Advances on plant–pathogen interactions from molecular toward systems biology perspectives

Summary In the past 2 decades, progress in molecular analyses of the plant immune system has revealed key elements of a complex response network. Current paradigms depict the interaction of pathogen‐secreted molecules with host target molecules leading to the activation of multiple plant response pathways. Further research will be required to fully understand how these responses are integrated in space and time, and exploit this knowledge in agriculture. In this review, we highlight systems biology as a promising approach to reveal properties of molecular plant–pathogen interactions and predict the outcome of such interactions. We first illustrate a few key concepts in plant immunity with a network and systems biology perspective. Next, we present some basic principles of systems biology and show how they allow integrating multiomics data and predict cell phenotypes. We identify challenges for systems biology of plant–pathogen interactions, including the reconstruction of multiscale mechanistic models and the connection of host and pathogen models. Finally, we outline studies on resistance durability through the robustness of immune system networks, the identification of trade‐offs between immunity and growth and in silico plant–pathogen co‐evolution as exciting perspectives in the field. We conclude that the development of sophisticated models of plant diseases incorporating plant, pathogen and climate properties represent a major challenge for agriculture in the future.

[1]  B. Palsson,et al.  Insight into human alveolar macrophage and M. tuberculosis interactions via metabolic reconstructions , 2010, Molecular systems biology.

[2]  Jonathan D. G. Jones,et al.  Plant pathogens and integrated defence responses to infection , 2001, Nature.

[3]  B. Palsson,et al.  Stoichiometric flux balance models quantitatively predict growth and metabolic by-product secretion in wild-type Escherichia coli W3110 , 1994, Applied and environmental microbiology.

[4]  M. Metzker Sequencing technologies — the next generation , 2010, Nature Reviews Genetics.

[5]  D. Bebber Range-expanding pests and pathogens in a warming world. , 2015, Annual review of phytopathology.

[6]  Martin Ackermann,et al.  A functional perspective on phenotypic heterogeneity in microorganisms , 2015, Nature Reviews Microbiology.

[7]  D. Roby,et al.  Resistance to phytopathogens e tutti quanti: placing plant quantitative disease resistance on the map. , 2014, Molecular plant pathology.

[8]  Hur-Song Chang,et al.  Quantitative Nature of Arabidopsis Responses during Compatible and Incompatible Interactions with the Bacterial Pathogen Pseudomonas syringae Online version contains Web-only data. Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.007591. , 2003, The Plant Cell Online.

[9]  Li Yang,et al.  Convergent targeting of a common host protein-network by pathogen effectors from three kingdoms of life. , 2014, Cell host & microbe.

[10]  R. Hückelhoven Cell wall-associated mechanisms of disease resistance and susceptibility. , 2007, Annual review of phytopathology.

[11]  Daniel B. Müller,et al.  The Plant Microbiota: Systems-Level Insights and Perspectives. , 2016, Annual review of genetics.

[12]  Jonathan D. G. Jones,et al.  Evidence for Network Evolution in an Arabidopsis Interactome Map , 2011, Science.

[13]  R. Callen,et al.  Thermodynamics and an Introduction to Thermostatistics, 2nd Edition , 1985 .

[14]  Davide Heller,et al.  STRING v10: protein–protein interaction networks, integrated over the tree of life , 2014, Nucleic Acids Res..

[15]  J. Brownstein,et al.  Emerging fungal threats to animal, plant and ecosystem health , 2012, Nature.

[16]  Anwar Hussain,et al.  Integrated Systems View on Networking by Hormones in Arabidopsis Immunity Reveals Multiple Crosstalk for Cytokinin[W] , 2012, Plant Cell.

[17]  H. Yoshioka,et al.  A Receptor Pair with an Integrated Decoy Converts Pathogen Disabling of Transcription Factors to Immunity , 2015, Cell.

[18]  Bernard Henrissat,et al.  Survival trade-offs in plant roots during colonization by closely related beneficial and pathogenic fungi , 2016, Nature Communications.

