The Genetic and Molecular Basis of Plant Resistance to Pathogens

Plant pathogens have evolved numerous strategies to obtain nutritive materials from their host,and plants in turn have evolved the preformed physical and chemical barriers as well as sophisticated two-tiered immune system to combat pathogen attacks.Genetically, plant resistance to pathogens can be divided into qualitative and quantitative disease resistance,conditioned by major gene(s) and multiple genes with minor effects,respectively.Qualitative disease resistance has been mostly detected in plant defense against biotrophic pathogens,whereas quantitative disease resistance is involved in defense response to all plant pathogens,from biotrophs,hemibiotrophs to necrotrophs.Plant resistance is achieved through interception of pathogen-derived effectors and elicitation of defense response.In recent years,great progress has been made related to the molecular basis underlying host-pathogen interactions.In this review,we would like to provide an update on genetic and molecular aspects of plant resistance to pathogens.     

Mechanisms of inducible resistance against Bacillus thuringiensis endotoxins in invertebrates

Resistance in insect pests against the endotoxin of Bacillus thuringiensis （Berliner） （Bt） is a major threat to the usefulness of this biopesticide, both used as traditional formulations and in transgenic crops. A crucial requirement for the development of successful resistance management strategies is a molecular understanding of the nature and inheritance of resistance mechanisms. This information can be used to design management strategies that will delay or counteract Bt resistance. The best known Bt resistance mechanism is inactivation of brush border membrane receptors. This type of resistance has a largely recessive mode of inheritance, which has enabled the design of resistance management approaches involving high dose and refuge strategies. Recent observations suggest that other resistance mechanisms are possible, including a mechanism that sequesters the toxin in the gut lumen through inducible immune reactions. The elevated immune status associated with tolerance to the toxin can be transmitted to subsequent generations by a maternal effect, which has implications for resistance management in the field. The high dose/refuge strategy may not be appropriate for the management of these alternative resistance mechanisms and other strategies have to be developed if inducible dominant resistance or tolerance mechanisms occur frequently in the field.     

Yersinia type Ⅲ effectors perturb host innate immune responses

The innate immune system is the first line of defense against invading pathogens. Innate immune cells recognize molecular patterns from the pathogen and mount a response to resolve the infection. The production of proinflammatory cytokines and reactive oxygen species, phagocytosis, and induced programmed cell death are processes initiated by innate immune cells in order to combat invading pathogens. However, pathogens have evolved various virulence mechanisms to subvert these responses. One strategy utilized by Gram-negative bacterial pathogens is the deployment of a complex machine termed the type Ⅲ secretion system(T3SS). The T3SS is composed of a syringe-like needle structure and the effector proteins that are injected directly into a target host cell to disrupt a cellular response. The three human pathogenic Yersinia spp.(Y. pestis, Y. enterocolitica, and Y. pseudotuberculosis) are Gramnegative bacteria that share in common a 70 kb virulence plasmid which encodes the T3 SS. Translocation of the Yersinia effector proteins(YopE, YopH, YopT, YopM, YpkA/YopO, and YopP/J) into the target host cell results in disruption of the actin cytoskeleton to inhibit phagocytosis, downregulation of proinflammatory cytokine/chemokine production, and induction of cellular apoptosis of the target cell. Over the past 25 years, studies on the Yersinia effector proteins have unveiled tremendous knowledge of how the effectors enhance Yersinia virulence. Recently, the long awaited crystal structure of YpkA has been solved providing further insights into the activation of the YpkA kinase domain. Multisite autophosphorylation by YpkA to activate its kinase domain was also shown and postulated to serve as a mechanism to bypass regulation by host phosphatases. In addition, novel Yersinia effector protein targets, such as caspase-1, and signaling pathways including activation of the inflammasome were identified. In this review, we summarize the recent discoveries made on Yersinia effector proteins and their contribution to Yersinia pathogenesis.     

