期刊
JOURNAL OF GENERAL VIROLOGY
卷 102, 期 9, 页码 -出版社
MICROBIOLOGY SOC
DOI: 10.1099/jgv.0.001657
关键词
cGAS STING; collagens; flavivirus; innate immunity; TMT quantitative proteomics; TLR2
资金
- DST/SERB [EMR/2015/001506]
- THSTI
- RCB
- DBT [BT/PR5480/INF/22/158/2012]
- DBT-Big Data Initiative grant [BT/PR16456/BID/7/624/2016]
- Translational Research Program (TRP) at THSTI - DBT
Advances in proteomics have provided a comprehensive understanding of host-pathogen interactions, with a specific focus on Japanese encephalitis virus (JEV) infection-driven changes in mouse embryonic fibroblast (MEF) proteomes. The study identified alterations in innate immune sensing, interferon responses, inflammation, and other biological pathways in response to JEV infection. Functional validation demonstrated the crucial role of anti-viral innate immune proteins in restricting viral replication and the impact of TLR2 signaling in modulating inflammatory cytokine production. Additionally, the study revealed significant downregulation of proteins related to cell adhesion, transport, and lipid biosynthesis in infected cells.
Advances in proteomics have enabled a comprehensive understanding of host-pathogen interactions. Here we have characterized Japanese encephalitis virus (JEV) infection-driven changes in the mouse embryonic fibroblast (MEF) proteome. Through tandem mass tagging (TMT)-based mass spectrometry, we describe changes in 7.85% of the identified proteome due to JEV infection. Pathway enrichment analysis showed that proteins involved in innate immune sensing, interferon responses and inflammation were the major upregulated group, along with the immunoproteasome and poly ADP-ribosylation proteins. Functional validation of several upregulated anti-viral innate immune proteins, including an active cGAS-STING axis, was performed. Through siRNA depletion, we describe a crucial role of the DNA sensor cGAS in restricting JEV replication. Further, many interferon-stimulated genes (ISGs) were observed to be induced in infected cells. We also observed activation of TLR2 and inhibition of TLR2 signalling using TLR1/2 inhibitor CU-CPT22-blocked production of inflammatory cytokines IL6 and TNF-alpha from virus-infected N9 microglial cells. The major proteins that were downregulated by infection were involved in cell adhesion (collagens), transport (solute carrier and ATP-binding cassette transporters), sterol and lipid biosynthesis. Several collagens were found to be transcriptionally downregulated in infected MEFs and mouse brain. Collectively, our data provide a bird's-eye view into how fibroblast protein composition is rewired following JEV infection.
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