[19]  Detlef Weigel,et al.  Microbial Hub Taxa Link Host and Abiotic Factors to Plant Microbiome Variation , 2016, PLoS biology.

[20]  T. Kroj,et al.  Integration of decoy domains derived from protein targets of pathogen effectors into plant immune receptors is widespread , 2016, The New phytologist.

[21]  T. Szyperski Biosynthetically directed fractional 13C-labeling of proteinogenic amino acids. An efficient analytical tool to investigate intermediary metabolism. , 1995, European journal of biochemistry.

[22]  Adelin Barbacci,et al.  Thermodynamical journey in plant biology , 2015, Front. Plant Sci..

[23]  D. Fell,et al.  Responses to Light Intensity in a Genome-Scale Model of Rice Metabolism1[C][W][OA] , 2013, Plant Physiology.

[24]  Qi Yin,et al.  Comprehensive proteomic analysis of the wheat pathogenic fungus Zymoseptoria tritici , 2016, Proteomics.

[25]  T. Dandekar,et al.  The Role of Auxin-Cytokinin Antagonism in Plant-Pathogen Interactions , 2012, PLoS pathogens.

[26]  U. Güldener,et al.  Pathogenicity Determinants in Smut Fungi Revealed by Genome Comparison , 2010, Science.

[27]  N LeNovère Quantitative and logic modelling of molecular and gene networks. , 2015 .

[28]  T. Sauter,et al.  Constraint Based Modeling Going Multicellular , 2016, Front. Mol. Biosci..

[29]  S. Raffaele,et al.  Genome evolution in filamentous plant pathogens: why bigger can be better , 2012, Nature Reviews Microbiology.

[30]  Jeffrey D Orth,et al.  What is flux balance analysis? , 2010, Nature Biotechnology.

[31]  Marcel Salathé,et al.  Parasites lead to evolution of robustness against gene loss in host signaling networks , 2008, Molecular systems biology.

[32]  J. Glazebrook,et al.  Network Properties of Robust Immunity in Plants , 2009, PLoS genetics.

[33]  Björn H. Junker,et al.  Flux Balance Analysis of Barley Seeds: A Computational Approach to Study Systemic Properties of Central Metabolism1[W] , 2008, Plant Physiology.

[34]  M. Persicke,et al.  Establishment, in silico analysis, and experimental verification of a large-scale metabolic network of the xanthan producing Xanthomonas campestris pv. campestris strain B100. , 2013, Journal of biotechnology.

[35]  Karsten M. Borgwardt,et al.  Arabidopsis Defense against Botrytis cinerea: Chronology and Regulation Deciphered by High-Resolution Temporal Transcriptomic Analysis[C][W][OA] , 2012, Plant Cell.

[36]  B. Vinatzer,et al.  The influence of the accessory genome on bacterial pathogen evolution , 2011, Mobile genetic elements.

[37]  Steffen Klamt,et al.  SBML qualitative models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools , 2013, BMC Systems Biology.

[38]  N. Hall,et al.  Horizontal gene transfer facilitated the evolution of plant parasitic mechanisms in the oomycetes , 2011, Proceedings of the National Academy of Sciences.

[39]  U. Sauer High-throughput phenomics: experimental methods for mapping fluxomes. , 2004, Current opinion in biotechnology.

[40]  E. Schadt,et al.  Single molecule-level detection and long read-based phasing of epigenetic variations in bacterial methylomes , 2014, Nature Communications.

[41]  D. di Bernardo,et al.  How to infer gene networks from expression profiles , 2007, Molecular systems biology.

[42]  G. Martin,et al.  Strategies used by bacterial pathogens to suppress plant defenses. , 2004, Current opinion in plant biology.

[43]  Yunfei Hu,et al.  Chitin-Induced Dimerization Activates a Plant Immune Receptor , 2012, Science.

