bims-mevinf 2023-10-22 papers

Virol J. 2023 Oct 18. 20(1): 239

Dysregulation of intracellular redox homeostasis by the SARS-CoV-2 ORF6 protein.

Marta De Angelis, Gabriele Anichini, Anna Teresa Palamara, Lucia Nencioni, Gianni Gori Savellini.

SARS-CoV-2 has evolved several strategies to overcome host cell defenses by inducing cell injury to favour its replication. Many viruses have been reported to modulate the intracellular redox balance, affecting the Nuclear factor erythroid 2-Related Factor 2 (NRF2) signaling pathway. Although antioxidant modulation by SARS-CoV-2 infection has already been described, the viral factors involved in modulating the NRF2 pathway are still elusive. Given the antagonistic activity of ORF6 on several cellular pathways, we investigated the role of the viral protein towards NRF2-mediated antioxidant response. The ectopic expression of the wt-ORF6 protein negatively impacts redox cell homeostasis, leading to an increase in ROS production, along with a decrease in NRF2 protein and its downstream controlled genes. Moreover, when investigating the Δ61 mutant, previously described as an inactive nucleopore proteins binding mutant, we prove that the oxidative stress induced by ORF6 is substantially related to its C-terminal domain, speculating that ORF6 mechanism of action is associated with the inhibition of nuclear mRNA export processes. In addition, activation by phosphorylation of the serine residue at position 40 of NRF2 is increased in the cytoplasm of wt-ORF6-expressing cells, supporting the presence of an altered redox state, although NRF2 nuclear translocation is hindered by the viral protein to fully antagonize the cell response. Furthermore, wt-ORF6 leads to phosphorylation of a stress-activated serine/threonine protein kinase, p38 MAPK, suggesting a role of the viral protein in regulating p38 activation. These findings strengthen the important role of oxidative stress in the pathogenesis of SARS-CoV-2 and identify ORF6 as an important viral accessory protein hypothetically involved in modulating the antioxidant response during viral infection.

Keywords: Antagonistic proteins; NRF2; ORF6; Oxidative stress; SARS-CoV-2

DOI: https://doi.org/10.1186/s12985-023-02208-7

J Virol. 2023 Oct 16. e0120923

DHA and EPA inhibit porcine coronavirus replication by alleviating ER stress.

Xiaoyi Suo, Jing Wang, Danping Wang, Guoqiang Fan, Mingjun Zhu, Baochao Fan, Xiaojing Yang, Bin Li.

The 2019 coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlighted significant gaps in our mechanisms to prevent and control cross-species transmission of animal coronaviruses. Porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), and porcine delta coronavirus (PDCoV) are common porcine coronaviruses with similar clinical features. In the absence of effective drugs and methods of prevention and control, outbreaks of these viruses have led to significant economic losses in the global pig industry. Here, we report the effect of five fatty acids against porcine coronaviruses: sodium butyrate, lauric acid, palmitic acid, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). DHA and EPA reduced viral replication by attenuating the endoplasmic reticulum stress and inhibiting PEDV, TGEV, and PDCoV infections in vero cells, PK-15 cells, and LLC-PK1 cells in vitro, respectively. Additionally, DHA and EPA increased the host antioxidant levels and reduced inflammation. In conclusion, we report here for the first time the antiviral effects of DHA and EPA on porcine coronaviruses and provide a molecular basis for the development of new fatty acid-based therapies to control porcine coronavirus infection and transmission. IMPORTANCE Porcine epidemic diarrhea caused by porcine coronaviruses remains a major threat to the global swine industry. Fatty acids are extensively involved in the whole life of the virus. In this study, we found that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) significantly reduced the viral load of porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), and porcine delta coronavirus (PDCoV) and acted on the replication of the viruses rather than attachment and entry. We further confirmed that DHA and EPA inhibited PEDV replication by alleviating the endoplasmic reticulum stress. Meanwhile, DHA and EPA alleviate PEDV-induced inflammation and reactive oxygen species (ROS) levels and enhance the cellular antioxidant capacity. These data indicate that DHA and EPA have antiviral effects on porcine coronaviruses and provide a molecular basis for the development of new fatty acid-based therapies to control porcine coronavirus infection and transmission.

Keywords: anti-viral; docosahexaenoic acid; eicosapentaenoic acid; endoplasmic reticulum stress; porcine coronaviruses

DOI: https://doi.org/10.1128/jvi.01209-23

Sci Adv. 2023 Oct 20. 9(42): eadj4198

Hepatoviruses promote very-long-chain fatty acid and sphingolipid synthesis for viral RNA replication and quasi-enveloped virus release.

Tomoyuki Shiota, Zhucui Li, Guan-Yuan Chen, Kevin L McKnight, Takayoshi Shirasaki, Bryan Yonish, Heyjeong Kim, Ethan J Fritch, Timothy P Sheahan, Masamichi Muramatsu, Maryna Kapustina, Craig E Cameron, You Li, Qibin Zhang, Stanley M Lemon.

Virus-induced changes in host lipid metabolism are an important but poorly understood aspect of viral pathogenesis. By combining nontargeted lipidomics analyses of infected cells and purified extracellular quasi-enveloped virions with high-throughput RNA sequencing and genetic depletion studies, we show that hepatitis A virus, an hepatotropic picornavirus, broadly manipulates the host cell lipid environment, enhancing synthesis of ceramides and other sphingolipids and transcriptionally activating acyl-coenzyme A synthetases and fatty acid elongases to import and activate long-chain fatty acids for entry into the fatty acid elongation cycle. Phospholipids with very-long-chain acyl tails (>C22) are essential for genome replication, whereas increases in sphingolipids support assembly and release of quasi-enveloped virions wrapped in membranes highly enriched for sphingomyelin and very-long-chain ceramides. Our data provide insight into how a pathogenic virus alters lipid flux in infected hepatocytes and demonstrate a distinction between lipid species required for viral RNA synthesis versus nonlytic quasi-enveloped virus release.

DOI: https://doi.org/10.1126/sciadv.adj4198