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Biotechnology Advances 22 (2004) 363 – 382 www.elsevier.com/locate/biotechadv Research review paper Plants as models for the study of human pathogenesis David S. Guttman * Department of Botany, University of Toronto, 25 Willcocks St., Toronto, ON, Canada M5s 3B2 Received 25 September 2003; accepted 20 November 2003 Abstract There are many common disease mechanisms used by bacterial pathogens of plants and humans. They use common means of attachment, secretion and genetic regulation. They share many virulence factors, such as extracellular polysaccharides and some type III secreted effectors. Plant and human innate immune systems also share many similarities. Many of these shared bacterial virulence mechanisms are homologous, but even more appear to have independently converged on a common function. This combination of homologous and analogous systems reveals conserved and critical steps in the disease process. Given these similarities, and the many experimental advantages of plant biology, including ease of replication, stringent genetic and reproductive control, and high throughput with low cost, it is proposed that plants would make excellent models for the study of human pathogenesis. D 2003 Elsevier Inc. All rights reserved. Keywords: Plant pathogens; Animal pathogens; Virulence; Innate immunity; Type III secretion; Extracellular polysaccharides 1. Introduction The discovery that very different human pathogens rely on a fairly small set of common mechanisms to cause disease sparked an intellectual revolution that has had a profound influence on how we view, study and combat infectious agents (Finlay and Falkow, 1989, 1997). Yet, for many years, these advances did not substantially influence the study of plant pathogenesis. Medical microbiology and plant pathology seemed worlds apart in their intellectual traditions and scientific methods, with even the * Correspondence. Tel.: +1-416-978-6865; fax: +1-416-978-5878. E-mail address: [email protected] (D.S. Guttman). 0734-9750/$ - see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.biotechadv.2003.11.001 364 D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 terminology used by the two disciplines acting more to polarize than unify. This is not hard to understand, after all, how could pathogenesis in humans and plants have any significant similarities when these very divergent hosts are so radically different in their genetic systems, cell structures, and immune systems? However, despite the many very real differences, recent studies are finding numerous and significant areas of similarity among the mechanisms used by bacterial pathogens of plants and humans. These similarities include the use of common toxins, secretion systems, mechanisms of adhesion, invasion and regulation (Buttner and Bonas, 2003; Cao et al., 2001; Lugtenberg et al., 2002; Staskawicz et al., 2001). Why is it significant that plant and human pathogens share common mechanisms for causing disease? There are three reasons that the study of human pathogenesis could benefit tremendously from knowledge of plant pathology. First, virulence factors that are conserved across hosts ranging from humans to plants are likely to be evolutionary constrained, and perhaps essential virulence mechanisms. These constrained systems are logical targets for antimicrobials and vaccines. Second, the comparative study of human and plant pathogenesis has identified numerous virulence factors and mechanisms that are not related by evolutionary descent, yet which have evolved common functions. These analogous systems are perhaps our best window into the complex interactions that occur during pathogenesis. They may reveal processes so critical to eukaryotic cellular function, that different pathogens have independently evolved similar mechanisms to exploit them in highly dissimilar hosts. By identifying these critical steps in pathogenesis, we will be in a better position to control and treat infectious agents. Finally, plants provide tremendous benefits for experimental studies of pathology. They can be grown easily, inexpensively and rapidly. Thousands of plants can be grown and propagated with negligible costs and regulation, while animal models typically cost thousands of dollars per animal, and impose a tremendous maintenance and regulatory burden. Plants can be reproductively and genetically manipulated in ways that are unavailable for most animal systems. For instance, they can be self-fertilized, clonally propagated and hybridized to other species. Plants can be assayed in very large numbers providing a level of statistical rigor not available in animal systems. Finally, there are extensive genomic and proteomic resources available for a number of model plants, most notably Arabidopsis thaliana. In this review, I will describe some of the common mechanisms used by bacterial pathogens of humans and plants. I will almost exclusively focus on Gram-negative bacterial pathogens, although there are certainly commonalities with other bacterial, viral, and even fungal pathogens. This is not meant to be a fully comprehensive assessment of all the similarities between pathogenesis