Molecular evolution and expression pattern of Toll-like receptor 3 from the lamprey Lampetra japonica

Toll-like receptors(TLRs)are type I transmembrane proteins that are important components of innate immunity and play essential roles in inducing acquired immune responses[1].These proteins consist of three parts:the cytoplasmic domain,transmembrane domain,and extracellular domain.The extracellular domain is composed of 18–33 leucine-rich repeat(LRR)sequences that enable the host to specifically recognize pathogen-associated molecular patterns and are the core of TLR recognition ligands[2].The cytoplasmic domain is homologous with the interleukin 1 receptor(IL-1R)family and known as the Toll-IL-1 receptor homology domain,which is highly conserved and plays a key role in signal transduction[1].TLR3 recognizes viral dsRNA during immune protection from viruses[3].After the host is infected by a virus,the LRR region of TLR3 recognizes the viral dsRNA,and the Toll/IL-1 receptor(TIR)domain recruits the adaptor protein TIR domain-containing molecule 1(also known as TRIF)for signal cascade transmission[4].The activation of TLR3 finally leads to cytokine secretion,especially the production of type I interferon[4].Lamprey,the most primitive marine jawless vertebrate,is an ideal model for studying vertebrate embryo development,organ differentiation,and immune system evolution[5].Although jawless vertebrates contain three variable lymphocyte receptors,they have not been found to possess the recombinational antigen receptors shared by all jawed vertebrates[6].Compared with that in higher vertebrates,the mechanism of acquired immunity in lampreys is still not complete,and lampreys rely mainly on innate immunity to fight against pathogenic microorganisms.Although TLR3 has been extensively studied in jawed vertebrates,little is known about the molecular evolutionary history and expression patterns of TLR3 in jawless vertebrates.     

Intestinal Microbiota in Early Life and Its Implications on Childhood Health

Trillions of microbes reside in the human body and participate in multiple physiological and pathophysiological processes that affect host health throughout the life cycle. The microbiome is hallmarked by distinctive compositional and functional features across different life periods.Accumulating evidence has shown that microbes residing in the human body may play fundamental roles in infant development and the maturation of the immune system. Gut microbes are thought to be essential for the facilitation of infantile and childhood development and immunity by assisting in breaking down food substances to liberate nutrients, protecting against pathogens, stimulating or modulating the immune system, and exerting control over the hypothalamic–pituitary–adrenal axis.This review aims to summarize the current understanding of the colonization and development of the gut microbiota in early life, highlighting the recent findings regarding the role of intestinal microbes in pediatric diseases. Furthermore, we also discuss the microbiota-mediated therapeutics that can reconfigure bacterial communities to treat dysbiosis.     

Allelic Polymorphism,Gene Duplication and Balancing Selection of MHC Class ⅡB Genes in the Omei Treefrog(Rhacophorus omeimontis)

The worldwide declines in amphibian populations have largely been caused by infectious fungi and bacteria. Given that vertebrate immunity against these extracellular pathogens is primarily functioned by the major histocompatibility complex(MHC) class Ⅱ molecules, the characterization and the evolution of amphibian MHC class Ⅱ genes have attracted increasing attention. The polymorphism of MHC class Ⅱ genes was found to be correlated with susceptibility to fungal pathogens in many amphibian species, suggesting the importance of studies on MHC class Ⅱ genes for amphibians. However, such studies on MHC class Ⅱ gene evolution have rarely been conducted on amphibians in China. In this study, we chose Omei treefrog(Rhacophorus omeimontis), which lived moist environments easy for breeding bacteria, to study the polymorphism of its MHC class Ⅱ genes and the underlying evolutionary mechanisms. We amplified the entire MHC class ⅡB exon 2 sequence in the R. omeimontis using newly designed primers. We detected 102 putative alleles in 146 individuals. The number of alleles per individual ranged from one to seven, indicating that there are at least four loci containing MHC class ⅡB genes in R. omeimontis. The allelic polymorphism estimated from the 102 alleles in R. omeimontis was not high compared to that estimated in other anuran species. No significant gene recombination was detected in the 102 MHC class ⅡB exon 2 sequences. In contrast, both gene duplication and balancing selection greatly contributed to the variability in MHC class ⅡB exon 2 sequences of R. omeimontis. This study lays the groundwork for the future researches to comprehensively analyze the evolution of amphibian MHC genes and to assess the role of MHC gene polymorphisms in resistance against extracellular pathogens for amphibians in China.     

Roles of small RNAs in plant disease resistance

The interaction between plants and pathogens represents a dynamic competition between a robust immune system and efficient infectious strategies. Plant innate immunity is composed of complex and highly regulated molecular networks, which can be triggered by the perception of either conserved or race‐specific pathogenic molecular signatures. Small RNAs are emerging as versatile regulators of plant development, growth and response to biotic and abiotic stresses. They act in different tiers of plant immunity, including the pathogen‐associated molecular pattern‐triggered and the effector‐triggered immunity. On the other hand, pathogens have evolved effector molecules to suppress or hijack the host small RNA pathways. This leads to an arms race between plants and pathogens at the level of small RNA‐mediated defense.Here, we review recent advances in small RNA‐mediated defense responses and discuss the challenging questions in this area.     