[44]  Ying Li,et al.  Single Nucleus Genome Sequencing Reveals High Similarity among Nuclei of an Endomycorrhizal Fungus , 2014, PLoS genetics.

[45]  D. Bebber,et al.  Crop-destroying fungal and oomycete pathogens challenge food security. , 2015, Fungal genetics and biology : FG & B.

[46]  S. Schornack,et al.  An Effector-Targeted Protease Contributes to Defense against Phytophthora infestans and Is under Diversifying Selection in Natural Hosts1[W] , 2010, Plant Physiology.

[47]  A. Hegeman,et al.  Recent advances in stable isotope-enabled mass spectrometry-based plant metabolomics. , 2017, Current opinion in biotechnology.

[48]  Jonathan D. G. Jones,et al.  Bacterial disease resistance in Arabidopsis through flagellin perception , 2004, Nature.

[49]  U. Conrath,et al.  Priming for enhanced defense. , 2015, Annual review of phytopathology.

[50]  D. Fell,et al.  A Genome-Scale Metabolic Model of Arabidopsis and Some of Its Properties1[C][W] , 2009, Plant Physiology.

[51]  R. Terauchi,et al.  Host specialization of the blast fungus Magnaporthe oryzae is associated with dynamic gain and loss of genes linked to transposable elements , 2016, BMC Genomics.

[52]  A. Heck,et al.  Next-generation proteomics: towards an integrative view of proteome dynamics , 2012, Nature Reviews Genetics.

[53]  M. Valls,et al.  Novel plant inputs influencing Ralstonia solanacearum during infection , 2013, Front. Microbiol..

[54]  B. Moulia,et al.  The power and control of gravitropic movements in plants: a biomechanical and systems biology view. , 2009, Journal of experimental botany.

[55]  M. Bhattacharyya,et al.  The plant immunity inducer pipecolic acid accumulates in the xylem sap and leaves of soybean seedlings following Fusarium virguliforme infection. , 2016, Plant science : an international journal of experimental plant biology.

[56]  Bruno Moulia,et al.  Integrative Mechanobiology of Growth and Architectural Development in Changing Mechanical Environments , 2011 .

[57]  C. Maranas,et al.  Zea mays iRS1563: A Comprehensive Genome-Scale Metabolic Reconstruction of Maize Metabolism , 2011, PloS one.

[58]  T. Kroj,et al.  A novel conserved mechanism for plant NLR protein pairs: the “integrated decoy” hypothesis , 2014, Front. Plant Sci..

[59]  M. Anisimova,et al.  Repertoire, unified nomenclature and evolution of the Type III effector gene set in the Ralstonia solanacearum species complex , 2013, BMC Genomics.

[60]  C. Janeway,et al.  Innate Immunity: The Virtues of a Nonclonal System of Recognition , 1997, Cell.

[61]  L. Quek,et al.  AraGEM, a Genome-Scale Reconstruction of the Primary Metabolic Network in Arabidopsis1[W] , 2009, Plant Physiology.

[62]  S. L. Tausta,et al.  Plant cell types: reporting and sampling with new technologies. , 2008, Current opinion in plant biology.

[63]  Orkun S. Soyer,et al.  Metabolic modelling in a dynamic evolutionary framework predicts adaptive diversification of bacteria in a long-term evolution experiment , 2016, BMC Evolutionary Biology.

[64]  Alexandre Jousset,et al.  Trophic network architecture of root-associated bacterial communities determines pathogen invasion and plant health , 2015, Nature Communications.

[65]  Orkun S. Soyer,et al.  Evolutionary systems biology: What it is and why it matters , 2013, BioEssays : news and reviews in molecular, cellular and developmental biology.

[66]  C. Zipfel,et al.  Plant PRRs and the activation of innate immune signaling. , 2014, Molecular cell.

[67]  S. Meyer,et al.  The quick and the deadly: growth vs virulence in a seed bank pathogen. , 2010, The New phytologist.

[68]  N. P. Money Insights on the mechanics of hyphal growth , 2008 .

