bims-mevinf 2023-10-08 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023‒10‒08
nine papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Respiratory syncytial virus co-opts hypoxia-inducible factor-1α-mediated glycolysis to favor the production of infectious virus.
SARS-CoV-2 infection and dysregulation of nuclear factor erythroid-2-related factor 2 (Nrf2) pathway.
Oxidative stress and ROS-mediated cellular events in RSV infection: potential protective roles of antioxidants.
Oxidative stress sensor Keap1 recognizes HBx protein to activate the Nrf2/ARE signaling pathway, thereby inhibiting hepatitis B virus replication.
Zika virus modulates mitochondrial dynamics, mitophagy, and mitochondria-derived vesicles to facilitate viral replication in trophoblast cells.
ATP release from influenza-infected lungs enhances neutrophil activation and promotes disease progression.
Selenomethionine alleviates environmental heat stress induced hepatic lipid accumulation and glycogen infiltration of broilers via maintaining mitochondrial and endoplasmic reticulum homeostasis.
AMPK inhibitor, compound C, inhibits coronavirus replication in vitro.
25-hydroxycholesterol: an integrator of antiviral ability and signaling.

mBio. 2023 Oct 05. e0211023

Respiratory syncytial virus co-opts hypoxia-inducible factor-1α-mediated glycolysis to favor the production of infectious virus.

Li-Feng Chen, Jun-Xing Cai, Jing-Jing Zhang, Yu-Jun Tang, Jia-Yi Chen, Si Xiong, Yao-Lan Li, Hong Zhang, Zhong Liu, Man-Mei Li.

  Glycolysis, a series of oxidative reactions used to metabolize glucose and provide energy to host cells, is also required for respiratory syncytial virus (RSV) infection. However, the role of glycolysis during RSV infection and its underlying molecular mechanisms remain to be further explored. In this study, we investigated the function of hypoxia-inducible factor (HIF)-1α-mediated glycolysis in HEp-2 cells and mouse models during RSV infection. The results showed that RSV infection activated the insulin receptor (IR)-PI3K-Akt axis, upregulated the translation and activity of HIF-1α, increased the expression of glucose transporters (Glut1, Glut3, and Glut4), hexokinase (HK) 1 and 2, and platelet-type phosphofructokinase (PFKP), and promoted glucose uptake and glycolysis. In addition, mitochondrial damage induced by RSV resulted in the generation of large amounts of reactive oxygen species (ROS) in infected cells, which contributed to the stabilization and activation of HIF-1α. An energy map of the glycolytic ATP production rate (Glyco-ATP) versus the mitochondrial ATP production rate (mito-ATP) confirmed a switch from oxidative phosphorylation (OXPHOS) to glycolysis. Inhibition of IR-PI3K-Akt signaling, ROS, or HIF-1α effectively reversed the RSV-induced increase in glycolysis by blocking HIF-1α activation. Importantly, HIF-1α-mediated glycolysis provided energy for the production of progeny RSV virions. The production of infectious virions was nearly abolished after knocking down HIF-1α. PX-478, an orally active HIF-1α inhibitor, effectively inhibited RSV infection in vivo. Collectively, these results indicate the role of HIF-1α-mediated glycolysis in RSV infection and highlight HIF-1α as a potential target for anti-RSV drug development. IMPORTANCE Respiratory syncytial virus (RSV) is the leading etiological agent of lower respiratory tract illness. However, efficacious vaccines or antiviral drugs for treating RSV infections are currently not available. Indeed, RSV depends on host cells to provide energy needed to produce progeny virions. Glycolysis is a series of oxidative reactions used to metabolize glucose and provide energy to host cells. Therefore, glycolysis may be helpful for RSV infection. In this study, we show that RSV increases glycolysis by inducing the stabilization, transcription, translation, and activation of hypoxia-inducible factor (HIF)-1α in infected cells, which is important for the production of progeny RSV virions. This study contributes to understanding the molecular mechanism by which HIF-1α-mediated glycolysis controls RSV infection and reveals an effective target for the development of highly efficient anti-RSV drugs.

Keywords:  HIF-1α; IR-PI3K-Akt signaling; ROS; glycolysis; mitochondria; respiratory syncytial virus

DOI:  https://doi.org/10.1128/mbio.02110-23
Cell Stress Chaperones. 2023 Oct 05.

SARS-CoV-2 infection and dysregulation of nuclear factor erythroid-2-related factor 2 (Nrf2) pathway.

Rabab S Hamad, Hayder M Al-Kuraishy, Athanasios Alexiou, Marios Papadakis, Eman A Ahmed, Hebatallah M Saad, Gaber El-Saber Batiha.