Unexpected complexity of multidrug resistance in the mcr-1-harbouring Escherichia coli

正Dear Editor,The discovery that the mobile colistin resistance gene(mcr-1)is encoded by plasmids and is prevalent in food animals and human beings worldwide(Hasman et al.,2015;Liu et al.,2015)has challenged greatly our traditional idea that polymyxin(consisting of two isoforms:polymyxin B and polymyxin E(colistin))acts as an ultimate line of refuge in the clinical treatment against the severe infections by the multidrug-resistant Gram-negative pathogens(Nation et al.,2015;Paterson and Harris,2015).To make matters     

Resin foraging dynamics in Varroa destructor-infested hives: a case of medication of kin?

t Social insects have evolved colony behavioral, physiological, and organiza. tional adaptations (social immunity) to reduce the risks of parasitization and/or disease transmission. The collection of resin from various plants and its use in the hive as propolis is a clear example of behavioral defense. For Apis mellifera, an increased propolis content in the hive may correspond to variations in the microbial load of the colony and to a downregulation of an individual bee's immune response. However, many aspects of such antimicrobial mechanism still need to be clarified. Assuming that bacterial and fungal infection mechanisms differ from the action of a parasite, we studied the resin collection dynamics in Varroa destructor-infested honeybee colonies. Comparative experiments involving hives with different mite infestation levels were conducted in order to assess the amount of resin collected and propolis quality within the hive, over a 2-year period (2014 and 2015). Our study demonstrates that when A. mellifera colonies are under stress because of Varroa infestation, an increase in the number of resin foragers is recorded, even if a general intensification of the foraging activity is not observed. A reduction in the total polyphenolic content in propolis produced in infested versus uninfested hives was also noticed. Considering that different propolis types show varying levels of inhibition against a variety of honey bee pathogens in vitro, it would be very important to study the effects against Varroa of two diverse types of propolis: from Varroa-free and from Varroa-infested hives.     

Strain competition restricts colonization of an enteric pathogen and prevents colitis

The microbiota is a major source of protection against intestinal pathogens; however, the specific bacteria and underlying mechanisms involved are not well understood. As a model of this interaction, we sought to determine whether colonization of the murine host with symbiotic non‐toxigenic Bacteroides fragilis could limit acquisition of pathogenic enterotoxigenic B. fragilis. We observed strain‐specific competition with toxigenic B. fragilis, dependent upon type VI secretion, identifying an effector–immunity pair that confers pathogen exclusion. Resistance against host acquisition of a second non‐toxigenic strain was also uncovered, revealing a broader function of type VI secretion systems in determining microbiota composition. The competitive exclusion of enterotoxigenic B. fragilis by a non‐toxigenic strain limited toxin exposure and protected the host against intestinal inflammatory disease. Our studies demonstrate a novel role of type VI secretion systems in colonization resistance against a pathogen. This understanding of bacterial competition may be utilized to define a molecularly targeted probiotic strategy.     

GENETIC VARIATION IN RESISTANCE AND FECUNDITY TOLERANCE IN A NATURAL HOST–PATHOGEN INTERACTION

Individuals vary in their ability to defend against pathogens. Determining how natural selection maintains this variation is often difficult, in part because there are multiple ways that organisms defend themselves against pathogens. One important distinction is between mechanisms of resistance that fight off infection, and mechanisms of tolerance that limit the impact of infection on host fitness without influencing pathogen growth. Theory predicts variation among genotypes in resistance, but not necessarily in tolerance. Here, we study variation among pea aphid (Acyrthosiphon pisum) genotypes in defense against the fungal pathogen Pandora neoaphidis. It has been well established that pea aphids can harbor symbiotic bacteria that protect them from fungal pathogens. However, it is unclear whether aphid genotypes vary in defense against Pandora in the absence of protective symbionts. We therefore measured resistance and tolerance to fungal infection in aphid lines collected without symbionts, and found variation among lines in survival and in the percent of individuals that formed a sporulating cadaver. We also found evidence of variation in tolerance to the effects of pathogen infection on host fecundity, but no variation in tolerance of pathogen‐induced mortality. We discuss these findings in light of theoretical predictions about host‐pathogen coevolution.     