[69]  W. Boerjan,et al.  The role of the secondary cell wall in plant resistance to pathogens , 2014, Front. Plant Sci..

[70]  Leighton Pritchard,et al.  A systems biology perspective on plant-microbe interactions: biochemical and structural targets of pathogen effectors. , 2011, Plant science : an international journal of experimental plant biology.

[71]  R. Nelson,et al.  Shades of gray: the world of quantitative disease resistance. , 2009, Trends in plant science.

[72]  Jonathan D. G. Jones,et al.  Genome sequence and analysis of the Irish potato famine pathogen Phytophthora infestans , 2009, Nature.

[73]  Detlef Weigel,et al.  Natural allelic variation underlying a major fitness tradeoff in Arabidopsis thaliana , 2010, Nature.

[74]  S. Turner,et al.  Real-time DNA sequencing from single polymerase molecules. , 2010, Methods in enzymology.

[75]  J. Traas,et al.  Force-Driven Polymerization and Turgor-Induced Wall Expansion. , 2016, Trends in plant science.

[76]  Norikuni Saka,et al.  Loss of Function of a Proline-Containing Protein Confers Durable Disease Resistance in Rice , 2009, Science.

[77]  A. Sarkar,et al.  Laser Assisted Microdissection, an Efficient Technique to Understand Tissue Specific Gene Expression Patterns and Functional Genomics in Plants , 2015, Molecular Biotechnology.

[78]  Bruno Moulia,et al.  Mechanosensitive control of plant growth: bearing the load, sensing, transducing, and responding , 2015, Front. Plant Sci..

[79]  Liam J McGuffin,et al.  Structure and evolution of barley powdery mildew effector candidates , 2012, BMC Genomics.

[80]  C. Gilligan,et al.  Thirteen challenges in modelling plant diseases. , 2015, Epidemics.

[81]  J. Vorholt,et al.  Metabolic footprint of epiphytic bacteria on Arabidopsis thaliana leaves , 2015, The ISME Journal.

[82]  Charles R Steele,et al.  An anisotropic-viscoplastic model of plant cell morphogenesis by tip growth. , 2006, The International journal of developmental biology.

[83]  M. S. Mukhtar,et al.  Independently Evolved Virulence Effectors Converge onto Hubs in a Plant Immune System Network , 2011, Science.

[84]  J. Gouzy,et al.  A Resource Allocation Trade-Off between Virulence and Proliferation Drives Metabolic Versatility in the Plant Pathogen Ralstonia solanacearum , 2016, PLoS pathogens.

[85]  Alexandra M. E. Jones,et al.  Effector Specialization in a Lineage of the Irish Potato Famine Pathogen , 2014, Science.

[86]  Eleftherios Pilalis,et al.  An in silico compartmentalized metabolic model of Brassica napus enables the systemic study of regulatory aspects of plant central metabolism , 2011, Biotechnology and bioengineering.

[87]  S. Kamoun,et al.  From Guard to Decoy: A New Model for Perception of Plant Pathogen Effectors , 2008, The Plant Cell Online.

[88]  A. Lamond,et al.  Multidimensional proteomics for cell biology , 2015, Nature Reviews Molecular Cell Biology.

[89]  G. S. van Doorn,et al.  Coevolutionary feedback elevates constitutive immune defence: a protein network model , 2016, BMC Evolutionary Biology.

[90]  G. Salmond,et al.  Top 10 plant pathogenic bacteria in molecular plant pathology. , 2012, Molecular plant pathology.

[91]  Jonathan D. G. Jones,et al.  Comparative analysis of plant immune receptor architectures uncovers host proteins likely targeted by pathogens , 2016, BMC Biology.

[92]  C. Zipfel,et al.  Trade-off between growth and immunity: role of brassinosteroids. , 2015, Trends in plant science.

[93]  S. Hardin Real‐time DNA sequencing , 2005 .