in these divergent hosts, but instead a critical review of the major underlying themes. The goal of the review is to illustrate that there are as many commonalities between plant and human pathogenesis as there are among mechanisms used by different human pathogens. Given these similarities, and the numerous advantages inherent in plant experimental biology, plant pathology has the potential to provide new and valuable insight into the essential mechanisms used by bacteria that attack humans. D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 365 2. Attachment Before anything else, bacterial pathogens must first come in contact with and recognize their eukaryotic hosts. Both plant and human pathogens interact with their hosts’ cells through pili and fimbriae (Sauer et al., 2000; Soto and Hultgren, 1999). There are a number of distinct types of pili and fimbriae, the most relevant for this review being those produced by the type III secretion system (TTSS, discussed below) and the type IV pilus (Tfp) (Wall and Kaiser, 1999). Pseudomonas syringae, the causal agent of a wide range of important bacterial spot, speck and blight diseases in plants, uses both systems for adhesion. Evidence of the role played by these attachment systems in host colonization can be seen with Tfp mutants. These strains are washed from leaves more readily, and are less efficient at initiating colonization in the laboratory (Romantschuk and Bamford, 1986; Romantschuk et al., 1993; Suoniemi et al., 1995). Both TTSS and Tfp mutants grow to lower densities that wildtype strains in the field (Hirano et al., 1999; Roine et al., 1998), although in the former case it is not clear if the growth deficit is due to reduced attachment ability, or if the defective TTSS can no longer be used to acquire resources for growth or to repel eukaryotic competitors. The role of pili in human pathogenesis, particularly with respect to Escherichia coli, has been well established and heavily reviewed (Finlay and Falkow, 1997; Mulvey, 2002; Nougayrede et al., 2003). In general, Tfp are essential for bacterial motility and virulence (Wall and Kaiser, 1999). Their exact function in virulence is not entirely clear, although they contribute to adhesion, bacterial movement and even signal transduction. The Tfp can both bring a pathogen into contact with an appropriate eukaryotic cell, and maintain that contact, thereby facilitating the transfer of other virulence factors such at TTSS effectors (see below) (Wall and Kaiser, 1999). In Pseudomonas aeruginosa, an opportunistic human pathogen that is a major cause of hospital infections, and the leading cause of death for Cystic Fibrosis (CF) patients, the Tfp is responsible for 90% of the adherence function in human lung cells, while non-piliated strains are 10-fold less virulent in mouse models (Hahn, 1997). Although it is clear that bacterial pathogens of both plants and animals rely on a variety of attachment mechanism in the disease process, it is likely that these same attachment mechanisms are also important for commensal and beneficial bacteria. Antimicrobial treatments that target common factors and kill bacteria indiscriminately will invariably open up the infected host to secondary infections. Consequently, although attachment mechanisms are shared between pathogens of both plants and animals, they would make poor therapeutic targets. 3. Secretion systems Three classes of secretion systems have been implicated in virulence, and are widely distributed and highly conserved among bacterial pathogens of plants and humans (Fig. 1). 366 D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 Fig. 1. Bacterial secretion systems directly implicated in virulence. The type I secretion system forms a continuous channel that spans both bacterial membranes, enabling the secretion of a variety of toxins, proteases and lipases into the environment. The type III section system (TTSS) forms a direct connection between the bacterial and eukaryotic host cell. TTSS effectors are directly injected into the host cytosol via the TTSS pilus. The type IV secretion system permits the movement of DNA or protein – DNA complexes between bacterial cells, or directly into the cytosol of a eukaryotic hosts. PM, plasma membrane; OM, outer bacterial membrane; PPS, periplasmic space; IM, inner bacterial membrane. 3.1. Type I secretion The type I secretion system is the simplest of the major secretion apparatuses. It consists of three major proteins that form a continuous channel that spans the bacterial inner membrane, the periplasmic space, and the bacterial outer membrane (Binet et al., 1997; Thanassi and Hultgren, 2000). This system depends on ABC protein mediated transporters, and secretes a variety of toxins, proteases and lipases into the environment. It is exemplified by E. coli hemolysin secretion (Gentschev et al., 2002), a toxin that causes the lysis of red blood cells. Serratia marcescens is an opportunistic human pathogen that is one of the leading causes of hospital-related infections. It secretes hemoprotein HasA through the type I secretion system to sequester iron, an element essential for both bacterial and host enzymatic reactions (Letoffe et al., 1994). The plant pathogens Erwinia amylovora, the causal agent of fire blight, and Erwinia chrysanthemi uses a type I secretion system to secrete metalloproteases, which have been shown to be required for leaf colonization (Gentschev et al., 2002; Zhang et al., 1999). 