An overview of insect innate immunity

Due to the exposure of insects to various sources of pathogens during different stages of their life cycle and their vulnerability towards subsequent infections, moreover lack of morality issues, economical breeding and short‐term‐life cycle, insect's immunity has been considered as a high‐potential candidate to study underlying mechanisms of defense responses against all sort of invaders, as well as pandemic diseases. Currently, the world is enduring monumental pressure to meet global food production demands. One viable option would be to mass rear edible insects, such as coleopteran meal worm Tenebrio molitor, which is thought to be a substantial protein source. In addition, using antimicrobial peptides as an alternative for antibiotic source against multidrug‐resistant pathogens, makes insects a valuable option to solve this health issue. As a consequence, sufficient knowledge of insect immunity will lead us to reach advanced diagnostic and treatment technologies. To accomplish these goals, crucial importance of identification and functional characterization of the main signaling pathways, such as Toll and immune deficiency (IMD), prompted us to review the mechanisms of the signaling pathways involved in immune response in well‐known insect models.     

Innate immunity to mycobacteria: vitamin D and autophagy

Autophagy is an ancient mechanism of protein degradation and a novel antimicrobial strategy. With respect to host defences against mycobacteria, autophagy plays a crucial role in antimycobacterial resistance, and contributes to immune surveillance of intracellular pathogens and vaccine efficacy. Vitamin D3 contributes to host immune responses against Mycobacterium tuberculosis through LL‐37/hCAP‐18, which is the only cathelicidin identified to date in humans. In this review, we discuss recent advances in our understanding of host immune strategies against mycobacteria, including vitamin D‐mediated innate immunity and autophagy activation. This review also addresses our current understanding regarding the autophagy connection to principal innate machinery, such as ubiquitin‐ or inflammasome‐involved pathways. Integrated dialog between autophagy and innate immunity may contribute to adequate host immune defences against mycobacterial infection.     

Alcohol resistance in Drosophila is modulated by the Toll innate immune pathway

A growing body of evidence has shown that alcohol alters the activity of the innate immune system and that changes in innate immune system activity can influence alcohol‐related behaviors. Here, we show that the Toll innate immune signaling pathway modulates the level of alcohol resistance in Drosophila. In humans, a low level of response to alcohol is correlated with increased risk of developing an alcohol use disorder. The Toll signaling pathway was originally discovered in, and has been extensively studied in Drosophila. The Toll pathway is a major regulator of innate immunity in Drosophila, and mammalian Toll‐like receptor signaling has been implicated in alcohol responses. Here, we use Drosophila‐specific genetic tools to test eight genes in the Toll signaling pathway for effects on the level of response to ethanol. We show that increasing the activity of the pathway increases ethanol resistance whereas decreasing the pathway activity reduces ethanol resistance. Furthermore, we show that gene products known to be outputs of innate immune signaling are rapidly induced following ethanol exposure. The interaction between the Toll signaling pathway and ethanol is rooted in the natural history of Drosophila melanogaster.     

Bacterial inhibition of inflammatory responses via TLR‐independent mechanisms

Identification of cellular processes modulated by microbial organisms that undermine and disarm mammalian host defences against bacterial invaders has been the focus of significant biomedical research. In this microreview we will illustrate the role of bacterial N‐acyl homoserine lactones (AHL) as a strategy utilized by Gram‐negative bacterial pathogens to enable colonization of the host through AHL‐mediated inhibition of inflammation induced via innate immune receptor mechanisms. We will also highlight some of the signalling pathways in which the study of AHL‐mediated effects on mammalian cells might lead to the discovery of global underlying principles linking inflammation and immunity to many chronic human diseases, including cancer and obesity.     

