Systems biology of infectious diseases: a focus on fungal infections.

The study of infectious disease concerns the interaction between the host species and a pathogen organism. The analysis of such complex systems is improving with the evolution of high-throughput technologies and advanced computational resources. This article reviews integrative, systems-oriented approaches to understanding mechanisms underlying infection, immune response and inflammation to find biomarkers of disease and design new drugs. We focus on the systems biology process, especially the data gathering and analysis techniques rather than the experimental technologies or latest computational resources.

[1]  Terry Roemer,et al.  Essential Gene Identification and Drug Target Prioritization in Aspergillus fumigatus , 2007, PLoS pathogens.

[2]  B. Klein,et al.  Virulence Factors of Medically Important Fungi , 1996 .

[3]  J. Nosanchuk,et al.  Monoclonal Antibodies to Heat Shock Protein 60 Alter the Pathogenesis of Histoplasma capsulatum , 2009, Infection and Immunity.

[4]  P. Puccetti,et al.  Balancing inflammation and tolerance in vivo through dendritic cells by the commensal Candida albicans , 2009, Mucosal Immunology.

[5]  Doulaye Dembélé,et al.  Fuzzy C-means Method for Clustering Microarray Data , 2003, Bioinform..

[6]  Gabriela R. Moura,et al.  A Genetic Code Alteration Is a Phenotype Diversity Generator in the Human Pathogen Candida albicans , 2007, PloS one.

[7]  H. Parkinson,et al.  A global map of human gene expression , 2010, Nature Biotechnology.

[8]  Jennifer P. Wang,et al.  Cooperative Stimulation of Dendritic Cells by Cryptococcus neoformans Mannoproteins and CpG Oligodeoxynucleotides , 2008, PloS one.

[9]  K. P. Murphy,et al.  Janeway's immunobiology , 2007 .

[10]  M. Mattingsdal,et al.  Expression of genes in normal human monocytes in response to Aspergillus fumigatus. , 2008, Medical mycology.

[11]  H. Kitano,et al.  Computational systems biology , 2002, Nature.

[12]  L. Romani Immunity to fungal infections , 2011, Nature Reviews Immunology.

[13]  J. P. Woods Histoplasma capsulatum molecular genetics, pathogenesis, and responsiveness to its environment. , 2002, Fungal genetics and biology : FG & B.

[14]  S. Falkow What is a pathogen , 1997 .

[15]  Anton J. Enright,et al.  A logic-based diagram of signalling pathways central to macrophage activation , 2008, BMC Systems Biology.

[16]  Simona Toti,et al.  Eu.Gene Analyzer a tool for integrating gene expression data with pathway databases , 2007, Bioinform..

[17]  S. Busby,et al.  DNA sampling: a method for probing protein binding at specific loci on bacterial chromosomes , 2009, Nucleic acids research.

[18]  Ibrahim Emam,et al.  Gene Expression Atlas at the European Bioinformatics Institute , 2009, Nucleic Acids Res..

[19]  Attila Csikász-Nagy,et al.  Computational systems biology of the cell cycle , 2009, Briefings Bioinform..

[20]  P. T. Magee,et al.  Recent developments in molecular genetics of Candida albicans. , 2000, Annual review of microbiology.

[21]  G. Giaever,et al.  Quantitative Phenotyping via Deep Barcode Sequencing , 2022 .

[22]  Peter D. Karp,et al.  EcoCyc: a comprehensive database resource for Escherichia coli , 2004, Nucleic Acids Res..

[23]  M. Netea,et al.  The incidence of acute graft-versus-host disease increases with Candida colonization depending the dectin-1 gene status. , 2010, Clinical immunology.

[24]  Wei Keat Lim,et al.  The transcriptional network for mesenchymal transformation of brain tumors , 2009, Nature.

