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Title: Unfolded protein response (UPR) gene expression during antibody-dependent enhanced infection of cultured monocytes correlates with dengue disease severity
Authors: Paradkar, P.N.
Ooi, E.E.
Hanson, B.J.
Gubler, D.J. 
Vasudevan, S.G. 
Keywords: Antibody-dependent enhancement (ADE)
Dengue biomarker
THP-1 monocyte
Unfolded protein response (UPR)
Issue Date: Jun-2011
Citation: Paradkar, P.N., Ooi, E.E., Hanson, B.J., Gubler, D.J., Vasudevan, S.G. (2011-06). Unfolded protein response (UPR) gene expression during antibody-dependent enhanced infection of cultured monocytes correlates with dengue disease severity. Bioscience Reports 31 (3) : 221-230. ScholarBank@NUS Repository.
Abstract: DENV (dengue virus) induces UPR (unfolded protein response) in the host cell, which strikes a balance between pro-survival and pro-apoptotic signals. We previously showed that Salubrinal, a drug that targets the UPR, inhibits DENV replication. Here, we examine the impact on UPR after direct or ADE (antibody-dependent enhanced) infection of cells with DENV clinical isolates. THP-1 cells in the presence of subneutralizing concentration of humanized antibody 4G2 (cross-reactive with flavivirus envelope protein) or HEK-293 cells (human embryonic kidney 293 cells) were infected with DENV-1-4 serotypes. UPR gene expression was monitored under these infection conditions using real-time RT-PCR (reverse transcription-PCR) and Western blots to analyse serotype-dependent variations. Subsequently, in a blinded study, strain-specific differences were compared between DENV-2 clinical isolates obtained from a single epidemic. Results showed that THP-1 cells were infected efficiently and equally by DENV-1-4 in the ADE mode. At 48 hpi (h post infection), DENV-1 and -3 showed a higher replication rate and induced higher expression of several UPR genes such as BiP (immunoglobulin heavy-chain-binding protein), GADD34 (growth arrest DNA damage-inducible protein 34) and CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein]. The ADE infection of THP-1 cells with epidemic DENV-2 high-UPR-gene-expressing strains appears to correlate with severe disease; however, no such correlation could be made when the same viruses were used to infect HEK-293 cells. Our finding that UPR gene expression in THP-1 cells during ADE infection correlates with dengue disease severity is consistent with a previous study [Morens, Marchette, Chu and Halstead (1991) Am. J. Trop. Med. Hyg. 45, 644-651] that showed that the growth of DENV 2 isolates in human peripheral blood leucocytes correlated with severe and mild dengue diseases. ©The Authors Journal compilation ©2011 Biochemical Society.
Source Title: Bioscience Reports
ISSN: 01448463
DOI: 10.1042/BSR20100078
Appears in Collections:Staff Publications

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