[94]  B. Li,et al.  Multi-omics analysis of niche specificity provides new insights into ecological adaptation in bacteria , 2016, The ISME Journal.

[95]  H. Kanamori,et al.  Simultaneous RNA-Seq Analysis of a Mixed Transcriptome of Rice and Blast Fungus Interaction , 2012, PloS one.

[96]  L. Nielsen,et al.  Metabolic Reconstruction of Setaria italica: A Systems Biology Approach for Integrating Tissue-Specific Omics and Pathway Analysis of Bioenergy Grasses , 2016, Front. Plant Sci..

[97]  Y. Kraepiel,et al.  Gram-negative phytopathogenic bacteria, all hemibiotrophs after all? , 2016, Molecular plant pathology.

[98]  G. Martin,et al.  Genetic disassembly and combinatorial reassembly identify a minimal functional repertoire of type III effectors in Pseudomonas syringae , 2011, Proceedings of the National Academy of Sciences.

[99]  Olivier Hamant,et al.  How do plants read their own shapes? , 2016, The New phytologist.

[100]  Cristiana G O Dal'molin,et al.  C 4 GEM , a Genome-Scale Metabolic Model to Study C 4 Plant Metabolism , 2010 .

[101]  Eva-Maria Willing,et al.  Chromosome-level assembly of Arabidopsis thaliana Ler reveals the extent of translocation and inversion polymorphisms , 2016, Proceedings of the National Academy of Sciences.

[102]  G. Gierz,et al.  Evidence that Spitzenkörper behavior determines the shape of a fungal hypha: a test of the hyphoid model. , 1995, Experimental mycology.

[103]  Yin Hoon Chew,et al.  Multiscale digital Arabidopsis predicts individual organ and whole-organism growth , 2014, Proceedings of the National Academy of Sciences.

[104]  B. Moulia,et al.  Biomechanical study of the effect of a controlled bending on tomato stem elongation: local strain sensing and spatial integration of the signal. , 2000, Journal of experimental botany.

[105]  She Chen,et al.  The Decoy Substrate of a Pathogen Effector and a Pseudokinase Specify Pathogen-Induced Modified-Self Recognition and Immunity in Plants. , 2015, Cell host & microbe.

[106]  A. Arkin,et al.  Stochastic mechanisms in gene expression. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[107]  Milton H. Saier,et al.  TCDB: the Transporter Classification Database for membrane transport protein analyses and information , 2005, Nucleic Acids Res..

[108]  T. Szyperski Biosynthetically Directed Fractional 13C‐labeling of Proteinogenic Amino Acids , 1995 .

[109]  Neil Swainston,et al.  Towards a genome-scale kinetic model of cellular metabolism , 2010, BMC Systems Biology.

[110]  D. Roby,et al.  A MYB Transcription Factor Regulates Very-Long-Chain Fatty Acid Biosynthesis for Activation of the Hypersensitive Cell Death Response in Arabidopsis[W][OA] , 2008, The Plant Cell Online.

[111]  Anja Geitmann,et al.  The cellular mechanics of an invasive lifestyle. , 2013, Journal of experimental botany.

[112]  Michael F. Seidl,et al.  Single-Molecule Real-Time Sequencing Combined with Optical Mapping Yields Completely Finished Fungal Genome , 2015, mBio.

[113]  Alexandra M. E. Jones,et al.  Phytophthora infestans effector AVRblb2 prevents secretion of a plant immune protease at the haustorial interface , 2011, Proceedings of the National Academy of Sciences.

[114]  H. Kitano Systems Biology: A Brief Overview , 2002, Science.

[115]  Thomas Badet,et al.  Emerging Trends in Molecular Interactions between Plants and the Broad Host Range Fungal Pathogens Botrytis cinerea and Sclerotinia sclerotiorum , 2016, Front. Plant Sci..

[116]  A. Molina,et al.  Disease resistance or growth: the role of plant hormones in balancing immune responses and fitness costs , 2013, Front. Plant Sci..