[25]  C. Nombela,et al.  Decoding Serological Response to Candida Cell Wall Immunome into Novel Diagnostic, Prognostic, and Therapeutic Candidates for Systemic Candidiasis by Proteomic and Bioinformatic Analyses* , 2006, Molecular & Cellular Proteomics.

[26]  C. Sander,et al.  The HUPO PSI's Molecular Interaction format—a community standard for the representation of protein interaction data , 2004, Nature Biotechnology.

[27]  S. Oyonarte,et al.  TNFR1 mRNA Expression Level and TNFR1 Gene Polymorphisms are Predictive Markers for Susceptibility to Develop Invasive Pulmonary Aspergillosis , 2010, International journal of immunopathology and pharmacology.

[28]  Jacques Fellay,et al.  Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance , 2009, Nature.

[29]  David J. Reiss,et al.  Integrated biclustering of heterogeneous genome-wide datasets for the inference of global regulatory networks , 2006, BMC Bioinformatics.

[30]  A. Casadevall,et al.  What is a pathogen? , 2002, Annals of medicine.

[31]  T. Wienker,et al.  Polymorphisms in the chemokine (C-X-C motif) ligand 10 are associated with invasive aspergillosis after allogeneic stem-cell transplantation and influence CXCL10 expression in monocyte-derived dendritic cells. , 2008, Blood.

[32]  D. Campa,et al.  Candida albicans isolates with different genomic backgrounds display a differential response to macrophage infection. , 2006, Microbes and infection.

[33]  K. Kuchler,et al.  Fungal attacks on mammalian hosts: pathogen elimination requires sensing and tasting. , 2010, Current opinion in microbiology.

[34]  Manuel A. S. Santos,et al.  A genetic code alteration generates a proteome of high diversity in the human pathogen Candida albicans , 2007, Genome Biology.

[35]  H. Kitano A robustness-based approach to systems-oriented drug design , 2007, Nature Reviews Drug Discovery.

[36]  Kumar Rajakumar,et al.  A consensus on fungal polymerase chain reaction diagnosis?: a United Kingdom-Ireland evaluation of polymerase chain reaction methods for detection of systemic fungal infections. , 2006, The Journal of molecular diagnostics : JMD.

[37]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[38]  D. Sanglard,et al.  Antifungal drug resistance mechanisms in fungal pathogens from the perspective of transcriptional gene regulation. , 2009, FEMS yeast research.

[39]  Zhaolei Zhang,et al.  An atlas of chaperone–protein interactions in Saccharomyces cerevisiae: implications to protein folding pathways in the cell , 2009, Molecular systems biology.

[40]  D. Sanglard,et al.  Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. , 2002, The Lancet. Infectious diseases.

[41]  Hiroaki Kitano,et al.  Perspectives on systems biology , 2000, New Generation Computing.

[42]  S. Gaffen,et al.  Host responses to Candida albicans: Th17 cells and mucosal candidiasis. , 2010, Microbes and infection.

[43]  A. Espinel-Ingroff Mechanisms of resistance to antifungal agents: yeasts and filamentous fungi. , 2008, Revista iberoamericana de micologia.

[44]  L. Pirofski,et al.  The Absence of Serum IgM Enhances the Susceptibility of Mice to Pulmonary Challenge with Cryptococcus neoformans , 2010, The Journal of Immunology.

[45]  G. Getz,et al.  Outcome signature genes in breast cancer: is there a unique set? , 2005, Breast Cancer Research.

[46]  Maureen A. O’Malley,et al.  Fundamental issues in systems biology. , 2005, BioEssays : news and reviews in molecular, cellular and developmental biology.

[47]  J. Ruland,et al.  Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17 , 2007, Nature Immunology.

[48]  Jeremy Seto,et al.  Antiviral Response Dictated by Choreographed Cascade of Transcription Factors , 2010, The Journal of Immunology.

[49]  P. van Dijck,et al.  Fungal pathogens research: novel and improved molecular approaches for the discovery of antifungal drug targets. , 2005, Current drug targets.

