Gene interaction network to unravel the role of gut bacterial species in cardiovascular diseases: E. coli O157: H7 host-bacterial interaction study

BACKGROUND Cardiovascular Disease (CVD) is one of the most common causes of mortality in humans. Presently, the role of pathogens in the initiation and progression of the CVDs is not clearly understood. Hence, it is essential to understand the molecular-level interactions between the human proteins and the microbial proteins to deduce their functional roles in the CVDs. METHOD The host-pathogen interactions (HPI) related to CVDs in the case of E. coli str. O157:H7 colonization were curated, and also the protein-protein interactions (PPI) between humans and E. coli were collected. Gene interaction network (GIN) and functional enrichment analyses (FEA) were utilized for this. RESULTS The GIN revealed dense interactions between the functional partners. The FEA indicated that the essential pathways played a significant role in humans as well as in E. coli. The primary responses against most of the bacterial pathogens in humans are different from that of E. coli; Terpenoid biosynthesis and production of secondary metabolite pathways aid the survival of the E. coli inside the host. Interestingly, network analysis divulged that the E. coli genes ksgA, rpsT, ispE, rpsI, ispH, and the human genes TP53, CASP3, CYCS, EP300, RHOA communicated by significant numbers in direct interactions. CONCLUSIONS The results obtained from the present study will help researchers understand the molecular-level interactions in the CVDs between the human and the E. coli genes. The important genes with vital interactions can be considered as hub molecules and can be exploited for new drug discovery.

[1]  S. López-Briones,et al.  The Role of Escherichia coli in the Development and Progression of Cancer , 2017 .

[2]  M. Desvaux,et al.  Intestinal Pathogenic Escherichia coli: Insights for Vaccine Development , 2018, Front. Microbiol..

[3]  Soumya K. Srivastava,et al.  Dimethyl adenosine transferase (KsgA) contributes to cell-envelope fitness in Salmonella Enteritidis. , 2018, Microbiological research.

[4]  B. Finlay,et al.  Enteropathogenic E. coli (EPEC) Transfers Its Receptor for Intimate Adherence into Mammalian Cells , 1997, Cell.

[5]  Tetsuya Hayashi,et al.  NleC, a Type III Secretion Protease, Compromises NF-κB Activation by Targeting p65/RelA , 2010, PLoS pathogens.

[6]  W. Eisenreich,et al.  Studies on the nonmevalonate terpene biosynthetic pathway: Metabolic role of IspH (LytB) protein , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Judith A. Blake,et al.  Gene Ontology annotations: what they mean and where they come from , 2008, BMC Bioinformatics.

[8]  T. Salman,et al.  Role of chronic E. coli infection in the process of bladder cancer- an experimental study , 2012, Infectious Agents and Cancer.

[9]  S. Hazen,et al.  Gut Microbiota in Cardiovascular Health and Disease , 2017, Circulation research.

[10]  Gary D Bader,et al.  A travel guide to Cytoscape plugins , 2012, Nature Methods.

[11]  Md. Muzahidul Islam,et al.  Advances and Applications in Bioinformatics and Chemistry Dovepress Identification of Potential Drug Targets by Subtractive Genome Analysis of Escherichia Coli O157:h7: an in Silico Approach , 2022 .

[12]  Gary D. Bader,et al.  An automated method for finding molecular complexes in large protein interaction networks , 2003, BMC Bioinformatics.

[13]  J. J. Valdez-Alarcón,et al.  Wnt/β-Catenin Signaling as a Molecular Target by Pathogenic Bacteria , 2019, Front. Immunol..

[14]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[15]  Sudha Ramaiah,et al.  Exploring the multi-drug resistance in Escherichia coli O157:H7 by gene interaction network: A systems biology approach. , 2019, Genomics.

[16]  I. Velasco,et al.  CD16 promotes Escherichia coli sepsis through an FcRγ inhibitory pathway that prevents phagocytosis and facilitates inflammation , 2007, Nature Medicine.

[17]  T. Wassenaar.  E. coli and colorectal cancer: a complex relationship that deserves a critical mindset , 2018, Critical reviews in microbiology.

[18]  Anand Anbarasu,et al.  Elucidating the multi-drug resistance mechanism of Enterococcus faecalis V583: A gene interaction network analysis. , 2020, Gene.

[19]  Y. Ilan,et al.  The heart-gut axis: new target for atherosclerosis and congestive heart failure therapy , 2019, Open Heart.

[20]  W. Eisenreich,et al.  Biosynthesis of terpenoids: YchB protein of Escherichia coli phosphorylates the 2-hydroxy group of 4-diphosphocytidyl-2C-methyl-D-erythritol. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Damian Szklarczyk,et al.  The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored , 2010, Nucleic Acids Res..

