Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation

Abstract

A virus that reproduces in a host without killing cells can easily establish a successful infection. Previously, we showed that dengue-2, a virus that threatens 40% of the world, induces autophagy, enabling dengue to reproduce in cells without triggering cell death. Autophagy further protects the virus-laden cells from further insults. In this study, we evaluate how it does so; we show that dengue upregulates host pathways that increase autophagy, namely endoplasmic reticulum (ER) stress and ataxia telangiectasia mutated (ATM) signaling followed by production of reactive oxygen species (ROS). Inhibition of ER stress or ATM signaling abrogates the dengue-conferred protection against other cell stressors. Direct inhibition of ER stress response in infected cells decreases autophagosome turnover, reduces ROS production and limits reproduction of dengue virus. Blocking ATM activation, which is an early response to infection, decreases transcription of ER stress response proteins, but ATM has limited impact on production of ROS and virus titers. Production of ROS determines only late-onset autophagy in infected cells and is not necessary for dengue-induced protection from stressors. Collectively, these results demonstrate that among the multiple autophagy-inducing pathways during infection, ER stress signaling is more important to viral replication and protection of cells than either ATM or ROS-mediated signaling. To limit virus production and survival of dengue-infected cells, one must address the earliest phase of autophagy, induced by ER stress.

Mitochondrial Functions in Infection and Immunity

“…Similarly, an HIV protein, called the viral protein R, translocates to OMM upon viral infection, inhibits Mfn2, and disrupts mitochondrial membrane potential, leading ultimately to cell death induction [62,63]. Interestingly, in contrast to HIV and Influenza A, some viruses, including Dengue [64], Zika [65], and Chikungunya [66] viruses, promote autophagy in the host, which inhibits cell death and promotes viral replication and dissemination. Similarly, measles virus enhances mitophagy in host cells, which limits apoptosis, but induces necrotic cell death in the later stages due to reduced levels of ATP [67].…”

Retraction statement: ‘Urotensin II inhibits autophagy in renal tubular epithelial cells and induces extracellular matrix production in early diabetic mice’ by Guan‐Jong Chen, Fei Wu, Xin‐Xin Pang, Ai‐Hua Zhang, Jun‐Bao Shi, Min Lu and Chao‐Shu Tang

“…To be more specific, the expression level of UII is associated with endoplasmic reticulum stress in patients with severe pre-eclampsia. As mentioned previously and in numerous studies, endoplasmic reticulum stress can be associated with autophagy 19,30,31 . However, to the best of our knowledge, no study explored the association between UII and the process of autophagy.…”

Implications of autophagy on arbovirus infection of mosquitoes

“…ER-stress) (Figure 1) [16,20,22,23]. Often times the effects of autophagy on virus replication are perceived and reported as either being beneficial or detrimental.…”