bims-mevinf 2023-10-29 papers

Front Immunol. 2023 ;14 1216278

Altered sphingolipid pathway in SARS-CoV-2 infected human lung tissue.

Rabisa J Khan, Sierra L Single, Christopher S Simmons, Mohammad Athar, Yuelong Liu, Sandeep Bodduluri, Paul V Benson, Kayla F Goliwas, Jessy S Deshane.

Introduction: The SARS-CoV-2 mediated COVID-19 pandemic has impacted millions worldwide. Hyper-inflammatory processes, including cytokine storm, contribute to long-standing tissue injury and damage in COVID-19. The metabolism of sphingolipids as regulators of cell survival, differentiation, and proliferation has been implicated in inflammatory signaling and cytokine responses. Sphingosine-kinase-1 (SK1) and ceramide-synthase-2 (CERS2) generate metabolites that regulate the anti- and pro-apoptotic processes, respectively. Alterations in SK1 and CERS2 expression may contribute to the inflammation and tissue damage during COVID-19. The central objective of this study is to evaluate structural changes in the lung post-SARS-CoV-2 infection and to investigate whether the sphingolipid rheostat is altered in response to SARS-CoV-2 infection.
Methods: Central and peripheral lung tissues from COVID-19+ or control autopsies and resected lung tissue from COVID-19 convalescents were subjected to histologic evaluation of airspace and collagen deposisiton, and immunohistochemical evaluation of SK1 and CERS2.
Results: Here, we report significant reduction in air space and increase in collagen deposition in lung autopsy tissues from patients who died from COVID-19 (COVID-19+) and COVID-19 convalescent individuals. SK1 expression increased in the lungs of COVID-19+ autopsies and COVID-19 convalescent lung tissue compared to controls and was mostly associated with Type II pneumocytes and alveolar macrophages. No significant difference in CERS2 expression was noted. SARS-CoV-2 infection upregulates SK1 and increases the ratio of SK1 to CERS2 expression in lung tissues of COVID-19 autopsies and COVID-19 convalescents.
Discussion: These data suggest an alteration in the sphingolipid rheostat in lung tissue during COVID-19, suggesting a potential contribution to the inflammation and tissue damage associated with viral infection.

Keywords: COVID-19; COVID-19 convalescence; SARS-CoV-2; lung structural remodeling; sphingolipid signaling

DOI: https://doi.org/10.3389/fimmu.2023.1216278

Curr Issues Mol Biol. 2023 Sep 28. 45(10): 7956-7973

The Sphingolipid-Signaling Pathway as a Modulator of Infection by SARS-CoV-2.

Simona Fenizia, Melania Gaggini, Cristina Vassalle.

Ceramides and other related sphingolipids, important cellular components linked to metabolic homeostasis and cardiometabolic diseases, have been found to be involved in different steps of the SARS-CoV-2 life cycle. Hence, changes in their physiological levels are identified as predictors of COVID-19 severity and prognosis, as well as potential therapeutic targets. In this review, an overview of the SARS-CoV-2 life cycle is given, followed by a description of the sphingolipid metabolism and its role in viral infection, with a particular focus on those steps required to finalize the viral life cycle. Furthermore, the use and development of pharmaceutical strategies to target sphingolipids to prevent and treat severe and long-term symptoms of infectious diseases, particularly COVID-19, are reviewed herein. Finally, research perspectives and current challenges in this research field are highlighted. Although many aspects of sphingolipid metabolism are not fully known, this review aims to highlight how the discovery and use of molecules targeting sphingolipids with reliable and selective properties may offer new therapeutic alternatives to infectious and other diseases, including COVID-19.

Keywords: COVID-19; biomarkers; ceramides; lipids; sphingosine-1-phosphate; viral infection

DOI: https://doi.org/10.3390/cimb45100503

mSystems. 2023 Oct 24. e0072623

Methylprednisolone therapy induces differential metabolic trajectories in severe COVID-19 patients.