3.2. Type III secretion The type III secretion system (TTSS) is directly responsible for many of the most devastating diseases known to plants and humans (Cornelis and Van Gijsegem, 2000; Galan and Collmer, 1999; He, 1998; Hueck, 1998, Lee, 1997; Lee and Schneewind, 1999; D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 367 Lindgren, 1997; Mecsas and Strauss, 1996). This specialized protein secretion system is required for pathogenesis in a wide range of human pathogens (e.g. E. coli, P. aeruginosa, Salmonella enterica, Shigella spp. and Yersinia spp.) and plant pathogens (e.g. P. syringae, Xanthomonas spp. and Erwinia spp.). It is used to strategically inject proteins (effectors) directly from the bacterial cell into the cytoplasm of its host. The TTSS is a complex apparatus that spans both bacterial membranes and the periplasmic space. It is encoded by 20 or more genes, many of which are highly conserved among both plant and human pathogens. These genes are typically clustered in a so-called ‘pathogenicity island’ on the bacterial genome or an accessory plasmid. The TTSS is believed to have evolved from the flagellar system, as a number of the inner membrane components of the TTSS show similarity to proteins of the flagellar basal body (Aizawa, 2001). TTSS effectors interact with host proteins both inside and outside the host cell to modulate the host response. In many cases, effectors are necessary for pathogenesis and are directly responsible for determining host specificity. They have been shown to interfere with signal transduction, cause cytoskeletal changes, and to have a direct cytotoxic effect (Hueck, 1998). They also are known to induce immune responses in resistant animal and plant hosts. Given their prominent role in determining the course and fate of pathogen – host interactions, it is reasonable to consider them as one of the pathogen’s primary offensive weapons. As more TTSS effectors are discovered and functionally characterized, it is becoming clear that they can be divided into functional classes, and that these classes are shared among human and plant pathogens. In most cases, it appears that the common mechanism is not due to homology, but rather analogy—similarity due to convergent evolution. In other words, there has been convergence of function in TTSS effectors of plant and human pathogens. The fact that pathogens have independently evolved similar mechanisms to attack very different hosts strongly supports there being important commonalities among the disease processes of humans and plants. Some examples of conserved effector function include two classes of cysteine proteases. The YopJ class of cysteine proteases was originally isolated from Yersinia pestis, the causal agent of bubonic and pneumonic plague. This protein induces apoptosis and inhibits the host immune response by disrupting the MAPK and NFnB signaling pathways (Orth, 2002). The catalytic residues of YopJ have been identified and shown to be necessary for Yersinia virulence (Orth et al., 2000). Proteins with the same conserved catalytic residues as YopJ have been found in the S. enterica, the causal agent of gastroenteritis and typhoid fever, and in the plant pathogens P. syringae, E. amylovora, Ralstonia solanacearum and Xanthomonas campestris (Staskawicz et al., 2001; Ciesiolka et al., 1999; Lavie et al., 2002). These conserved catalytic residues have been shown to be required for the induction of the defense response in plants resistant to X. campestris, the causal agent of bacterial spot of pepper and tomato (Orth et al., 2000). YopT is the second class of TTSS-dependent cysteine protease. This Yersinia protein cleaves Rho GTPases, which are regulators of the eukaryotic actin cytoskeleton. Cleavage and release of Rho GTPases from the plasma membrane causes the disruption of actin stress fibers (Aepfelbacher and Heesemann, 2001; Aepfelbacher et al., 2003), thereby disrupting the phagocytotic uptake of the pathogen by the host immune cells. YopT shares 368 D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 invariant residues with P. syringae TTSS effectors AvrPphB, AvrPpiC2, HopPtoC and HopPtoN, in addition to proteins from E. coli, Haemophilus spp., Pasteurella multocida, and Chlamydia muridarum (Buttner and Bonas, 2003; Collmer et al., 2002; Shao et al., 2002). These residues are essential for the YopT protease activity as well as the induction of the AvrPphB-mediated hypersensitive reaction (HR) defense response in resistant plants (Shao et al., 2002). Another class of shared virulence factors are the ADP-ribosyltransferase toxins. Some of these are TTSS-dependent, such as P. aeruginosa’s ExoS and ExoT, and P. syringae’s HopPtoO (HopPtoS1), HopPtoS2 and HopPtoS3 (Collmer et al., 2002; Guttman et al., 2002). The injection of ExoS into the host cells elicits a cytotoxic and antiphagocytic response, corresponding to the disruption of the actin microfilament