Differential unfolded protein response during Chikungunya and Sindbis virus infection: CHIKV nsP4 suppresses eIF2α phosphorylation

Abhay P S Rathore,Mah-Lee Ng,Subhash G Vasudevan

doi:10.1186/1743-422x-10-36

Abhay P S Rathore, Mah-Lee Ng + Show 1 more

Open Access

https://doi.org/10.1186/1743-422x-10-36

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Abstract

Chikungunya (CHIKV) and Sindbis (SINV) are arboviruses belonging to the alphavirus genus within the Togaviridae family. They cause frequent epidemics of febrile illness and long-term arthralgic sequelae that affect millions of people each year. Both viruses replicate prodigiously in infected patients and in vitro in mammalian cells, suggesting some level of control over the host cellular translational machinery that senses and appropriately directs the cell’s fate through the unfolded protein response (UPR). The mammalian UPR involves BIP (or GRP78), the master sensor in the endoplasmic reticulum (ER) together with the three downstream effector branches: inositol-requiring ser/thr protein kinase/endonuclease (IRE-1), PKR-like ER resident kinase (PERK) and activating transcription factor 6 (ATF-6). Through careful analysis of CHIKV and SINV infections in cell culture we found that the former selectively activates ATF-6 and IRE-1 branches of UPR and suppresses the PERK pathway. By separately expressing each of the CHIKV proteins as GFP-fusion proteins, we found that non-structural protein 4 (nsP4), which is a RNA-dependent-RNA polymerase, suppresses the serine-51 phosphorylation of eukaryotic translation initiation factor, alpha subunit (eIF2α), which in turn regulates the PERK pathway. This study provides insight into a mechanism by which CHIKV replication responds to overcome the host UPR machinery.

Highlights

Chikungunya virus (CHIKV) is a member of the alphavirus genus, which contains 26 known arboviruses with a wide host range [1]
Growth kinetics of CHIKV and SINV in vitro Since the study is primarily investigating CHIKV growth, we first determined the infectivity and growth kinetics of CHIKV in various cultured mammalian cell types in order to align our data with others in the field
Several key immune cells like primary human peripheral blood mononuclear cells (PBMC), peripheral blood monocytic cells (THP-1 & K562) and T lymphocytic cells (Jurkat) were found to be poorly infected with CHIKV, suggesting that immune cells may not be the primary targets for infection (Figure 1A)

Summary

Introduction

Chikungunya virus (CHIKV) is a member of the alphavirus genus, which contains 26 known arboviruses with a wide host range [1]. Its discovery, CHIKV has spread widely and currently Chikungunya fever has been detected in nearly 40 countries with a potential to affect millions of people worldwide [3]. Several studies have shown that alphavirus replication in mammalian cells usually results in severe cytopathicity, mainly caused by dramatic shutdown of host translation machinery [16,17,18,19,20]. The mechanism by which CHIKV maintains such a high replication rate in the infected cells is poorly understood

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