Lipoprotein immunoproteomics question the potential of Staphylococcus aureus TLR2 agonists as vaccine antigens

Toll‐like receptor 2 (TLR2) is regarded as the major innate immunity sensor in infections caused by the Gram‐positive bacterial pathogen Staphylococcus aureus. However, previous studies on the roles of TLR2 in S. aureus infections have been elusive and in part contradictory. It has remained particularly unclear if bacterial lipoproteins, the major TLR2 ligands, could serve as antigens with intrinsic adjuvant property for the development of protective vaccines. The study by Vu et al. published in this issue of Proteomics analyzed the antibody and T‐cell responses in human sera against major S. aureus lipoproteins. Notably, even lipoproteins released to culture filtrates at similar levels as established immunodominant antigens elicited only very weak or no detectable antibody and T‐cell responses, indicating that the potent TLR2‐stimulating capacity of S. aureus lipoproteins does not promote and may rather impair robust immune responses so lipoprpteins. Among several potential explanations it is tempting to speculate that the role of TLR2 in S. aureus infections may be more complex and more ambiguous than previously thought. The study of Vu et al. may thus provoke more detailed investigations on the roles of lipoproteins and TLR2 in innate and adaptive immunity against bacterial pathogens.     

Plum pox virus capsid protein suppresses plant pathogen‐associated molecular pattern (PAMP)‐triggered immunity

The perception of pathogen‐associated molecular patterns (PAMPs) by immune receptors launches defence mechanisms referred to as PAMP‐triggered immunity (PTI). Successful pathogens must suppress PTI pathways via the action of effectors to efficiently colonize their hosts. So far, plant PTI has been reported to be active against most classes of pathogens, except viruses, although this defence layer has been hypothesized recently as an active part of antiviral immunity which needs to be suppressed by viruses for infection success. Here, we report that Arabidopsis PTI genes are regulated upon infection by viruses and contribute to plant resistance to Plum pox virus (PPV). Our experiments further show that PPV suppresses two early PTI responses, the oxidative burst and marker gene expression, during Arabidopsis infection. In planta expression of PPV capsid protein (CP) was found to strongly impair these responses in Nicotiana benthamiana and Arabidopsis, revealing its PTI suppressor activity. In summary, we provide the first clear evidence that plant viruses acquired the ability to suppress PTI mechanisms via the action of effectors, highlighting a novel strategy employed by viruses to escape plant defences.     

Cytokinin response induces immunity and fungal pathogen resistance,and modulates trafficking of the PRR LeEIX2 in tomato

Plant immunity is often defined by the immunity hormones: salicylic acid (SA), jasmonic acid (JA), and ethylene (ET). These hormones are well known for differentially regulating defence responses against pathogens. In recent years, the involvement of other plant growth hormones such as auxin, gibberellic acid, abscisic acid, and cytokinins (CKs) in biotic stresses has been recognized. Previous reports have indicated that endogenous and exogenous CK treatment can result in pathogen resistance. We show here that CK induces systemic immunity in tomato (Solanum lycopersicum), modulating cellular trafficking of the pattern recognition receptor (PRR) LeEIX2, which mediates immune responses to Xyn11 family xylanases, and promoting resistance to Botrytis cinerea and Oidium neolycopersici in an SA- and ET-dependent mechanism. CK perception within the host underlies its protective effect. Our results support the notion that CK promotes pathogen resistance by inducing immunity in the host.     

The genetic architecture of defence as resistance to and tolerance of bacterial infection in Drosophila melanogaster

Defence against pathogenic infection can take two forms: resistance and tolerance. Resistance is the ability of the host to limit a pathogen burden, whereas tolerance is the ability to limit the negative consequences of infection at a given level of infection intensity. Evolutionarily, a tolerance strategy that is independent of resistance could allow the host to avoid mounting a costly immune response and, theoretically, to avoid a co‐evolutionary arms race between pathogen virulence and host resistance. Biomedically, understanding the mechanisms of tolerance and how they relate to resistance could potentially yield treatment strategies that focus on health improvement instead of pathogen elimination. To understand the impact of tolerance on host defence and identify genetic variants that determine host tolerance, we defined genetic variation in tolerance as the residual deviation from a binomial regression of fitness under infection against infection intensity. We then performed a genomewide association study to map the genetic basis of variation in resistance to and tolerance of infection by the bacterium Providencia rettgeri. We found a positive genetic correlation between resistance and tolerance, and we demonstrated that the level of resistance is highly predictive of tolerance. We identified 30 loci that predict tolerance, many of which are in genes involved in the regulation of immunity and metabolism. We used RNAi to confirm that a subset of mapped genes have a role in defence, including putative wound repair genes grainy head and debris buster. Our results indicate that tolerance is not an independent strategy from resistance, but that defence arises from a collection of physiological processes intertwined with canonical immunity and resistance.