structure (FrithzLindsten et al., 1997). ExoT enables P. aeruginosa to inhibit epithelial wound repair by causing actin cytoskeleton collapse, cell rounding and cell detachment (Kazmierczak and Engel, 2002). The function of the P. syringae ADP-ribosyltransferase toxins has not been determined. There are also a number of other notable human pathogens that secrete ADPribosyltransferases, although not in a TTSS-dependent manner. These include the P. aeruginosa exotoxin A, Corynebacterium diphtheriae diphtheria toxin, Vibrio cholera cholera toxin, and Bordetella pertussis pertussis toxin (Okazaki and Moss, 1994). A final class of TTSS-dependent virulence factors shared by plant and human pathogens are pore-forming molecules. Shigella flexneri, the causal agent of bacterial dysentery, effectors IpaB and IpaC (Blocker et al., 1999), Yersinia effectors YopB and YopD (Tardy et al., 1999), and P. syringae effector HrpZ (Lee et al., 2001) create pores in synthetic lipid bilayers. Although these proteins are not homologous, they appear to be another example of functional convergence. It is not clear if the goal of pore formation in the eukaryotic plasma membrane is to assist in the translocation of other effectors, or to cause the leakage of nutrients. 3.3. Type IV secretion The type IV secretion system has two distinct claims to fame. It encodes the well known conjugative pilus used by bacteria to exchange plasmids. It has also been intensively investigated for its ability to move DNA – protein complexes and toxins into eukaryotic cells (Foulongne et al., 2002). The plant pathogen Agrobacterium tumefaciens has the best-studied type IV secretion system. It delivers gall-forming (oncogenic) DNA – protein complexes into plant cells through its VirB type IV system (Lai and Kado, 2000). Human pathogens, such as Haemophilus influenzae, S. flexneri, and Legionella pneumophila also use a type IV system (Finlay and Falkow, 1997; Foulongne et al., 2002). B. pertussis delivers the pertussis toxin via a type IV system (Weiss et al., 1993), while Helicobacter pylori uses its type IV system to inhibit phagocytosis (Ernst, 2000). Type IV systems have also been found in P. syringae (Sexton and Vogel, 2002) (Stavrinides and Guttman, unpublished data) and X. campestris pv. vesicatoria (Ojanen-Reuhs et al., 1997), where type IV mutant strains exhibit reduced aggregation in the laboratory, but still retain wildtype virulence toward their tomato host. Secretion systems represent the most significant evolutionary and functional link between plant and animal pathogens. The TTSS in particular is both evolutionary D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 369 conserved and necessary for pathogenesis among both plant and animal pathogens. Given their central role in pathogenesis, secretion systems have justifiably attracted attention as potential targets for development of vaccines and therapeutics (Kauppi et al., 2003; Muller et al., 2001). Whereas we know a tremendous amount about the secretion systems, we know much less about the effectors that travel those systems. These molecules are on the front line during a bacterial attack. They come into more intimate contact with the host than any other pathogen-derived molecule, often being directly injected into the host cell. Unfortunately, we know very little about the natural genetic variation underlying these effectors. What we do know is that their distribution among strains of a species is extraordinarily variable, largely due to the action of horizontal gene transfer. What we do not know is the extent and importance of allelic variation in these important molecules, and the specific causal or correlative associations between this variation and disease. These studies are a necessary step in the development of widely effective and durable treatments. 4. Exopolysaccharides and biofilms Exopolysaccharides (EPS) are vital virulence determinants of many pathogens. They play their most important role as key components of the slime layer, or glycocalyx, of bacterial biofilms (Costerton et al., 1999; Davey and O’TooleG, 2000; Donlan, 2001; Dunne, 2002; Miller and Bassler, 2001; Pulcini, 2001). Biofilms are highly structured polymer matrices produced by sessile bacteria, which provide for the free flow of water, nutrients, and signaling molecules, in addition to protection from dehydration, antimicrobials, environmental extremes and predators. EPS are required for P. aeruginosa biofilm production, and biofilms are necessary for the colonization of the lungs of CF patients (Costerton, 2001; Lyczak et al., 2000). Vibrio cholerae EPS mutants are unable to form biofilms and have reduced virulence (Watnick and Kolter, 1999). It is also believed that V. cholerae biofilm mutants do not survive as well in their natural aquatic environment (Watnick and Kolter, 1999). X. campestris produces biofilms upon infection of its plant host. Strains that were defective in biofilm formation had smaller lesions due to a reduced ability to spread through the leaf vasculature (Dow et al., 2003). Although P. syringae has not been shown to produce biofilms via microscopic examination or in vitro adhesion assays, it does produce