[50]  T. Ideker,et al.  A new approach to decoding life: systems biology. , 2001, Annual review of genomics and human genetics.

[51]  J. C. Hinshaw,et al.  Discovering Modes of Action for Therapeutic Compounds Using a Genome-Wide Screen of Yeast Heterozygotes , 2004, Cell.

[52]  Donald Geman,et al.  Merging microarray data from separate breast cancer studies provides a robust prognostic test , 2008, BMC Bioinformatics.

[53]  J. Cutler,et al.  Putative virulence factors of Candida albicans. , 1991, Annual review of microbiology.

[54]  M. Netea,et al.  Early stop polymorphism in human DECTIN-1 is associated with increased candida colonization in hematopoietic stem cell transplant recipients. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[55]  Patrick Lambrix,et al.  Representations of molecular pathways: an evaluation of SBML, PSI MI and BioPAX , 2005, Bioinform..

[56]  Charles Auffray,et al.  From functional genomics to systems biology: concepts and practices. , 2003, Comptes rendus biologies.

[57]  H. Einsele,et al.  Genetic susceptibility to infections with Aspergillus fumigatus , 2010, Critical reviews in microbiology.

[58]  P. Pappas Opportunistic Fungi: A View to the Future , 2010, The American journal of the medical sciences.

[59]  M. McGrath,et al.  Balanced Macrophage Activation Hypothesis: A Biological Model for Development of Drugs Targeted at Macrophage Functional States , 2000, Pathobiology.

[60]  W. Paul,et al.  Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome , 2008, Nature.

[61]  A. B. Hill The Environment and Disease: Association or Causation? , 1965, Proceedings of the Royal Society of Medicine.

[62]  David R Soll,et al.  Candida commensalism and virulence: the evolution of phenotypic plasticity. , 2002, Acta tropica.

[63]  Limin Fu,et al.  FLAME, a novel fuzzy clustering method for the analysis of DNA microarray data , 2007, BMC Bioinformatics.

[64]  A. Casadevall,et al.  Ab binding alters gene expression in Cryptococcus neoformans and directly modulates fungal metabolism. , 2010, The Journal of clinical investigation.

[65]  Ana Espinel-Ingroff,et al.  Antifungal drug resistance mechanisms , 2009, Expert review of anti-infective therapy.

[66]  S. Levitz Innate Recognition of Fungal Cell Walls , 2010, PLoS pathogens.

[67]  J. Renauld,et al.  IL-22 defines a novel immune pathway of antifungal resistance , 2010, Mucosal Immunology.

[68]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[69]  J. Mcdermott,et al.  Separating the Drivers from the Driven: Integrative Network and Pathway Approaches Aid Identification of Disease Biomarkers from High-Throughput Data , 2010, Disease markers.

[70]  R. Miller,et al.  A Small Subpopulation of Blastospores in Candida albicans Biofilms Exhibit Resistance to Amphotericin B Associated with Differential Regulation of Ergosterol and β-1,6-Glucan Pathway Genes , 2006, Antimicrobial Agents and Chemotherapy.

[71]  P. Le Pape,et al.  Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature. , 2010, Diagnostic microbiology and infectious disease.

[72]  A. Schäffer,et al.  A homozygous CARD9 mutation in a family with susceptibility to fungal infections. , 2009, The New England journal of medicine.

[73]  Xinxia Peng,et al.  Virus-host interactions: from systems biology to translational research. , 2009, Current opinion in microbiology.

[74]  Shi-Hong Jiang TH17 cells in health and disease , 2011 .

[75]  A. Casadevall,et al.  Host-pathogen interactions: the attributes of virulence. , 2001, The Journal of infectious diseases.

[76]  Pedro Beltrão,et al.  Comparative evolutionary genomics unveils the molecular mechanism of reassignment of the CTG codon in Candida spp. , 2003, Genome research.

[77]  Arturo Casadevall,et al.  Host-Pathogen Interactions: Redefining the Basic Concepts of Virulence and Pathogenicity , 1999, Infection and Immunity.

