Abstract
Rubella virus (RV) causes severe congenital defects when acquired during the first trimester of pregnancy. RV cytopathic effect has been shown to be due to caspase-dependent apoptosis in a number of susceptible cell lines, and it has been suggested that this apoptotic induction could be a causal factor in the development of such defects. Often the outcome of apoptotic stimuli is dependent on apoptotic, proliferative and survival signaling mechanisms in the cell. Therefore we investigated the role of phosphoinositide 3-kinase (PI3K)-Akt survival signaling and Ras-Raf-MEK-ERK proliferative signaling during RV-induced apoptosis in RK13 cells. Increasing levels of phosphorylated ERK, Akt and GSK3β were detected from 24–96 hours post-infection, concomitant with RV-induced apoptotic signals. Inhibition of PI3K-Akt signaling reduced cell viability, and increased the speed and magnitude of RV-induced apoptosis, suggesting that this pathway contributes to cell survival during RV infection. In contrast, inhibition of the Ras-Raf-MEK-ERK pathway impaired RV replication and growth and reduced RV-induced apoptosis, suggesting that the normal cellular growth is required for efficient virus production.
Highlights
Rubella virus (RV) is the sole member of the Rubivirus genus of the Togaviridae
Phosphorylation of Akt, ERK1/2 and their downstream targets during RV infection The effect of RV infection on phosphoinositide 3-kinase (PI3K)-Akt and Ras-Raf-MEKERK pathways was investigated by examining the expression and phosphorylation profiles of Akt, ERK1/2 and their downstream targets
Phosphorylated Akt and ERK1/2 could be detected in RVinfected cells from 48 hours p.i., and band intensity increased from 48–96 hours p.i. compared to total levels (Fig. 1A)
Summary
Rubella virus (RV) is the sole member of the Rubivirus genus of the Togaviridae. It has a positive-sense single stranded RNA genome that is 9762 nucleotides (nt) in length and contains two non-overlapping open-reading frames (ORFs). Infection during the first trimester of pregnancy results in fetal infection, and in more than 75% of cases this leads to the development of congenital abnormalities. These abnormalities include sensorineural deafness, mental retardation, and congenital heart defects, and are collectively termed congenital rubella syndrome (CRS) [5]. Apoptosis is a key component of developmental processes in mammals, which functions to delete vestigial structures, control cell number and remodel tissues and organs [13]. It has (page number not for citation purposes)
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