[22]  A. Belot,et al.  The pyrin inflammasome: from sensing RhoA GTPases-inhibiting toxins to triggering autoinflammatory syndromes , 2018, Pathogens and disease.

[23]  H. Seifert,et al.  ksgA mutations confer resistance to kasugamycin in Neisseria gonorrhoeae. , 2009, International journal of antimicrobial agents.

[24]  M. Saleh,et al.  Cell death in the host response to infection , 2008, Cell Death and Differentiation.

[25]  Protein binding sites on Escherichia coli 16S RNA; RNA regions that are protected by proteins S7, S14 and S19 in the presence or absence of protein S9. , 1987, Nucleic acids research.

[26]  J. Tavernier,et al.  The Small GTPase Arf6: An Overview of Its Mechanisms of Action and of Its Role in Host–Pathogen Interactions and Innate Immunity , 2019, International journal of molecular sciences.

[27]  A. Levine,et al.  The p53 pathway: positive and negative feedback loops , 2005, Oncogene.

[28]  Anthony W. Purcell,et al.  Linear ubiquitination prevents inflammation and regulates immune signalling , 2011, Nature.

[29]  J. Manfredi,et al.  The p53 tumor suppressor participates in multiple cell cycle checkpoints , 2006, Journal of cellular physiology.

[30]  K. Hirata,et al.  Gut Microbiome and Cardiovascular Diseases , 2018, Diseases.

[31]  V. Malik.  Microbial secondary metabolism , 1980 .

[32]  B. McCormick,et al.  Bacterial secreted effectors and caspase-3 interactions , 2014, Cellular microbiology.

[33]  R. Brenk,et al.  IspE Inhibitors Identified by a Combination of In Silico and In Vitro High-Throughput Screening , 2012, PloS one.

[34]  Houkai Li,et al.  The Role of Gut Microbiota in Atherosclerosis and Hypertension , 2018, Front. Pharmacol..

[35]  Damian Szklarczyk,et al.  The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible , 2016, Nucleic Acids Res..

[36]  H. O'Farrell,et al.  Staphylococcus aureus and Escherichia coli have disparate dependences on KsgA for growth and ribosome biogenesis , 2012, BMC Microbiology.

[37]  P. Sansonetti,et al.  Calcium signalling during cell interactions with bacterial pathogens , 2004, Biology of the cell.

[38]  M. Ehrenberg,et al.  Ribosomes lacking protein S20 are defective in mRNA binding and subunit association. , 2010, Journal of molecular biology.

[39]  Anand Anbarasu,et al.  Gene interaction network approach to elucidate the multidrug resistance mechanisms in the pathogenic bacterial strain Proteus mirabilis , 2020, Journal of cellular physiology.

[40]  Trey Ideker,et al.  Cytoscape 2.8: new features for data integration and network visualization , 2010, Bioinform..

[41]  N. V. van Sorge,et al.  Bacterial Immune Evasion through Manipulation of Host Inhibitory Immune Signaling , 2015, PLoS pathogens.

[42]  M. Inouye,et al.  Dissection of 16S rRNA Methyltransferase (KsgA) Function in Escherichia coli , 2007, Journal of bacteriology.

[43]  Anand Anbarasu,et al.  Role of SHV-11, a Class A β-Lactamase, Gene in Multidrug Resistance Among Klebsiella pneumoniae Strains and Understanding its Mechanism by Gene Network Analysis. , 2020, Microbial drug resistance.

[44]  Damian Szklarczyk,et al.  STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets , 2018, Nucleic Acids Res..

[45]  C. Sasakawa,et al.  EspG, a Novel Type III System-Secreted Protein from Enteropathogenic Escherichia coli with Similarities to VirA of Shigella flexneri , 2001, Infection and Immunity.

[46]  A. Blumenthal,et al.  Functions of the WNT Signaling Network in Shaping Host Responses to Infection , 2019, Front. Immunol..

[47]  O. Franco,et al.  Exploring the Pharmacological Potential of Promiscuous Host-Defense Peptides: From Natural Screenings to Biotechnological Applications , 2011, Front. Microbio..

[48]  E. Martínez-Salas,et al.  Emerging Roles of Gemin5: From snRNPs Assembly to Translation Control , 2020, International journal of molecular sciences.

[49]  Sonika Bhatnagar,et al.  MorCVD: A Unified Database for Host-Pathogen Protein-Protein Interactions of Cardiovascular Diseases Related to Microbes , 2019, Scientific Reports.

[50]  W. W. Lathem,et al.  The StcE Protease Contributes to Intimate Adherence of Enterohemorrhagic Escherichia coli O157:H7 to Host Cells , 2005, Infection and Immunity.