copious amount of the EPS alginate. P. syringae alginate mutants were found to be significantly impaired in their ability to colonize leaves, form less severe lesion, and reach lower population densities than wildtype strains (Keith et al., 2003; Osman et al., 1986; Yu et al., 1999). Membrane-derived oligosaccharides are an important class of EPS. These glucans are produced by homologs of the mdoGH locus, and are secreted into the periplasmic space of many Gram-negative bacteria. They are important components of the bacterial cell envelope, and have been found to play a role in a wide range of functions, from osmoregulation to virulence. P. syringae mutants deficient for these glucans lose the ability to cause disease on susceptible hosts and do not induce a defense response on resistant hosts (Mukhopadhyay et al., 1988). In E. chrysanthemi periplasmic glucan mutants were complete avirulent, and unable to grow in planta (Page et al., 2001). In P. aeruginosa mdoH mutants were severely reduced in their virulence toward Caenorhabdi- 370 D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 tis elegans (Mahajan-Miklos et al., 1999). MdoGH homologues are also found in Shigella spp., S. enterica, and V. cholerae (Bohin, 2000). EPS and biofilms pose more of a challenge than opportunity for the development of antimicrobials, as they are notoriously non-immunogenic due to their unpredictable structures. They also render many bacteria resistant to treatment and environmental perturbations (Drenkard and Ausubel, 2002). As a consequence, therapies that disrupt the production of EPS and biofilms are rapidly gaining in significance. One of the most exciting areas of research is the use of bacteriophage to penetrate biofilms and directly attack pathogens (Davies, 2002; Hughes et al., 1998). Bacteriophages are natural predators of bacteria, and some carry genes that enable them to effectively depolymerize biofilms (Adams and Park, 1956). This work is still in the very early stages, and faces the daunting task of dealing with bacterial resistance, but has been shown to be effective under laboratory conditions (Hughes et al., 1998; Corbin et al., 2001; Doolittle et al., 1995). 5. Regulatory pathways and regulators Plant and human pathogens use conserved regulatory mechanisms to respond to their environments and induce virulence-associated genes. The most important class of these systems is the two-component regulators. These systems are composed of a transmembrane sensor and a cytosolic response regulator. Upon receiving an extracellular signal, the sensor will cause a change in the associated response regulator. The now active response regulator will then induce or repress the appropriate genetic systems either directly, as a transcriptional regulator, or indirectly via a signal transduction cascade. The most important of this class of molecules is the global-activator two-component system (gacA/gacS), which controls a wide range of virulence phenotypes in both plant and human pathogens. It is near the top of the signal transduction cascade that is responsible for the production of extracellular enzymes, toxins and antibiotics in the human pathogens P. aeruginosa (Reimmann et al., 1997) and V. cholerae (Wong et al., 1998), and plant pathogens P. syringae (Bender et al., 1999), and Erwinia carotovora (Cui et al., 2001). It also controls alginate production in P. aeruginosa (Reimmann et al., 1997), swarming in P. syringae (Kinscherf and Willis, 1999), and cell invasion in S. enterica (Johnston et al., 1996). Quorum sensing (which is under gac control in many species) is another very important regulatory system that has been implicated in virulence in nearly every bacterial pathogen studied (Miller and Bassler, 2001; Donabedian, 2003). Quorum sensing systems in Gramnegative bacteria typically consist of an autoinducer, which produces a free diffusible molecule, and a receptor/transcriptional activator protein, which monitors the concentration of the autoinducer. As the bacterial population grows, the level of autoinducer in the environment increases. When the concentration of the autoinducer reaches a critical threshold level, the receptor protein is activated, which induces or represses a range of target genes. In general, bacterial pathogens use quorum sensing to ensure that virulence genes are only expressed after their population has reached a critical size. This unified attack strategy makes it more difficult for the host to mount an effective defense. Quorum sensing has been shown to directly control biofilm formation, the expression of virulence D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 371 genes, swarming, conjugation, and the production of secondary metabolites. Its role in pathogenesis, has been extensively reviewed (Miller and Bassler, 2001; Donabedian, 2003; Smith and Iglewski, 2003; Von Bodman et al., 2003), and therefore will not be further discussed here. There are a number of regulatory elements that are shared among pathogens of plant and humans. The most important of these are the alternative sigma factors, such as j54, which is encoded by the rpoN locus (Cao et al., 2001). This protein controls the regulatory cascade