[117]  Yoko Nishizawa,et al.  Plant cells recognize chitin fragments for defense signaling through a plasma membrane receptor. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[118]  I. Somssich,et al.  Physical interaction between RRS1-R, a protein conferring resistance to bacterial wilt, and PopP2, a type III effector targeted to the plant nucleus , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[119]  C. Broeckling,et al.  Evaluating plant immunity using mass spectrometry-based metabolomics workflows , 2014, Front. Plant Sci..

[120]  J. Cheverud,et al.  The genetic basis of quantitative variation in susceptibility of Arabidopsis thaliana to Pseudomonas syringae (Pst DC3000): evidence for a new genetic factor of large effect. , 2007, The New phytologist.

[121]  Hiroaki Kitano,et al.  The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models , 2003, Bioinform..

[122]  H. Puthalakath,et al.  Programmed Cell Death , 2016, Methods in Molecular Biology.

[123]  E. Danchin,et al.  Horizontal Gene Transfer from Bacteria Has Enabled the Plant-Parasitic Nematode Globodera pallida to Feed on Host-Derived Sucrose. , 2016, Molecular biology and evolution.

[124]  N. V. van Riel,et al.  A genome-scale metabolic network reconstruction of tomato (Solanum lycopersicum L.) and its application to photorespiratory metabolism. , 2016, The Plant journal : for cell and molecular biology.

[125]  H. Feng,et al.  Horizontal gene transfer drives adaptive colonization of apple trees by the fungal pathogen Valsa mali , 2016, Scientific Reports.

[126]  M. Gerstein,et al.  RNA-Seq: a revolutionary tool for transcriptomics , 2009, Nature Reviews Genetics.

[127]  Mark Meuwese Cooperation and Conflict , 2011 .

[128]  Andrea A. Gust Peptidoglycan Perception in Plants , 2015, PLoS pathogens.

[129]  J. Schiefelbein Molecular phenotyping of plant single cell-types enhances forward genetic analyses , 2015, Front. Plant Sci..

[130]  Cyril Zipfel,et al.  News from the frontline: recent insights into PAMP-triggered immunity in plants. , 2008, Current opinion in plant biology.

[131]  T. Gjetting,et al.  Differential gene expression in individual papilla-resistant and powdery mildew-infected barley epidermal cells. , 2004, Molecular plant-microbe interactions : MPMI.

[132]  Zachary A. King,et al.  Constraint-based models predict metabolic and associated cellular functions , 2014, Nature Reviews Genetics.

[133]  B. Palsson,et al.  A protocol for generating a high-quality genome-scale metabolic reconstruction , 2010 .

[134]  Y. Couder,et al.  Developmental Patterning by Mechanical Signals in Arabidopsis , 2009 .

[135]  Fumiaki Katagiri,et al.  Network Modeling Reveals Prevalent Negative Regulatory Relationships between Signaling Sectors in Arabidopsis Immune Signaling , 2010, PLoS pathogens.

[136]  Jacques Dumais,et al.  Quantifying Green Life: Grand Challenges in Plant Biophysics and Modeling , 2011, Front. Plant Sci..

[137]  R. Aebersold,et al.  The quantitative and condition-dependent Escherichia coli proteome , 2015, Nature Biotechnology.

[138]  M. Tabor,et al.  Mathematical modeling of hyphal tip growth , 2008 .

[139]  S. Grün,et al.  Dual Roles of Reactive Oxygen Species and NADPH Oxidase RBOHD in an Arabidopsis-Alternaria Pathosystem1[W] , 2009, Plant Physiology.

[140]  Peter D. Karp,et al.  The MetaCyc Database , 2002, Nucleic Acids Res..

[141]  D. Weigel,et al.  Cooperation and Conflict in the Plant Immune System , 2016, PLoS pathogens.

[142]  John P. Rathjen,et al.  Plant immunity: towards an integrated view of plant–pathogen interactions , 2010, Nature Reviews Genetics.

