title: Temporal retinal transcriptome and systems biology analysis identifies key pathways and hub genes in Staphylococcus aureus endophthalmitis.
abstract: Bacterial endophthalmitis remains a devastating inflammatory condition associated with permanent vision loss. Hence, assessing the host response in this disease may provide new targets for intervention. Using a mouse model of Staphylococcus aureus (SA) endophthalmitis and performing retinal transcriptome analysis, we discovered progressive changes in the expression of 1,234 genes. Gene ontology (GO) and pathway analyses revealed the major pathways impacted in endophthalmitis includes: metabolism, inflammatory/immune, antimicrobial, cell trafficking, and lipid biosynthesis. Among the immune/inflammation pathways, JAK/Stat and IL-17A signaling were the most significantly affected. Interactive network-based analyses identified 13 focus hub genes (IL-6, IL-1β, CXCL2, STAT3, NUPR1, Jun, CSF1, CYR61, CEBPB, IGF-1, EGFR1, SPP1, and TGM2) within these important pathways. The expression of hub genes confirmed by qRT-PCR, ELISA (IL-6, IL-1β, and CXCL2), and Western blot or immunostaining (CEBP, STAT3, NUPR1, and IGF1) showed strong correlation with transcriptome data. Since TLR2 plays an important role in SA endophthalmitis, counter regulation analysis of TLR2 ligand pretreated retina or the use of retinas from TLR2 knockout mice showed the down-regulation of inflammatory regulatory genes. Collectively, our study provides, for the first time, a comprehensive analysis of the transcriptomic response and identifies key pathways regulating retinal innate responses in staphylococcal endophthalmitis.
authors: BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, MA.
authors: Deepa
authors: D
authors: Rajamani
authors: Kresge Eye Institute, Wayne State University, Detroit, MI.|Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI.
authors: Pawan Kumar
authors: PK
authors: Singh
authors: Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI.
authors: Bruce G
authors: BG
authors: Rottmann
authors: BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, MA.
authors: Natasha
authors: N
authors: Singh
authors: BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, MA.|Department of Medicine, Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors: Manoj K
authors: MK
authors: Bhasin
authors: Kresge Eye Institute, Wayne State University, Detroit, MI.|Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI.|Department of Immunology and Microbiology, Wayne State University, Detroit, MI.
authors: Ashok
authors: A
authors: Kumar
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D009877:Endophthalmitis / Q000235:genetics* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058977:Molecular Sequence Annotation; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D025341:Principal Component Analysis; D012160:Retina / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D015398:Signal Transduction; D013203:Staphylococcal Infections / Q000235:genetics* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000472:pathogenicity / Q000502:physiology; D049490:Systems Biology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D059467:Transcriptome
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C491644:Nupr1 protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2