Respiratory Syncytial Virus and Cellular Stress Responses: Impact on Replication and Physiopathology

Abstract

Human respiratory syncytial virus (RSV), a member of the Paramyxoviridae family, is a major cause of severe acute lower respiratory tract infection in infants, elderly and immunocompromised adults. Despite decades of research, a complete integrated picture of RSV-host interaction is still missing. Several cellular responses to stress are involved in the host-response to many virus infections. The endoplasmic reticulum stress induced by altered endoplasmic reticulum (ER) function leads to activation of the unfolded-protein response (UPR) to restore homeostasis. Formation of cytoplasmic stress granules containing translationally stalled mRNAs is a means to control protein translation. Production of reactive oxygen species is balanced by an antioxidant response to prevent oxidative stress and the resulting damages. In recent years, ongoing research has started to unveil specific regulatory interactions of RSV with these host cellular stress responses. Here, we discuss the latest findings regarding the mechanisms evolved by RSV to induce, subvert or manipulate the ER stress, the stress granule and oxidative stress responses. We summarize the evidence linking these stress responses with the regulation of RSV replication and the associated pathogenesis.

iTRAQ-based Proteomic Analysis of Porcine Kidney Epithelial PK15 cells Infected with Pseudorabies virus

“…ER reside on many molecular chaperones that assist protein folding and assembly 34 . Numerous studies show that viral infections can alter endoplasmic reticulum (ER) and activate the unfolded-protein response (UPR), thereby facilitating viral replication [35][36][37][38] . In the current study, 21 of the differentially expressed proteins were involved in protein processing in the endoplasmic reticulum.…”

“…Similarly, hsp27 was also significant altered at 4 h of PRV infction in Madin-Darby bovine kidney cells using SILAC mass spectrometry methods, since only a small number of host cell proteins changed during early stages of PRV infection, other stress-related proteins did not show significant variations 7,8 . Heat-shock proteins can facilitate protein folding, heat-shock response activation might be a virus-specific function ensuring proper protein synthesis and; therefore, ER stress proteins may also be important for virus replication 37,39,40 . Hsp90 is involved in the assembly and nuclear transport of viral RNA polymerase subunits and facilitates viral replication in HIV-1, Ebola virus, hepatitis B virus, hepatitis C virus, and Rotavirus [41][42][43][44][45][46] .…”

The innate immune response to RSV: Advances in our understanding of critical viral and host factors

“…Host cell stress responses, including endoplasmic reticulum (ER) stress, stress granule (SG) formation, and oxidative stress, have been associated with the antiviral response to RSV[69]. ER stress results from the accumulation of unfolded or misfolded proteins in the ER lumen.…”

“…RSV infection elicits an oxidative stress response that associates with the stimulation of antiviral immunity (reviewed in [69, 81]). During RSV infection, ROS produced in response to the activity of the NADPH oxidase 2 (NOX2) activates the transcription factor NF-kB and promotes efficient RIG-I mediated IRF3 activation[82–84] while RSV interferes with expression of the dual oxidase 2 (DUOX2) and limits DUOX2-mediated production of H 2 O 2 [85].…”

“…During RSV infection, ROS produced in response to the activity of the NADPH oxidase 2 (NOX2) activates the transcription factor NF-kB and promotes efficient RIG-I mediated IRF3 activation[82–84] while RSV interferes with expression of the dual oxidase 2 (DUOX2) and limits DUOX2-mediated production of H 2 O 2 [85]. Interestingly, RSV also limits the activity of host antioxidant enzymes, thereby promoting the accumulation of high levels of ROS (reviewed in [69, 81]). High levels of ROS are associated with worsened lung pathology suggesting a delicate protective/pathogenic balance of the oxidative response during RSV infection.…”