[78]  Gordon K Smyth,et al.  Statistical Applications in Genetics and Molecular Biology Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2011 .

[79]  M. Kretzler,et al.  Perspectives on Systems Biology Applications in Diabetic Kidney Disease , 2012, Journal of Cardiovascular Translational Research.

[80]  B. Vickery,et al.  An Interferon-Inducible Neutrophil-Driven Blood Transcriptional Signature in Human Tuberculosis , 2011, Pediatrics.

[81]  E. Lander,et al.  Human macrophage activation programs induced by bacterial pathogens , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[82]  R. Flavell,et al.  IL‐22 and inflammation: Leukin' through a glass onion , 2008, European journal of immunology.

[83]  R. Calderone,et al.  Virulence factors of Candida albicans. , 2001, Trends in microbiology.

[84]  C. Forst Host-pathogen systems biology. , 2006, Drug discovery today.

[85]  A. Mitchell Dimorphism and virulence in Candida albicans. , 1998, Current opinion in microbiology.

[86]  A Common Polymorphism in the Caspase Recruitment Domain of RIG-I Modifies the Innate Immune Response of Human Dendritic Cells , 2010, The Journal of Immunology.

[87]  N. Hacohen,et al.  Evolutionarily conserved recognition and innate immunity to fungal pathogens by the scavenger receptors SCARF1 and CD36 , 2009, The Journal of experimental medicine.

[88]  S. Holland,et al.  Invasive fungal disease in autosomal-dominant hyper-IgE syndrome. , 2010, The Journal of allergy and clinical immunology.

[89]  J. Uhm,et al.  The transcriptional network for mesenchymal transformation of brain tumours , 2010 .

[90]  Sarah M. Keating,et al.  Evolving a lingua franca and associated software infrastructure for computational systems biology: the Systems Biology Markup Language (SBML) project. , 2004, Systems biology.

[91]  D. Denning,et al.  Laboratory diagnosis of invasive aspergillosis. , 2005, The Lancet. Infectious diseases.

[92]  Inyoul Lee,et al.  Systems Biology and the Discovery of Diagnostic Biomarkers , 2010, Disease markers.

[93]  J. Latgé Tasting the fungal cell wall , 2010, Cellular microbiology.

[94]  M. Huynen,et al.  Dominant processes during human dendritic cell maturation revealed by integration of proteome and transcriptome at the pathway level. , 2010, Journal of proteome research.

[95]  Leroy Hood,et al.  Systems biology, proteomics, and the future of health care: toward predictive, preventative, and personalized medicine. , 2004, Journal of proteome research.

[96]  C. Rui Genetic variation in IL-28B and spontaneous clearance of hepatitis C virus , 2012 .

[97]  D. Lynn,et al.  Enabling a systems biology approach to immunology: focus on innate immunity. , 2009, Trends in immunology.

[98]  J. Ecker,et al.  Applications of DNA tiling arrays for whole-genome analysis. , 2005, Genomics.

[99]  Jerzy Krysiński,et al.  Artificial neural networks in prediction of antifungal activity of a series of pyridine derivatives against Candida albicans. , 2009, Journal of microbiological methods.

[100]  Daniel E. Zak,et al.  Systems biology of innate immunity , 2009, Immunological reviews.

[101]  David B. Goldstein,et al.  Genetic variation in IL28B and spontaneous clearance of hepatitis C virus , 2009, Nature.

[102]  Richard A. Young,et al.  Insights into host responses against pathogens from transcriptional profiling , 2005, Nature Reviews Microbiology.

[103]  David F. V. Lewis,et al.  Structure–activity relationship for human cytochrome P450 substrates and inhibitors , 2002, Drug metabolism reviews.

[104]  A. Aderem Systems Biology: Its Practice and Challenges , 2005, Cell.