  Coronavirus disease 2019 (COVID-19) is a recent pandemic caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) leading to pulmonary and extra-pulmonary manifestations due to the development of oxidative stress (OS) and hyperinflammation. The underlying cause for OS and hyperinflammation in COVID-19 may be related to the inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidative responses and cellular homeostasis. The Nrf2 pathway inhibits the expression of pro-inflammatory cytokines and the development of cytokine storm and OS in COVID-19. Nrf2 activators can attenuate endothelial dysfunction (ED), renin-angiotensin system (RAS) dysregulation, immune thrombosis, and coagulopathy. Hence, this review aimed to reveal the potential role of the Nrf2 pathway and its activators in the management of COVID-19. As well, we tried to revise the mechanistic role of the Nrf2 pathway in COVID-19.

Keywords:  COVID-19; Nuclear factor erythroid 2-related factor 2; Oxidative stress; SARS-CoV-2

DOI:  https://doi.org/10.1007/s12192-023-01379-0
Virol J. 2023 Oct 05. 20(1): 224

Oxidative stress and ROS-mediated cellular events in RSV infection: potential protective roles of antioxidants.

Xue Yang, Xue Liu, Yujun Nie, Fei Zhan, Bin Zhu.

  Respiratory syncytial virus (RSV), a member of the Pneumoviridae family, can cause severe acute lower respiratory tract infection in infants, young children, immunocompromised individuals and elderly people. RSV is associated with an augmented innate immune response, enhanced secretion of inflammatory cytokines, and necrosis of infected cells. Oxidative stress, which is mainly characterized as an imbalance in the production of reactive oxygen species (ROS) and antioxidant responses, interacts with all the pathophysiologic processes above and is receiving increasing attention in RSV infection. A gradual accumulation of evidence indicates that ROS overproduction plays an important role in the pathogenesis of severe RSV infection and serves as a major factor in pulmonary inflammation and tissue damage. Thus, antioxidants seem to be an effective treatment for severe RSV infection. This article mainly reviews the information on oxidative stress and ROS-mediated cellular events during RSV infection for the first time.

Keywords:  HMGB1; NETs; NLRP3; Nrf2; Oxidative stress; Reactive oxygen species; Respiratory syncytial virus

DOI:  https://doi.org/10.1186/s12985-023-02194-w
J Virol. 2023 Oct 06. e0128723

Oxidative stress sensor Keap1 recognizes HBx protein to activate the Nrf2/ARE signaling pathway, thereby inhibiting hepatitis B virus replication.

Adi Ariffianto, Lin Deng, Takayuki Abe, Chieko Matsui, Masahiko Ito, Akihide Ryo, Hussein Hassan Aly, Koichi Watashi, Tetsuro Suzuki, Masashi Mizokami, Yoshiharu Matsuura, Ikuo Shoji.

  Hepatitis B virus (HBV) infection promotes reactive oxygen species production while paradoxically inducing the expression of antioxidant enzymes. HBV-induced disorders of redox homeostasis are closely associated with the development of hepatic diseases. However, the molecular mechanisms underlying the HBV-induced antioxidant response are poorly understood. The NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is an intrinsic defense mechanism against oxidative stress. We here aim to elucidate the role of the Nrf2/ARE signaling pathway in the HBV life cycle. ARE-driven reporter assays revealed that expression of HBV X protein (HBx), but not HBV core, large HBV surface, or HBV polymerase, strongly enhanced ARE-luciferase activity, suggesting that HBx plays an important role in the HBV-induced antioxidant response. Knockdown of Nrf2 resulted in a marked decrease in HBx-induced ARE-luciferase activity. Immunoblot analysis and immunofluorescence staining suggested that HBx activates Nrf2 by increasing Nrf2 protein levels and enhancing Nrf2 nuclear localization. The oxidative stress sensor Kelch-like ECH-associated protein 1 (Keap1) is required for the ubiquitin-dependent degradation of Nrf2. Coimmunoprecipitation analysis revealed that HBx interacted with Keap1, suggesting that HBx competes with Nrf2 for interaction with Keap1. A cell-based ubiquitylation assay showed that HBx promoted polyubiquitylation of Nrf2 via K6-linked polyubiquitin chains, and that this action may be associated with Nrf2 stabilization. A chromatin immunoprecipitation assay suggested that Nrf2 interacts with the HBV core promoter. Overexpression of Nrf2 strongly suppressed HBV core promoter activity, resulting in a marked reduction in viral replication. Based on the above, we propose that Keap1 recognizes HBx to activate the Nrf2/ARE signaling pathway upon HBV infection, thereby inhibiting HBV replication.IMPORTANCEThe Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is one of the most important defense mechanisms against oxidative stress. We previously reported that a cellular hydrogen peroxide scavenger protein, peroxiredoxin 1, a target gene of transcription factor Nrf2, acts as a novel HBV X protein (HBx)-interacting protein and negatively regulates hepatitis B virus (HBV) propagation through degradation of HBV RNA. This study further demonstrates that the Nrf2/ARE signaling pathway is activated during HBV infection, eventually leading to the suppression of HBV replication. We provide evidence suggesting that Keap1 interacts with HBx, leading to Nrf2 activation and inhibition of HBV replication via suppression of HBV core promoter activity. This study raises the possibility that activation of the Nrf2/ARE signaling pathway is a potential therapeutic strategy against HBV. Our findings may contribute to an improved understanding of the negative regulation of HBV replication by the antioxidant response.

