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.

Upregulation of inflammatory gene transcripts in periosteum of chronic migraineurs: Implications for extracranial origin of headache

“…For each network, IPA calculates a score derived from the p-value of right-tailed Fisher exact test [score =-log (p-value)] and indicates the likelihood of focus genes appearing together in the network due to random chance 34–38 . A score of 2 or higher has at least a 99% probability of not being generated by random chance alone.…”

Transcriptomics & copy number variation of radiotoxicity points to altered mitochondrial and DNA repair mechanisms

“…It is interesting to note that TGM2 was over expressed in individuals receiving chemo & radiation therapy, suggesting its involvement in sensitivity to radiation [52,53]. Both, TGM2 and NUPR1 ( Fig 5) have been reported to be implicated in inflammation driven primarily via the JAK/Stat and IL-17A signaling pathway [54]. In the pathway we observe, NUPR1 has direct interaction with FAM72C/FAM27D and LOC100133315, both of which were identified from the copy number variation association.…”

Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry

“…It is interesting to note that TGM2 was over expressed in individuals receiving chemo & radiation therapy, suggesting its involvement in sensitivity to radiation [52,53]. Both, TGM2 and NUPR1 ( Fig 5) have been reported to be implicated in in ammation driven primarily via the JAK/Stat and IL-17A signaling pathway [54]. In the pathway we observe, NUPR1 has direct interaction with FAM72C/FAM27D and LOC100133315, both of which were identi ed from the copy number variation association.…”