressor of Pathogenesis-Related genes-1 (NPR1) in Arabidopsis can confer disease resistance to different pathogens in various plants, such as cotton ^[59] and Brassica juncea ^[60]. The AtNPR1 gene has been introduced into C. sativa and confirmed by PCR and RT-PCR, showing that Cannabis can be transformed to generate disease-resistant varieties ^[60].

A recent mini-review on hemp genome editing ^[61] discusses the opportunity offered by next-generation genome editing technology. The direct delivery of CRISPR/Cas (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-Associated Protein) ribonucleoprotein complexes into plant tissue overcomes the drawback of Agrobacterium-mediated transformation, by which external plasmid DNA is introduced into the crop genome. CRISPR/Cas technology, which is still less commonly used in Cannabis, can be applied to introduce a specific DNA fragment to a precise location in the genome. It could have broad applications in Cannabis breeding, modifying gene regulation and developing pathogen-resistant plants, as already performed in other recalcitrant plants, such as grapes ^[61]. For instance, a protocol for this type of transformation in C. sativa was developed, and genome-edited Cannabis was produced by CRISPR/Cas9 approach ^[61].

By using CRISPR/Cas9, the previously discussed results of the study of Mihalyov and Garfinkel ^[62], consisting of a set of R candidate genes, could be used as target genes to improve PM resistance in the crop.

Furthermore, results reported in other plants could provide useful inputs for Cannabis gene editing. For instance, the genetic transformation of wheat with TLP and glucanases resulted in enhanced resistance to Fusarium ^[63], and MLO-7 was used as a host susceptibility (S) gene to improve grapevine and apple disease resistance to PM ^[64].

Overall, this advanced genome editing approach, based on a transgene-free framework, can address many problems associated with transgenic-based approaches and could be applied to produce improved non-transgenic Cannabis, with the most industrially desirable traits, including pathogen resistance traits.

Another alternative to Agrobacterium transformation protocol is represented by the use of a nanoparticle-based transient gene; through this method, multiple gene plasmids were expressed simultaneously in Cannabis leaf cells ^[65]. However, the study of disease resistance through this method is still in its infancy. It offers promising new perspectives in regulating the content of secondary metabolites, inducing pathogen resistance genes, and obtaining transgenic disease-resistant plants ^[66]^[67].

On this basis, there is a real possibility to improve Cannabis disease resistance by acting on targeted R genes or on S genes. A deep understanding of the underlying molecular mechanisms in which they are involved, as well as of plant-pathogen interactions, and the application of innovative molecular techniques is leading to innovations in the development of pathogen-resistant plants ^[68].

To date, it is still challenging to produce transgenic or gene-edited Cannabis, but the previously reported studies, and several gene editing approaches applied in other plant species, constitute good reference points for further Cannabis resistance research.

To date, few Cannabis omics studies are focused on its defence mechanisms against pathogens and the associated resistance genes. However, these studies, along with omics investigations of disease resistance molecular mechanisms in other crops (see Table 2), could constitute a suitable starting point for further Cannabis research in this field, especially if combined with gene editing approaches which have recently made significant progress, opening new perspectives in regulating the content of secondary metabolites and inducing pathogen resistance genes.

Table 2. Table summarizing the main studies examined in this entry.

Pathogen	Crop	Resistance Genes/Gene Families and Proteins	References
PM, Fusarium, Botrytis cinerea, Pythium	Cannabis	-	^[12]
PM-Golovinomyces spp.	Hops	Genes encoding NBS proteins	^[69]
PM-Golovinomyces spp.	Cannabis	R gene, designated as PM1	^[62]
PM-Golovinomyces spp.	Cannabis	Genes encoding NBS-LRR proteins	^[62]
F. oxysporum	Arabidopsis	Genes encoding JA and P450 proteins	^[70]
F. oxysporum	Resistant crops	Genes encoding 4-coumarate-CoA ligase, polyphenol oxidase, cellulose synthase	^[71]
F. oxysporum	Arabidopsis	WAK gene family, genes encoding RLKs, WRKY, ERF, MYB, and NAC TFs	^[72]
F. oxysporum	Arabidopsis	Genes encoding dirigent-like protein, CAP family and wound-responsive family proteins, some ERF TFs	^[73]
F. oxysporum	Cannabis	WAK7	^[46]
Fusarium spp.	Cannabis	-	^[74]
Botrytis cinerea	Other crops	PRs, SA, JA, ET, ABA and BR gene family	^[75]^[76]
Botrytis cinerea	Cannabis	Genes involved in JA/ET, HEL, PAL, SA, PR1 and PR2 pathways	^[77]
Pythium	Other crops	Flg22 and PTI in plants	^[78]
Pythium	Cannabis	Harpin and Flg22 PAMPs	^[35]

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Subjects: Plant Sciences

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Tiziana M. Sirangelo

Richard A. Ludlow

Natasha D. Spadafora

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Update Date: 23 Aug 2023

Table of Contents

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1. Introduction

2. Overview of Cannabis Resistance Genes to Pathogens

3. Genome Editing to Generate Disease-Resistant Cannabis Varieties

References