[51]  C. Sasakawa,et al.  A Bacterial Effector Targets Mad2L2, an APC Inhibitor, to Modulate Host Cell Cycling , 2007, Cell.

[52]  C. Hill,et al.  Isoprenoid biosynthesis in bacterial pathogens. , 2012, Microbiology.

[53]  Xiaoping Zhou,et al.  The role of intestinal microbiota in cardiovascular disease , 2019, Journal of cellular and molecular medicine.

[54]  F. Shao,et al.  Structurally Distinct Bacterial TBC-like GAPs Link Arf GTPase to Rab1 Inactivation to Counteract Host Defenses , 2012, Cell.

[55]  Xun Xu,et al.  The gut microbiome in atherosclerotic cardiovascular disease , 2017, Nature Communications.

[56]  Sudha Ramaiah,et al.  Discerning molecular interactions: A comprehensive review on biomolecular interaction databases and network analysis tools. , 2018, Gene.

[57]  Sudha Ramaiah,et al.  Impact of bedaquiline and capreomycin on the gene expression patterns of multidrug‐resistant Mycobacterium tuberculosis H37Rv strain and understanding the molecular mechanism of antibiotic resistance , 2019, Journal of cellular biochemistry.

[58]  M. Russo,et al.  Cytochrome c Release upon Fas Receptor Activation Depends on Translocation of Full-length Bid and the Induction of the Mitochondrial Permeability Transition* , 2002, The Journal of Biological Chemistry.

[59]  G. Chiesa,et al.  The Gut Microbiota Affects Host Pathophysiology as an Endocrine Organ: A Focus on Cardiovascular Disease , 2019, Nutrients.

[60]  Anand Anbarasu,et al.  Systems biology studies in Pseudomonas aeruginosa PA01 to understand their role in biofilm formation and multidrug efflux pumps. , 2019, Microbial pathogenesis.

[61]  Mitchell A. Pallett,et al.  The Type III Secretion Effector NleF of Enteropathogenic Escherichia coli Activates NF-κB Early during Infection , 2014, Infection and Immunity.

[62]  Peter Uetz,et al.  The EHEC-host interactome reveals novel targets for the translocated intimin receptor , 2014, Scientific Reports.

[63]  Anand Anbarasu,et al.  Gene interaction network studies to decipher the multi-drug resistance mechanism in Salmonella enterica serovar typhi CT18 reveal potential drug targets. , 2020, Microbial pathogenesis.

[64]  D. Aunis,et al.  The C-terminal bisphosphorylated proenkephalin-A-(209-237)-peptide from adrenal medullary chromaffin granules possesses antibacterial activity. , 1996, European journal of biochemistry.

[65]  M. Gutierrez,et al.  Rab GTPases in Immunity and Inflammation , 2017, Front. Cell. Infect. Microbiol..

[66]  Laura M. Machesky,et al.  Role of Actin Polymerization and Adhesion to Extracellular Matrix in Rac- and Rho-induced Cytoskeletal Reorganization , 1997, The Journal of cell biology.

[67]  Z. Chen,et al.  Modulation of host signaling in the inflammatory response by enteropathogenic Escherichia coli virulence proteins , 2016, Cellular & Molecular Immunology.

[68]  Fidel Ramírez,et al.  Computing topological parameters of biological networks , 2008, Bioinform..

[69]  Feng Zhu,et al.  Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics , 2019, Nucleic Acids Res..

[70]  J. Lim,et al.  A brief overview of Escherichia coli O157:H7 and its plasmid O157. , 2010, Journal of microbiology and biotechnology.

[71]  H. Hakonarson,et al.  Whole-genome DNA/RNA sequencing identifies truncating mutations in RBCK1 in a novel Mendelian disease with neuromuscular and cardiac involvement , 2013, Genome Medicine.

[72]  Minsoo Kim,et al.  Cell death and infection: A double-edged sword for host and pathogen survival , 2011, The Journal of cell biology.

[73]  J. Nathans,et al.  Dlg1 activates beta-catenin signaling to regulate retinal angiogenesis and the blood-retina and blood-brain barriers , 2019, eLife.

[74]  H. Vankayalapati,et al.  Identification of novel small molecule inhibitors of 4-diphosphocytidyl-2-C-methyl-D-erythritol (CDP-ME) kinase of Gram-negative bacteria. , 2011, Bioorganic & medicinal chemistry.

[75]  Alan Hall,et al.  Rho GTPases Control Polarity, Protrusion, and Adhesion during Cell Movement , 1999, The Journal of cell biology.

[76]  M. Minczuk,et al.  TRNT1 deficiency: clinical, biochemical and molecular genetic features , 2016, Orphanet Journal of Rare Diseases.