Corticosteroids have become a choice for managing severe COVID-19, but the molecular mechanisms behind the response after corticosteroid administration remain incompletely understood. In order to unravel this, comparisons between temporal metabolic profiles in the plasma samples of methylprednisolone (MP)- and placebo-treated COVID-19 patients were performed at different time points. The patient plasma samples used were obtained from a double-blind, randomized, placebo-controlled Phase IIb clinical trial performed on severe COVID-19 patients in the Brazilian Amazon, where the patients received placebo or 0.5 mg/kg MP intravenously twice daily for 5 days. The MP treatment reduced the number of metabolites in the plasma of patients during follow-up. The longitudinal changes in the MP group were in eight metabolic pathways related to steroid hormones and eicosanoids. Direct comparison between the two groups, revealed differences at baseline, which peaked 5 days after initiation of MP treatment. The metabolic pathways differing between the two groups over time included galactose metabolism, glucose and gluconeogenesis, N-glycan metabolism, and prostaglandin formation from arachidonate. Deoxy-galactose, prostaglandin H2, sphingosine, and sphinganine exhibited differential trajectories by day 14 after initiating the MP treatment. Survival of MP-treated COVID-19 patients was associated with modulation of tryptophan metabolism and diminished levels of oxidized glutathione. Network analysis revealed that MP treatment is highly associated with alterations in pathways reflecting eicosanoid metabolism, such as arachidonic acid and prostaglandins. Curiously, there is a crosstalk between metabolomics, biochemistry, and cytokine components. Treatment of systemic and inflammatory conditions induced by SARS-CoV-2 viral infections with methylprednisolone modulates metabolic activity associated with tryptophan and inflammatory lipids.IMPORTANCEThe SARS-CoV-2 virus infection in humans induces significant inflammatory and systemic reactions and complications of which corticosteroids like methylprednisolone have been recommended as treatment. Our understanding of the metabolic and metabolomic pathway dysregulations while using intravenous corticosteroids in COVID-19 is limited. This study will help enlighten the metabolic and metabolomic pathway dysregulations underlying high daily doses of intravenous methylprednisolone in COVID-19 patients compared to those receiving placebo. The information on key metabolites and pathways identified in this study together with the crosstalk with the inflammation and biochemistry components may be used, in the future, to leverage the use of methylprednisolone in any future pandemics from the coronavirus family.

Keywords: COVID-19; SARS-CoV-2 virus; corticosteroid; metabolomics; methylprednisolone; profile

DOI: https://doi.org/10.1128/msystems.00726-23

J Virol. 2023 Oct 25. e0095323

The master antioxidant defense is activated during EBV latent infection.

Ling Wang, Mary E A Howell, Culton R Hensley, Katharine Ning, Jonathan P Moorman, Zhi Q Yao, Shunbin Ning.

Our recent publication shows for the first time that the master antioxidant pathway Keap1-NRF2 is constitutively activated in EBV- or HTLV1-transformed cells, with the mechanism being unclear (L. Wang, M. E. A. Howell, A. Sparks-Wallace, C. Hawkins, et al., PLoS Pathog 15:e1007541, 2019, https://doi.org/10.1371/journal.ppat.1007541). In this follow-up investigation, we show that EBV-triggered ROS production activates the Keap1-NRF2 pathway in EBV-transformed cells, and LMP1 plays a major role in this event. Further investigation shows that the mitochondria in cell lines with EBV Type 3 latency produce higher levels of mitochondrial ROS that are responsible for the activation of the Keap1-NRF2 pathway, compared with Type 1 latency. Moreover, using both pharmaceutical inhibitors and CRISPR-mediated gene editing, we show that the stress-related kinase TBK1 is required for NRF2 activation. As to the functional consequences, shRNA-mediated knockdown of NRF2 in EBV-transformed IB4 and HTLV1-transformed MT4 cells elevates endogenous reactive oxygen species levels, promotes DNA damage, downregulates cell proliferation, and promotes EBV reactivation. These findings, together with our previous report, disclose how EBV controls the intricate balance between oxidative stress and antioxidant defense, which greatly improve our understanding of EBV latency and pathogenesis and may be leveraged to opportunities toward the improvement of therapeutic outcomes in EBV-associated diseases. IMPORTANCE To our knowledge, this is the first report delineating the activation of the master antioxidant defense during EBV latency. We show that EBV-triggered reactive oxygen species production activates the Keap1-NRF2 pathway in EBV-transformed cells, and LMP1 plays a major role in this event, and the stress-related kinase TBK1 is required for NRF2 activation. Moreover, we show that the Keap1-NRF2 pathway is important for cell proliferation and EBV latency maintenance. Our findings disclose how EBV controls the balance between oxidative stress and antioxidant defense, which greatly improve our understanding of EBV latency and pathogenesis and may be leveraged to opportunities toward the improvement of therapeutic outcomes in EBV-associated diseases.