that induces the expression of the toxin coronatine and the TTSS in P. syringae (Hendrickson et al., 2000a,b). It also induces pili and alginate production in P. aeruginosa (Hendrickson et al., 2001), and capsular polysaccharide synthesis in Klebsiella pneumoniae (Arakawa et al., 1995). Another shared regulatory element is the periplasmic disulfide bond-forming enzyme DsbA. This protein has been implicated in the virulence of a wide range of bacterial pathogens (Cao et al., 2001). In P. aeruginosa DsbA is required for proper secretion of TTSS effectors (Ha et al., 2003). DsbA is also required for the secretion of the pertussis toxin by B. pertussis (Stenson and Weiss, 2002). Cell-to-cell transmission of the S. flexneri in hosts was disrupted in DsbA mutant strains (Yu et al., 2000). DsbA mutants of E. carotovora produced greatly reduced levels of pectate lyase, their primary virulence factor (Vincent-Sealy et al., 1999). Finally, the periplasmic protein DegP acts both as a chaperone and serine protease, depending on the environmental conditions. Its primary function is to degrade misfolded proteins in the periplasm. It also been shown to be necessary for virulence in P. syringae, P. aeruginosa, Yersinia and S. enterica (Cao et al., 2001; Pallen and Wren, 1997; Yorgey et al., 2001). Common regulatory mechanisms present a unique opportunity for the development of antimicrobials. These systems are often highly constrained, and as such present widespread and durable targets for therapeutics and vaccines. They also often control multiple components of virulence. The challenge will be to design strategies that specifically target these high level controls in pathogens, while avoiding the scorched earth indiscriminate killing of all bacteria, including commensal and beneficial species. If these regulatory systems could be selectively disrupted or turned off then many dangerous pathogens would effectively be turned into harmless commensals. 6. Common disease-associated genes in plant and animal hosts Comparative genomic analyses have also found a remarkable number of human disease-associated genes in diverse eukaryotes. Rubin et al. (2000) (also see mips.gsf.de/proj/thal/db/tables/tables_frame.html) mined the human, Drosophila melanogaster, C. elegans, Saccharomyces cerevisia, and A. thaliana genomes for human disease-associated genes. Of 289 total genes, D. melanogaster shared 230 (BLAST evalue < 10 6), C. elegans shared 209, S. cerevisia shared 119, and A. thaliana shared a remarkable 172 genes with humans. These genes span a wide spectrum of functions, from those involved in cancer, to immune and neurological disorders. Examples of human disease-associated genes that have greater protein similarity to A. thaliana proteins (as 372 Associated disease Cancer Ataxia telangiectasia Acute myeloid leukemia Breast cancer Gene AT DEK BRCA1 Putative function NCBI OMIM # BLASTP e-valuea D.m. 145 17 06 C.e. S.c. A.t. 2e 49 1e + 00 9e 11 4e 92 2e + 00 5e 05 1e 2e 2e 168 29 20 Breast cancer Tumor suppressor Tumor suppressor Type 1 hereditary nonpolyposis colon cancer Xeroderma pigmentosum Xeroderma pigmentosum BRCA2 CDKN2A CDKN1C MSH3 lipid-mediated signaling oncogene component of RNA polymerase II holoenzyme homologous recombination cyclin-dependent inhibitor cyclin-dependent inhibitor MutS homolog 208,900 125,264 113,705 1e 1e 2e 600,185 600,160 600,856 600,887 1e 03 5e 08 1e + 00 4e 67 2e + 00 1e 08 8e 08 2e 64 9e + 00 6e 05 1e + 00 1e 126 4e 9e 7e 7e 38 12 19 134 XPF XP7 nucleotide excision repair nucleotide excision repair 278,760 278,780 8e 1e 93 64 1e 8e 49 23 1e 6e 60 47 1e 7e 146 89 Neurological Dentatorubral-pallidoluysian atrophy Parkinson disease Retinitis pigmentosa Spinocerebellar ataxia Spinal muscular atrophy Stargardt macular dystrophy DRPLA UCHL1 RPGR SCA7 SMN1 ABCA4 atrophin family protein ubiquitin C-terminal hydrolase GTPase regulator nuclear matrix associated assembly factor for snRNPs ATP-binding cassette 125,370 191,342 312,610 164,500 600,354 601,691 2e 7e 9e 2e 5e 1e 10 41 34 03 07 119 4e 1e 1e 2e 1e 2e 03 24 19 02 04 95 9e 04 1e 07 9e 09 5e 06 1e + 00 4e 14 3e 4e 1e 8e 5e 3e 37 42 43 10 10 168 Cardiovascular Tangier disease ABCA1 ATP-binding cassette 600,046 1e 127 1e 103 7e 2e 181 13 D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 Table 1 Human disease-associated genes with highest protein similarity to A. thaliana CKN1 DNMT3B transcription-coupled repair methyltransferase 216,400 602,900 5e 9e CREBBP TCOF PEX1 CREB binding protein early embryonic development peroxisome biogenesis 600,140 154,500 302,136 Endocrine Congenital adrenal hyperplasia Hyperinsulinemic hypoglycemia Hypothyroidism CYP21A2 ABCC8 TRH cortisol biosynthesis ATP-binding cassette Thyrotropin-releasing hormone Renal Williams – Beuren syndrome ELN Immune Chronic granulomatous disease MHC class II deficiency 14 07 4e 1e 13 01 1e 14 2e + 00 2e 1e 43 08 330e 01 7e 06 3e 81 5e + 00 5e 05 2e 67 1e + 00 5e 01 7e 91 6e 4e 4e 07 15 125 201,910 600,509 275,120 1e 43 1e 160 6e + 00 2e 34 1e 160 1e + 00 1e 08 1e 176 1e + 00 6e 7e 2e 46 188 07 elastin 130,160 1e + 00 1e + 00 1e + 00 6e 44 CYBB MHC2TA NADPH oxidase MHC class II transactivator 306,400 600,005 