[105]  S. Kaufmann,et al.  Immunity to fungi: editorial overview. , 1998, Research in immunology.

[106]  H. Mewes,et al.  The FunCat, a functional annotation scheme for systematic classification of proteins from whole genomes. , 2004, Nucleic acids research.

[107]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[108]  A. Aderem,et al.  A systems approach to dissecting immunity and inflammation. , 2004, Seminars in immunology.

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

[110]  Steven C. Lawlor,et al.  MAPPFinder: using Gene Ontology and GenMAPP to create a global gene-expression profile from microarray data , 2003, Genome Biology.

[111]  Eric J Kunkel,et al.  Systems biology in drug discovery. , 2006, Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference.

[112]  H. Bussey,et al.  Large‐scale essential gene identification in Candida albicans and applications to antifungal drug discovery , 2003, Molecular microbiology.

[113]  Kathleen A. Kennedy,et al.  Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4 , 2006, Nature.

[114]  J. Corden,et al.  Combined effects of aerobiological pollutants, chemical pollutants and meteorological conditions on asthma admissions and A & E attendances in Derbyshire UK, 1993–96. , 2000, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[115]  Irma Joosten,et al.  The macrophage mannose receptor induces IL-17 in response to Candida albicans. , 2009, Cell host & microbe.

[116]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[117]  Trees Jansen,et al.  Human dectin-1 deficiency and mucocutaneous fungal infections. , 2009, The New England journal of medicine.

[118]  Rafael A Irizarry,et al.  Gene set enrichment analysis made simple , 2009, Statistical methods in medical research.

[119]  Alistair J. P. Brown,et al.  Fungal virulence studies come of age , 2001, Genome Biology.

[120]  P. Puccetti,et al.  Fungi, dendritic cells and receptors: a host perspective of fungal virulence. , 2002, Trends in microbiology.

[121]  Elizabeth A. Winzeler,et al.  Genomic profiling of drug sensitivities via induced haploinsufficiency , 1999, Nature Genetics.

[122]  P. Khatri,et al.  Profiling gene expression using onto-express. , 2002, Genomics.

[123]  A. Luca,et al.  TH17 Cells in Fungal Infections , 2011 .

[124]  Eva K. Lee,et al.  Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans , 2009, Nature Immunology.

[125]  Lincoln Stein,et al.  Reactome knowledgebase of human biological pathways and processes , 2008, Nucleic Acids Res..

[126]  A. De Luca,et al.  IL-17 and Therapeutic Kynurenines in Pathogenic Inflammation to Fungi1 , 2008, The Journal of Immunology.

[127]  Jelle J. Goeman,et al.  A global test for groups of genes: testing association with a clinical outcome , 2004, Bioinform..

[128]  D. Underhill,et al.  β‐glucan recognition by the innate immune system , 2009, Immunological reviews.

[129]  R. Drew,et al.  Antifungal Drug Resistance: Clinical Relevance and Impact of Antifungal Drug Use , 2010 .

[130]  N. Rothman,et al.  Systems biology of human benzene exposure. , 2010, Chemico-biological interactions.

[131]  Roberto Therón,et al.  A visual analytics approach for understanding biclustering results from microarray data , 2008, BMC Bioinformatics.

[132]  Gerald R. Fink,et al.  Transcriptional Response of Candida albicans upon Internalization by Macrophages , 2004, Eukaryotic Cell.

[133]  M. Netea,et al.  An integrated model of the recognition of Candida albicans by the innate immune system , 2008, Nature Reviews Microbiology.

[134]  M. Netea,et al.  Differential IL-17 Production and Mannan Recognition Contribute to Fungal Pathogenicity and Commensalism , 2010, The Journal of Immunology.

[135]  Julio R. Banga,et al.  Reverse Engineering Cellular Networks with Information , 2013 .

[136]  Inyoul Y. Lee,et al.  A systems approach to prion disease , 2009, Molecular systems biology.

