ABSTRACT
The replication of coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERSCoV), and the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is closely associated with the endoplasmic reticulum (ER) of infected cells. The unfolded protein response (UPR), which is mediated by ER stress (ERS), is a typical outcome in coronavirus-infected cells and is closely associated with the characteristics of coronaviruses. However, the interaction between virus-induced ERS and coronavirus replication is poorly understood. Here, we demonstrate that infection with the betacoronavirus porcine hemagglutinating encephalomyelitis virus (PHEV) induced ERS and triggered all three branches of the UPR signaling pathway both in vitro and in vivo. In addition, ERS suppressed PHEV replication in mouse neuro-2a (N2a) cells primarily by activating the protein kinase R-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) axis of the UPR. Moreover, another eIF2a phosphorylation kinase, interferon (IFN)-induced double-stranded RNA-dependent protein kinase (PKR), was also activated and acted cooperatively with PERK to decrease PHEV replication. Furthermore, we demonstrate that the PERK/PKR-eIF2a pathways negatively regulated PHEV replication by attenuating global protein translation. Phosphorylated eIF2a also promoted the formation of stress granules (SGs), which in turn repressed PHEV replication. In summary, our study presents a vital aspect of the host innate response to invading pathogens and reveals attractive host targets (e.g., PERK, PKR, and eIF2a) for antiviral drugs. [ FROM AUTHOR] Copyright of Journal of Virology is the property of American Society for Microbiology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)
ABSTRACT
Background: The initial outbreak of coronavirus disease 2019 (COVID-19) pandemic has rapidly extended globally, which brought huge detrimental to the whole society. While some countries and regions are currently experiencing another outbreak of COVID-19.Methods: In this study, by using the epidemic data from January 2 to February 11, 2021 in city Shijiazhuang, an extended SEIR model was established to evaluate the effectiveness of emergency response, nucleic acid testing (NAT) and stay-at-home order for all individuals, and to simulate the impact of delayed interventions.Findings: We estimated an initial effective reproduction number (Rt) was 4·70, and the Rt value gradually decreased with the implementation of government interventions. Meanwhile, the final cumulative number of confirmed cases decreased by 99·99% (898 cases), and peak of current confirmed cases decreased by 99·99% (763 cases) compared with that without intervention. With fewer interventions, the number of infected individuals will continue to increase. Delayed interventions were simulated which would show at least 80% (1614 cases), 218% (2854 cases), 464% (5061 cases), and 879% (8787 cases) more infections can be attained for Shijiazhuang city, if the intervention was delayed by 2, 4, 6, and 8 days, respectively.Interpretation: The Shijiazhuang government has effectively controlled the spread of the epidemic by adopting a series of comprehensive non-pharmacological interventions in time.Funding Information: The study was supported by grants from the National Social Science Foundation of China (20BRK041).Declaration of Interests: The authors declare that they have no competing interests.