title: Bioinformatics multivariate analysis determined a set of phase-specific biomarker candidates in a novel mouse model for viral myocarditis.
abstract: BACKGROUND
  Myocarditis is an inflammatory disease of the cardiac muscle and is mainly caused by viral infections. Viral myocarditis has been proposed to be divided into 3 phases: the acute viral phase, the subacute immune phase, and the chronic cardiac remodeling phase. Although individualized therapy should be applied depending on the phase, no clinical or experimental studies have found biomarkers that distinguish between the 3 phases. Theiler's murine encephalomyelitis virus belongs to the genus Cardiovirus and can cause myocarditis in susceptible mouse strains.
  
  
  RESULTS
  Using this novel model for viral myocarditis induced with Theiler's murine encephalomyelitis virus, we conducted multivariate analysis including echocardiography, serum troponin and viral RNA titration, and microarray to identify the biomarker candidates that can discriminate the 3 phases. Using C3H mice infected with Theiler's murine encephalomyelitis virus on 4, 7, and 60 days post infection, we conducted bioinformatics analyses, including principal component analysis and k-means clustering of microarray data, because our traditional cardiac and serum assays, including 2-way comparison of microarray data, did not lead to the identification of a single biomarker. Principal component analysis separated heart samples clearly between the groups of 4, 7, and 60 days post infection. Representative genes contributing to the separation were as follows: 4 and 7 days post infection, innate immunity-related genes, such as Irf7 and Cxcl9; 7 and 60 days post infection, acquired immunity-related genes, such as Cd3g and H2-Aa; and cardiac remodeling-related genes, such as Mmp12 and Gpnmb.
  
  
  CONCLUSIONS
  Sets of molecules, not single molecules, identified by unsupervised principal component analysis, were found to be useful as phase-specific biomarkers.
authors.affiliation: From the Departments of Microbiology and Immunology (S.O., E.K., F.S., N.E.M., I.T.) and Molecular and Cellular Physiology (G.V.C., J.S.A.), Louisiana State University Health Sciences Center, Shreveport; and Department of Computer Science, Louisiana State University Shreveport (P.A.R., U.C., M.T.).
authors.forename: Seiichi
authors.initials: S
authors.lastname: Omura
authors.affiliation: From the Departments of Microbiology and Immunology (S.O., E.K., F.S., N.E.M., I.T.) and Molecular and Cellular Physiology (G.V.C., J.S.A.), Louisiana State University Health Sciences Center, Shreveport; and Department of Computer Science, Louisiana State University Shreveport (P.A.R., U.C., M.T.).
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Kawai
authors.affiliation: From the Departments of Microbiology and Immunology (S.O., E.K., F.S., N.E.M., I.T.) and Molecular and Cellular Physiology (G.V.C., J.S.A.), Louisiana State University Health Sciences Center, Shreveport; and Department of Computer Science, Louisiana State University Shreveport (P.A.R., U.C., M.T.).
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Sato
authors.affiliation: From the Departments of Microbiology and Immunology (S.O., E.K., F.S., N.E.M., I.T.) and Molecular and Cellular Physiology (G.V.C., J.S.A.), Louisiana State University Health Sciences Center, Shreveport; and Department of Computer Science, Louisiana State University Shreveport (P.A.R., U.C., M.T.).
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Martinez
authors.affiliation: From the Departments of Microbiology and Immunology (S.O., E.K., F.S., N.E.M., I.T.) and Molecular and Cellular Physiology (G.V.C., J.S.A.), Louisiana State University Health Sciences Center, Shreveport; and Department of Computer Science, Louisiana State University Shreveport (P.A.R., U.C., M.T.).
authors.forename: Ganta V
authors.initials: GV
authors.lastname: Chaitanya
authors.affiliation: From the Departments of Microbiology and Immunology (S.O., E.K., F.S., N.E.M., I.T.) and Molecular and Cellular Physiology (G.V.C., J.S.A.), Louisiana State University Health Sciences Center, Shreveport; and Department of Computer Science, Louisiana State University Shreveport (P.A.R., U.C., M.T.).
authors.forename: Phoebe A
authors.initials: PA
authors.lastname: Rollyson
authors.affiliation: From the Departments of Microbiology and Immunology (S.O., E.K., F.S., N.E.M., I.T.) and Molecular and Cellular Physiology (G.V.C., J.S.A.), Louisiana State University Health Sciences Center, Shreveport; and Department of Computer Science, Louisiana State University Shreveport (P.A.R., U.C., M.T.).
authors.forename: Urska
authors.initials: U
authors.lastname: Cvek
authors.affiliation: From the Departments of Microbiology and Immunology (S.O., E.K., F.S., N.E.M., I.T.) and Molecular and Cellular Physiology (G.V.C., J.S.A.), Louisiana State University Health Sciences Center, Shreveport; and Department of Computer Science, Louisiana State University Shreveport (P.A.R., U.C., M.T.).
authors.forename: Marjan
authors.initials: M
authors.lastname: Trutschl
authors.affiliation: From the Departments of Microbiology and Immunology (S.O., E.K., F.S., N.E.M., I.T.) and Molecular and Cellular Physiology (G.V.C., J.S.A.), Louisiana State University Health Sciences Center, Shreveport; and Department of Computer Science, Louisiana State University Shreveport (P.A.R., U.C., M.T.).
authors.forename: J Steven
authors.initials: JS
authors.lastname: Alexander
authors.affiliation: From the Departments of Microbiology and Immunology (S.O., E.K., F.S., N.E.M., I.T.) and Molecular and Cellular Physiology (G.V.C., J.S.A.), Louisiana State University Health Sciences Center, Shreveport; and Department of Computer Science, Louisiana State University Shreveport (P.A.R., U.C., M.T.). itsuno@lsuhsc.edu.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Tsunoda
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D016000:Cluster Analysis; D019295:Computational Biology; D004195:Disease Models, Animal; D004452:Echocardiography; D007113:Immunity, Innate / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D015999:Multivariate Analysis; D009205:Myocarditis / Q000276:immunology / Q000473:pathology* / Q000821:virology; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D012367:RNA, Viral / Q000097:blood; D060888:Real-Time Polymerase Chain Reaction; D017945:Theilovirus / Q000235:genetics / Q000472:pathogenicity*; D014336:Troponin / Q000097:blood
chemical_list: D015415:Biomarkers; D012367:RNA, Viral; D014336:Troponin
keywords: Picornaviridae infections; T lymphocytes; computational biology; immunology; interferons; systems biology; transcriptome