Keywords: EBV; Keap1; NRF2; antioxidant stress

DOI: https://doi.org/10.1128/jvi.00953-23

J Virol. 2023 Oct 25. e0149723

Duck Tembusu virus NS3 protein induces apoptosis by activating the PERK/PKR pathway and mitochondrial pathway.

Yuhong Pan, Wenjun Cai, Anchun Cheng, Mingshu Wang, Juan Huang, Shun Chen, Qiao Yang, Ying Wu, Di Sun, Sai Mao, Dekang Zhu, Mafeng Liu, Xinxin Zhao, Shaqiu Zhang, Qun Gao, Xumin Ou, Bin Tian, Zhongqiong Yin, Renyong Jia.

Duck Tembusu virus (DTMUV) infection causes severe infectious diseases in poultry and can induce apoptosis in host cells. In this study, the mechanisms underlying DTMUV-induced apoptosis were investigated. First, DTMUV infection can activate the endoplasmic reticulum stress (ERS), and administration of the ERS inhibitor 4-phenylbutyric acid can protect cells from DTMUV-induced apoptosis, indicating that ERS is involved in DTMUV-induced apoptosis. Interestingly, suppression of either apoptosis or ERS led to impaired DTMUV proliferation. Then, we found that DTMUV activated three branches of unfolded protein response signaling [RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1, and activating transcription factor 6] in duck embryo fibroblasts. Further study revealed that activation of PERK-eukaryotic initiation factor 2α up-regulated CCAAT/enhancer-binding protein homologous protein and DNA damage-inducible protein 34, which subsequently promoted apoptosis. Moreover, we found that among the DTMUV viral proteins, the nonstructural protein 3 (NS3) is the main inducer of apoptosis. On the one hand, the PERK/PKR pathway is involved in the NS3-mediated mitochondrial apoptosis pathway. On the other hand, NS3 interacts with voltage-dependent anion channel 2 (VDAC2) and inhibits the anti-apoptotic protein VDAC2 to induce apoptosis, which is accompanied by the depolarization of mitochondrial membrane potential and accumulation of intracellular reactive oxygen species. This study provides a theoretical basis for revealing the pathogenic mechanism of DTMUV infection and lays a foundation for finding antiviral targets. IMPORTANCE Duck Tembusu virus (DTMUV) is an emerging pathogenic flavivirus that replicates well in mosquito, bird, and mammalian cells. An in vivo study revealed that BALB/c mice and Kunming mice were susceptible to DTMUV after intracerebral inoculation. Moreover, there are no reports about DTMUV-related human disease, but antibodies against DTMUV and viral RNA were detected in the serum samples of duck industry workers. This information implies that DTMUV has expanded its host range and poses a threat to mammalian health. Thus, understanding the pathogenic mechanism of DTMUV is crucial for identifying potential antiviral targets. In this study, we discovered that NS3 can induce the mitochondria-mediated apoptotic pathway through the PERK/PKR pathway; it can also interact with voltage-dependent anion channel 2 to induce apoptosis. Our findings provide a theoretical basis for understanding the pathogenic mechanism of DTMUV infection and identifying potential antiviral targets and may also serve as a reference for exploring the pathogenesis of other flaviviruses.

Keywords: DTMUV; NS3; PERK/PKR pathway; apoptosis; mitochondrial pathway

DOI: https://doi.org/10.1128/jvi.01497-23