[143]  M. Lahaye,et al.  Another Brick in the Cell Wall: Biosynthesis Dependent Growth Model , 2013, PloS one.

[144]  Christopher A. Penfold,et al.  Transcriptional Dynamics Driving MAMP-Triggered Immunity and Pathogen Effector-Mediated Immunosuppression in Arabidopsis Leaves Following Infection with Pseudomonas syringae pv tomato DC3000[OPEN] , 2015, Plant Cell.

[145]  T. Sharkey,et al.  Rewiring of jasmonate and phytochrome B signalling uncouples plant growth-defense tradeoffs , 2016, Nature Communications.

[146]  D. Roby,et al.  An Atypical Kinase under Balancing Selection Confers Broad-Spectrum Disease Resistance in Arabidopsis , 2013, PLoS genetics.

[147]  H. Callen Thermodynamics and an Introduction to Thermostatistics , 1988 .

[148]  Staffan Persson,et al.  Toward a Systems Approach to Understanding Plant Cell Walls , 2004, Science.

[149]  J. Burdon,et al.  Evolution of Virulence in a Plant Host-Pathogen Metapopulation , 2003, Science.

[150]  W. Frommer,et al.  Sugar transporters for intercellular exchange and nutrition of pathogens , 2010, Nature.

[151]  Christophe Godin,et al.  Physical models of plant development. , 2014, Annual review of cell and developmental biology.

[152]  J. Dubcovsky,et al.  A Kinase-START Gene Confers Temperature-Dependent Resistance to Wheat Stripe Rust , 2009, Science.

[153]  D. Büttner Behind the lines–actions of bacterial type III effector proteins in plant cells , 2016, FEMS microbiology reviews.

[154]  O. Hamant,et al.  Cell division plane orientation based on tensile stress in Arabidopsis thaliana , 2016, Proceedings of the National Academy of Sciences.

[155]  U. Sauer,et al.  Getting Closer to the Whole Picture , 2007, Science.

[156]  Antje Chang,et al.  BRENDA in 2015: exciting developments in its 25th year of existence , 2014, Nucleic Acids Res..

[157]  N. Novère Quantitative and logic modelling of molecular and gene networks , 2015, Nature Reviews Genetics.

[158]  G. Camañes,et al.  An untargeted global metabolomic analysis reveals the biochemical changes underlying basal resistance and priming in Solanum lycopersicum, and identifies 1-methyltryptophan as a metabolite involved in plant responses to Botrytis cinerea and Pseudomonas syringae. , 2015, The Plant journal : for cell and molecular biology.

[159]  P. Epple,et al.  Programmed cell death in the plant immune system , 2011, Cell Death and Differentiation.

[160]  B. Keller,et al.  A Putative ABC Transporter Confers Durable Resistance to Multiple Fungal Pathogens in Wheat , 2009, Science.

[161]  Jonathan D. G. Jones,et al.  Expression Profiling during Arabidopsis/Downy Mildew Interaction Reveals a Highly-Expressed Effector That Attenuates Responses to Salicylic Acid , 2014, PLoS pathogens.

[162]  Christopher A. Penfold,et al.  How to infer gene networks from expression profiles, revisited , 2011, Interface Focus.

[163]  L. Pritchard,et al.  The zigzag model of plant-microbe interactions: is it time to move on? , 2014, Molecular plant pathology.

[164]  M. Kreitman,et al.  Fitness costs of R-gene-mediated resistance in Arabidopsis thaliana , 2003, Nature.

[165]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[166]  L. Quek,et al.  C4GEM, a Genome-Scale Metabolic Model to Study C4 Plant Metabolism1[W][OA] , 2010, Plant Physiology.

[167]  Jonathan D. G. Jones,et al.  The plant immune system , 2006, Nature.

[168]  B. Thomma,et al.  Understanding plant immunity as a surveillance system to detect invasion. , 2015, Annual review of phytopathology.