Keywords:  HBx; Keap1/Nrf2/ARE; hepatitis B virus

DOI:  https://doi.org/10.1128/jvi.01287-23
Front Immunol. 2023 ;14 1203645

Zika virus modulates mitochondrial dynamics, mitophagy, and mitochondria-derived vesicles to facilitate viral replication in trophoblast cells.

Jae Kyung Lee, Ok Sarah Shin.

  Zika virus (ZIKV) remains a global public health threat with the potential risk of a future outbreak. Since viral infections are known to exploit mitochondria-mediated cellular processes, we investigated the effects of ZIKV infection in trophoblast cells in terms of the different mitochondrial quality control pathways that govern mitochondrial integrity and function. Here we demonstrate that ZIKV (PRVABC59) infection of JEG-3 trophoblast cells manipulates mitochondrial dynamics, mitophagy, and formation of mitochondria-derived vesicles (MDVs). Specifically, ZIKV nonstructural protein 4A (NS4A) translocates to the mitochondria, triggers mitochondrial fission and mitophagy, and suppresses mitochondrial associated antiviral protein (MAVS)-mediated type I interferon (IFN) response. Furthermore, proteomics profiling of small extracellular vesicles (sEVs) revealed an enrichment of mitochondrial proteins in sEVs secreted by ZIKV-infected JEG-3 cells, suggesting that MDV formation may also be another mitochondrial quality control mechanism manipulated during placental ZIKV infection. Altogether, our findings highlight the different mitochondrial quality control mechanisms manipulated by ZIKV during infection of placental cells as host immune evasion mechanisms utilized by ZIKV at the placenta to suppress the host antiviral response and facilitate viral infection.

Keywords:  mitochondria-derived vesicles (MDVs); mitochondrial quality control; mitophagy; nonstructural protein 4A (NS4A); zika virus (ZIKV)

DOI:  https://doi.org/10.3389/fimmu.2023.1203645
J Infect Dis. 2023 Oct 06. pii: jiad442. [Epub ahead of print]

ATP release from influenza-infected lungs enhances neutrophil activation and promotes disease progression.

Carola Ledderose, Eleftheria-Angeliki Valsami, Mark Elevado, Wolfgang G Junger.

  BACKGROUND: ATP enhances neutrophil responses, but little is known about the role of ATP in influenza infections.METHODS: We used a mouse influenza model to study if ATP release is associated with neutrophil activation and disease progression.
RESULTS: Influenza infection increased pulmonary ATP levels 5-fold and plasma ATP levels 3-fold over the levels in healthy mice. Adding ATP at those concentrations to blood from healthy mice primed their neutrophils and enhanced CD11b and CD63 expression, CD62L shedding, and reactive oxygen species production in response to formyl peptide receptor (FPR) stimulation. Influenza infection also primed neutrophils in vivo, resulting in FPR-induced CD11b expression and CD62L shedding up to 3-times higher than that of uninfected mice. In infected mice, large numbers of neutrophils entered the lungs. These cells were significantly more activated than peripheral neutrophils of infected and pulmonary neutrophils of healthy mice. Plasma ATP levels of infected mice and influenza disease progression corresponded with the numbers and activation level of their pulmonary neutrophils.
CONCLUSION: Our findings suggest that ATP release from the lungs of infected mice promotes influenza disease progression by priming peripheral neutrophils that become strongly activated and cause pulmonary tissue damage after their recruitment to the lungs.

Keywords:  ATP release; influenza; mice; neutrophil priming and activation; purinergic signaling

DOI:  https://doi.org/10.1093/infdis/jiad442
Redox Biol. 2023 Oct 03. pii: S2213-2317(23)00313-0. [Epub ahead of print]67 102912

Selenomethionine alleviates environmental heat stress induced hepatic lipid accumulation and glycogen infiltration of broilers via maintaining mitochondrial and endoplasmic reticulum homeostasis.

Jinzhong Jing, Huijin Zeng, Quanjun Shao, Jiayong Tang, Longqiong Wang, Gang Jia, Guangmang Liu, Xiaoling Chen, Gang Tian, Jingyi Cai, Bo Kang, Lianqiang Che, Hua Zhao.

