Endoplasmic reticulum: a focal point of Zika virus infection

Mohd Ropidi, Muhammad Izzuddin; Khazali, Ahmad Suhail; Nor Rashid, Nurshamimi; Yusof, Rohana

As previously mentioned, ER stress elevated the expression of CHOP to initiate apoptosis in ZIKVinfected cells [48, 49] . Prolonged ER stress could also trigger non-apoptotic cell death as demonstrated by an investigation using time-lapse and electron microscopy that revealed the formation of extensive ERderived vacuoles within the cytoplasm of ZIKVinfected cells, which eventually resulted in paraptosislike death [28] . This observation is consistent with earlier report that showed cytoplasmic vacuolization in ZIKV-infected human skin biopsy specimens [13] . Vacuole formation was inhibited with class I PI3K/Akt inhibitor treatment. More importantly, pan-caspase inhibitor, ZVAD-FMK, only slightly rescued cell survival but did not affect vacuolization [28] , implying that certain ZIKV strains, namely HD78788, PF13 and NC14, induce cell death primarily through paraptosislike death. The role of PI3K/Akt pathway in ZIKVinduced cell death was verified by a recent study that reported treatment with AR-12, a celecoxib derivative kinase inhibitor, significantly inhibited the replication of ZIKV in A129 mice and improved mice survival mainly through Akt down-regulation [92] .