title: A systems biological approach reveals multiple crosstalk mechanism between gram-positive and negative bacterial infections: an insight into core mechanism and unique molecular signatures.
abstract: BACKGROUND
  Bacterial infections remain a major threat and a leading cause of death worldwide. Most of the bacterial infections are caused by gram-positive and negative bacteria, which are recognized by Toll-like receptor (TLR) 2 and 4, respectively. Activation of these TLRs initiates multiple pathways that subsequently lead to effective immune response. Although, both the TLRs share common signaling mechanism yet they may exhibit specificity as well, resulting in the release of diverse range of inflammatory mediators which could be used as candidate biomolecules for bacterial infections.
  
  
  RESULTS
  We adopted systems biological approach to identify signaling pathways mediated by TLRs to determine candidate molecules associated with bacterial infections. We used bioinformatics concepts, including literature mining to construct protein-protein interaction network, prioritization of TLRs specific nodes using microarray data and pathway analysis. Our constructed PPI network for TLR 2 (nodes: 4091 and edges: 66068) and TLR 4 (node: 4076 and edges: 67898) showed 3207 common nodes, indicating that both the TLRs might share similar signaling events that are attributed to cell migration, MAPK pathway and several inflammatory cascades. Our results propose the potential collaboration between the shared signaling pathways of both the receptors may enhance the immune response against invading pathogens. Further, to identify candidate molecules, the TLRs specific nodes were prioritized using microarray differential expressed genes. Of the top prioritized TLR 2 molecules, 70% were co-expressed. A similar trend was also observed within TLR 4 nodes. Further, most of these molecules were preferentially found in blood plasma for feasible diagnosis.
  
  
  CONCLUSIONS
  The analysis reveals the common and unique mechanism regulated by both the TLRs that provide a broad perspective of signaling events in bacterial infections. Further, the identified candidate biomolecules could potentially aid future research efforts concerning the possibility in differential diagnosis of gram-positive and negative bacterial infections.
authors.affiliation: Department of Biotechnology, School of Bioengineering, SRM University, Tamil Nadu, India.
authors.forename: R
authors.initials: R
authors.lastname: Muthukumar
authors.affiliation: Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Tamil Nadu, India.
authors.forename: V
authors.initials: V
authors.lastname: Alexandar
authors.affiliation: Department of Biotechnology, School of Bioengineering, SRM University, Tamil Nadu, India.
authors.forename: Berla
authors.initials: B
authors.lastname: Thangam
authors.affiliation: Department of Computational Biology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Tamil Nadu, India.
authors.forename: Shiek S S J
authors.initials: SS
authors.lastname: Ahmed
mesh_terms: D001798:Blood Proteins / Q000235:genetics* / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006090:Gram-Negative Bacteria / Q000254:growth & development / Q000276:immunology; D016905:Gram-Negative Bacterial Infections / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D006094:Gram-Positive Bacteria / Q000254:growth & development / Q000276:immunology; D016908:Gram-Positive Bacterial Infections / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D006801:Humans; D007113:Immunity, Innate; D058977:Molecular Sequence Annotation; D020411:Oligonucleotide Array Sequence Analysis; D025941:Protein Interaction Mapping; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D049490:Systems Biology; D051195:Toll-Like Receptor 2 / Q000235:genetics* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000276:immunology
chemical_list: D001798:Blood Proteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4