  With the increasing of global mean surface air temperature, heat stress (HS) induced by extreme high temperature has become a key factor restricting the poultry industry. Liver is the main metabolic organ of broilers, HS induces liver damage and metabolic disorders, which impairs the health of broilers and affects food safety. As an essential trace element for animals, selenium (Se) involves in the formation of antioxidant system, and its biological functions are generally mediated by selenoproteins. However, the mechanism of Se against HS induced liver damage and metabolic disorders in broilers is inadequate. Therefore, we developed the chronic heat stress (CHS) broiler model and investigated the potential protection mechanism of organic Se (selenomethionine, SeMet) on CHS induced liver damage and metabolic disorders. In present study, CHS caused liver oxidative damage, and induced hepatic lipid accumulation and glycogen infiltration of broilers, which are accompanied by mitochondrial dysfunction, abnormal mitochondrial tricarboxylic acid (TCA) cycle and endoplasmic reticulum (ER) stress. Dietary SeMet supplementation increased the hepatic Se concentration and exhibited protective effects via promoting the expression of selenotranscriptome and several key selenoproteins (GPX4, TXNRD2, SELENOK, SELENOM, SELENOS, SELENOT, GPX1, DIO1, SELENOH, SELENOU and SELENOW). These key selenoproteins synergistically improved the antioxidant capacity, and mitigated the mitochondrial dysfunction, abnormal mitochondrial TCA cycle and ER stress, thus recovered the hepatic triglyceride and glycogen concentration. What's more, SeMet supplementation suppressed lipid and glycogen biosynthesis and promoted lipid and glycogen breakdown in liver of broilers exposed to CHS though regulating the AMPK signals. Overall, our present study reveals a potential mechanism that Se alleviates environment HS induced liver damage and glycogen and lipid metabolism disorders in broilers, which provides a preventive and/or treatment measure for environment HS-dependent hepatic metabolic disorders in poultry industry.

Keywords:  Broilers; ER stress; Heat stress; Hepatic metabolic disorder; Mitochondrial dysfunction; Selenoprotein

DOI:  https://doi.org/10.1016/j.redox.2023.102912
PLoS One. 2023 ;18(10): e0292309

AMPK inhibitor, compound C, inhibits coronavirus replication in vitro.

Minsu Jang, Rackhyun Park, Ayane Yamamoto, Yea-In Park, Yeonjeong Park, Siyun Lee, Junsoo Park.

The coronavirus disease (COVID-19) pandemic has resulted in more than six million deaths by October 2022. Vaccines and antivirals for severe acute respiratory syndrome coronavirus 2 are now available; however, more effective antiviral drugs are required for effective treatment. Here, we report that a potent AMP-activated protein kinase (AMPK) inhibitor, compound C/dorsomorphin, inhibits the replication of the human coronavirus OC43 strain (HCoV-OC43). We examined HCoV-OC43 replication in control and AMPK-knockout (KO) cells and found that the virus replication decreased in AMPK-KO cells. Next, we examined the effect of the AMPK inhibitor, compound C on coronavirus replication. Compound C treatment efficiently inhibited the replication and decreased the coronavirus-induced cytotoxicity, further inhibiting autophagy. In addition, treatment with compound C in combination with chloroquine synergistically inhibited coronavirus replication. These results suggest that compound C can be considered as a potential drug candidate for COVID-19.

DOI: https://doi.org/10.1371/journal.pone.0292309
Front Immunol. 2023 ;14 1268104

25-hydroxycholesterol: an integrator of antiviral ability and signaling.

Jialu Zhang, Yaohong Zhu, Xiaojia Wang, Jiufeng Wang.

  Cholesterol, as an important component in mammalian cells, is efficient for viral entry, replication, and assembly. Oxysterols especially hydroxylated cholesterols are recognized as novel regulators of the innate immune response. The antiviral ability of 25HC (25-Hydroxycholesterol) is uncovered due to its role as a metabolic product of the interferon-stimulated gene CH25H (cholesterol-25-hydroxylase). With the advancement of research, the biological functions of 25HC and its structural functions have been interpreted gradually. Furthermore, the underlying mechanisms of antiviral effect of 25HC are not only limited to interferon regulation. Taken up by the special biosynthetic ways and structure, 25HC contributes to modulate not only the cholesterol metabolism but also autophagy and inflammation by regulating signaling pathways. The outcome of modulation by 25HC seems to be largely dependent on the cell types, viruses and context of cell microenvironments. In this paper, we review the recent proceedings on the regulatory effect of 25HC on interferon-independent signaling pathways related to its antiviral capacity and its putative underlying mechanisms.

Keywords:  antiviral effect; cholesterol metabolism; interferon-independent pathways; oxysterol; signaling regulation

DOI:  https://doi.org/10.3389/fimmu.2023.1268104