[137]  S. Holgate,et al.  The Roles of Cells and Mediators in a Computer Model of Chronic Asthma , 2001, International Archives of Allergy and Immunology.

[138]  Olaf Wolkenhauer,et al.  Systems Biology: the Reincarnation of Systems Theory Applied in Biology? , 2001, Briefings Bioinform..

[139]  D. Allison,et al.  Microarray data analysis: from disarray to consolidation and consensus , 2006, Nature Reviews Genetics.

[140]  D. Cavalieri,et al.  A systems biology approach to the mutual interaction between yeast and the immune system. , 2010, Immunobiology.

[141]  Duccio Cavalieri,et al.  Using Pathway Signatures as Means of Identifying Similarities among Microarray Experiments , 2009, PloS one.

[142]  Susumu Goto,et al.  Systems biology approaches and pathway tools for investigating cardiovascular disease. , 2009, Molecular bioSystems.

[143]  J. Guarro,et al.  High genetic diversity and poor in vitro response to antifungals of clinical strains of Fusarium oxysporum. , 2009, The Journal of antimicrobial chemotherapy.

[144]  P. Puccetti,et al.  Protective tolerance to fungi: the role of IL-10 and tryptophan catabolism. , 2006, Trends in microbiology.

[145]  Terry Roemer,et al.  Genome-Wide Fitness Test and Mechanism-of-Action Studies of Inhibitory Compounds in Candida albicans , 2007, PLoS pathogens.

[146]  N. Chandra,et al.  A systems perspective of host-pathogen interactions: predicting disease outcome in tuberculosis. , 2010, Molecular bioSystems.

[147]  C. Nombela,et al.  Integrated Proteomics and Genomics Strategies Bring New Insight into Candida albicans Response upon Macrophage Interaction*S , 2007, Molecular & Cellular Proteomics.

[148]  P. Khatri,et al.  A systems biology approach for pathway level analysis. , 2007, Genome research.

[149]  Roland Eils,et al.  Group testing for pathway analysis improves comparability of different microarray datasets , 2006, Bioinform..

[150]  A. Luca,et al.  Intranasally delivered siRNA targeting PI3K/Akt/mTOR inflammatory pathways protects from aspergillosis , 2010, Mucosal Immunology.

[151]  A. Kansal Modeling approaches to type 2 diabetes. , 2004, Diabetes technology & therapeutics.

[152]  L. Ein-Dor,et al.  Thousands of samples are needed to generate a robust gene list for predicting outcome in cancer. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[153]  Arlindo L. Oliveira,et al.  Biclustering algorithms for biological data analysis: a survey , 2004, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[154]  A. Aderem,et al.  A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[155]  Joshua M. Korn,et al.  The plasticity of dendritic cell responses to pathogens and their components. , 2001, Science.

[156]  D. Pompliano,et al.  Drugs for bad bugs: confronting the challenges of antibacterial discovery , 2007, Nature Reviews Drug Discovery.

[157]  John R Perfect,et al.  Resistance to Antifungal Agents: Mechanisms and Clinical Impact , 2008 .

[158]  H. Einsele,et al.  Role of glycogen synthase kinase 3 (GSK-3) in innate immune response of human immature dendritic cells to Aspergillus fumigatus. , 2010, Medical mycology.

[159]  Duccio Cavalieri,et al.  Pathway Processor: a tool for integrating whole-genome expression results into metabolic networks. , 2002, Genome research.

[160]  Yang Li,et al.  PAP inhibitor with in vivo efficacy identified by Candida albicans genetic profiling of natural products. , 2008, Chemistry & biology.

[161]  Alexander E. Kel,et al.  TRANSFAC®: transcriptional regulation, from patterns to profiles , 2003, Nucleic Acids Res..

[162]  J. Ring,et al.  Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22. , 2008, The Journal of investigative dermatology.

[163]  Yoshihiro Yamanishi,et al.  KEGG for linking genomes to life and the environment , 2007, Nucleic Acids Res..