5e 2e 36 02 4e 9e 34 03 6e 4e 06 03 1e 9e 61 07 Metabolic Galactokinase deficiency GALK1 galactokinase 604,313 9e 15 2e 14 3e 10 4e 25 Other Ehlers – Danlos syndrome Epidermolytic palmoplantar keratoderma Osteogenesis imperfecta Spondyloepiphyseal dysplasia congenita Vohwinkel syndrome, ichthyosis COL3A1 KRT9 COL1A1 COL2A1 LOR collagen synthesis keratin synthesis collagen synthesis collagen synthesis Loricrin-component of epidermis cell envelope 120,180 144,200 120,150 120,140 152,445 2e 06 6e 22 7e 11 5e 18 1e + 00 1e + 00 7e 09 1e + 00 1e + 00 1e + 00 1e 8e 8e 2e 2e 35 81 35 36 60 1e 06 5e 26 9e 11 9e 20 1e + 00 D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 Malformation syndromes Cockayne syndrome Immunodeficiency-centromeric instability-facial anomalies Rubinstein – Taybi syndrome Treacher – Collins syndrome Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease D.m.—D. melanogaster, C.e.—C. elegans, S.c.—S. cerevisia, and A.t.—A. thaliana. a BLASTP data from Rubin et al. (2000) and mips.gsf.de/proj/thal/db/tables/tables_frame.html. 373 374 D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 determined by BLASTP e-value) than to homologous proteins in yeast, fly or worm are presented in Table 1. This analysis clearly shows that the cellular processes required for life are not fundamentally different in plants and animals. 7. Common pathogens of plants and animals An appreciation that most human diseases are zoonotic (transmitted from animals to humans) (Cleaveland et al., 2001; Taylor et al., 2001) has led to an increased interest in identifying and understanding the determinants of host specificity. A surprising outcome of this work is the discovery of pathogens that can attack both plants and animals. Examples of these cross-kingdom pathogens include Erwinia spp., a well-known cause of a variety of wilt diseases in plants, including bacterial fire blight of apples and pears. Recently, it has also been isolated from human wounds and abscesses (Cao et al., 2001). Burkholderia cepacia, the causal agent of soft rot in onion, can cause life-threatening infections in immunocompromised and CF patients (Cao et al., 2001). But by far the beststudied cross-kingdom pathogen is P. aeruginosa (Cao et al., 2001; Staskawicz et al., 2001; Mahajan-Miklos et al., 1999; Hendrickson et al., 2001; Yorgey et al., 2001; Choi et al., 2002; Hogan and Kolter, 2002; Jander et al., 2000; Mahajan-Miklos et al., 2000; Plotnikova et al., 2000; Pukatzki et al., 2002; Rahme et al., 1995, 1997, 2000; Tan et al., 1999). Recent work has shown that this pathogen can cause disease in such diverse hosts as mammals, insects (Jander et al., 2000), worms (Mahajan-Miklos et al., 1999), amoeba (Pukatzki et al., 2002), fungi (Hogan and Kolter, 2002), and plants (Plotnikova et al., 2000; Rahme et al., 1995, 1997). Many of the genetic systems necessary for human pathogenesis are also required for virulence in these diverse hosts (Cao et al., 2001; Staskawicz et al., 2001; Rahme et al., 2000). For example, the TTSS P. aeruginosa effector exoU is a highly cytotoxic molecule that is required for in vitro killing of epithelial cells and virulence in mouse models (Allewelt et al., 2000; Hauser et al., 1998). ExoU is also required for virulence in the social amoeba Dictyostelium discoideum (Pukatzki et al., 2002), the caterpillar Galleria mellonella (Miyata et al., 2003), and S. cerevisiae when introduced on a yeast vector (Rabin and Hauser, 2003). Cross-kingdom pathogens present tremendous opportunities for deciphering the mechanisms of host adaptation. What factors and processes are required for the exploitation of one host, but not others? Identification of these commonalities and differences will clearly define those virulence factors that are essential for human disease, and provide clear direction for the development of targeted therapeutics. 8. Innate immune response The animal immune system has often been viewed as being wholly unique and unlike anything found in plants. In actuality, a number of similarities have been found between the innate immune response of plants and humans. The animal innate immune system poses the first challenge to invading microbial pathogens. This system detects pathogenassociated molecular patterns (PAMPs) that are usually highly conserved within and D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 375 among a wide range of pathogenic species. Arrays of pattern recognition receptors (PRRs) recognize these PAMPs. An important family of PRRs is the cell-surface Toll-like receptors (Jebanathirajah et al., 2002; Takeda and Akira, 2003; Young, 2000), which are characterized by an extracellular leucine-rich-repeat (LRR) domain and a cytoplasmic TIR (Drosophila Toll/Interleukin-1 receptor) domain. The binding of specific pathogenassociated molecular patterns to these receptors results in the activation of a signal transduction cascade through NF-nB, which modulates the animal immune response and the production of inflammatory effectors such as cytokines (Staskawicz et al., 2001; Aderem and Ulevitch, 2000). The animal innate immune response also includes the activation of intracellular nucleotide-binding oligomerization domain (NOD) proteins (Inohara and Nunez, 2003; Inohara et al., 2002). These proteins require a C-terminal LRR, and an N-terminal effector-binding domain (EBD) that binds specific signals and activate NF-nB. The human genome is estimated to carry approximately 30 Nod proteins with varied N-terminal receptor domains that differ in their specificity (Staskawicz et al., 2001; Dangl and Jones, 2001) (Fig. 2). Plant innate immune systems also use LRR proteins analogous to the human Toll-like and NOD receptors. Plants also have the ability to mount a direct defense response, and to send systemic signals that can induce an acquired resistance, effectively blocking subsequent pathogen attack (Maleck and Dietrich, 1999). Because plants have no specialized and distinct immune system, each cell has the ability to respond to a pathogen attack. This defense capacity is maintained by a very large repertoire of rapidly evolving resistance (R) genes that constitute the plant’s innate immune system Fig. 2. A comparison of animal and plant innate immunity proteins. Animal membrane bound Toll-like receptors have an extracellular leucine-rich-repeat (LRR) domain and a cytoplasmic TIR (Drosophila Toll/Interleukin-1 receptor) domain. Animal intracellular nucleotide-binding oligomerization domain (NOD) proteins have a Cterminal LRR domain, a NOD domain, and a variable N-terminal effector-binding domain (EFD). Plant intracellular resistance proteins have a C-terminal LRR domain, a NOD domain, and an N-terminal TIR domain. 376 D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 (Dangl and Jones, 2001). The majority of these R genes have cytoplasmic NOD domains, C-terminal leucine-rich repeats (LRR), and N-terminal TIR domains (Dangl and Jones, 2001; Sessa and Martin, 2000), making them analogous to the human Tolllike and NOD proteins. The number of LRRs is extremely large and accounts for much of the flexibility in the innate immune system (Kajava, 1998; Kobe and Kajava, 2001; Parniske et al., 1997). For example, A. thaliana has approximately 150 NB-LRR genes (Anonymous, 2000). The finding that plants and animals use analogous proteins to recognize invading pathogens should not have been such a dramatic surprise. We now understand that many plant and animal pathogens are evolutionary cousins that have the ability and propensity to share genetic material. This review has illustrated many of these shared mechanisms and strategies. Are these common tactics a cause or consequence of analogous immune responses in divergent hosts? Given the greater evolutionary potential of bacterial pathogens (due to their rapid generation time and ability to exchange genetic material horizontally), it seems likely that their use of common mechanisms reflects the common molecular and cellular environment presented by their respective hosts. 9. Conclusion Bacterial pathogens of humans and plants share numerous mechanisms for causing disease. There are common mechanisms for adhesion, secretion, and regulation. There are homologous and analogous toxins and virulence molecules. There are remarkable similarities between the plant and human innate immune systems and disease-associated genes. Finally, there are pathogens that are quite adept at attacking both plants and animals. Given these similarities, it is reasonable to expect that what is learned about plant pathogenesis may have direct relevance to human pathogenesis. But given the extensive divergence between plants and humans, there must be some compelling reason to use plant pathogens as models for human pathogenesis. The compelling reason is that the study of plant pathogenesis provides many practical and scientific advantages. Plants provide the means to significantly increase experimental replication and throughput. They provide vastly greater reproductive control and tractability. They can be genetically manipulated with ease. All of these benefits come along with dramatically reduced experimental costs and regulation. The identification of virulence factors conserved across a broad range of hosts will help identify evolutionarily constrained, and perhaps essential virulence mechanisms. These are logical targets for the development of antimicrobials and therapeutics. Perhaps more importantly, identifying analogous virulence factors, not related by evolutionary descent, but with common functions, will reveal mechanisms fundamental to bacterial pathogenesis. If divergent pathogens have independently evolved similar virulence mechanisms in highly dissimilar hosts, then it is logical to assume that the pathogens have found a way to exploit common eukaryotic processes. Identifying these critical steps in pathogenesis will not only put us in a better position to control and treat infectious agents, it may also help us realize that leaves and roots aside, we may not be as different from plants as we like to think. D.S. Guttman / Biotechnology Advances 22 (2004) 363–382 377 Acknowledgements I would like to acknowledge Dr. Pauline Wang and an anonymous reviewer who provided significant insight and a valuable critique of this review, and Prof. Bernie Glick for his encouragement. 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