bims-mevinf 2024-12-15 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024–12–15
seven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Glutamine metabolism Is essential for coronavirus replication in host cells and in mice.
H5 subtype avian influenza virus induces Golgi apparatus stress response via TFE3 pathway to promote virus replication.
Negative regulation of SREBP-1/FAS signalling molecules activates the RIG-1/TBK1-mediated IFN-I pathway to inhibit BVDV replication.
Endoplasmic reticulum stress triggers unfolded protein response as an antiviral strategy of teleost erythrocytes.
Multiomics Analyses Reveal that Fatty Acid Metabolism and TCA Cycle Contribute to the Achievement of Functional Cure in Chronic Hepatitis B.
Matrine relieved DHAV-1-induced hepatocyte excessive interferon and pyroptosis by activating mitophagy.
Peroxisomes are underappreciated organelles hijacked by viruses.

J Biol Chem. 2024 Dec 09. pii: S0021-9258(24)02565-1. [Epub ahead of print] 108063

Glutamine metabolism Is essential for coronavirus replication in host cells and in mice.

Kai Su Greene, Annette Choi, Nianhui Yang, Matthew Chen, Ruizhi Li, Yijian Qiu, Shahrzad Ezzatpour, Katherine S Rojas, Jonathan Shen, Kristin F Wilson, William P Katt, Hector C Aguilar, Michael J Lukey, Gary R Whittaker, Richard A Cerione.

  Understanding the fundamental biochemical and metabolic requirements for the replication of coronaviruses within infected cells is of notable interest for the development of broad-based therapeutic strategies, given the likelihood of emergence of new pandemic-potential virus species, as well as future variants of SARS-CoV-2. Here we demonstrate members of the glutaminase family of enzymes (GLS and GLS2), which catalyze the hydrolysis of glutamine to glutamate (i.e., the first step in glutamine metabolism), play key roles in coronavirus replication in host cells. Using a range of human seasonal and zoonotic coronaviruses, we show three examples where GLS expression increases during coronavirus infection of host cells, and another where GLS2 is upregulated. The viruses hijack the metabolic machinery responsible for glutamine metabolism to generate the building blocks for biosynthetic processes and satisfy the bioenergetic requirements demanded by the 'glutamine addiction' of virus-infected cells. We demonstrate that genetic silencing of glutaminase enzymes reduces coronavirus infection and that newer members of two classes of allosteric inhibitors targeting these enzymes, designated as SU1, a pan-GLS/GLS2 inhibitor, and UP4, a specific GLS inhibitor, block viral replication in epithelial cells. Moreover, treatment of SARS-CoV-2 infected K18-human ACE2 transgenic mice with SU1 resulted in their complete survival compared to untreated control animals, which succumbed within 10 days post-infection. Overall, these findings highlight the importance of glutamine metabolism for coronavirus replication in human cells and mice and show that glutaminase inhibitors can block coronavirus infection and thereby may represent a novel class of broad-based anti-viral drug candidates.

Keywords:  GLS; GLS inhibitor UP4; GLS2; HCoV-229E; HCoV-OC43; SARS-CoV-2; glutamine metabolism; pan-glutaminase inhibitor SU1

DOI:  https://doi.org/10.1016/j.jbc.2024.108063
PLoS Pathog. 2024 Dec;20(12): e1012748

H5 subtype avian influenza virus induces Golgi apparatus stress response via TFE3 pathway to promote virus replication.

Yuncong Yin, Xianjin Kan, Xinyu Miao, Yingjie Sun, Sujuan Chen, Tao Qin, Chan Ding, Daxin Peng, Xiufan Liu.

During infection, avian influenza virus (AIV) triggers endoplasmic reticulum (ER) stress, a well-established phenomenon in previous research. The Golgi apparatus, situated downstream of the ER and crucial for protein trafficking, may be impacted by AIV infection. However, it remains unclear whether this induces Golgi apparatus stress (GAS) and its implications for AIV replication. We investigated the morphological changes in the Golgi apparatus and identified GAS response pathways following infection with the H5 subtype AIV strain A/Mallard/Huadong/S/2005. The results showed that AIV infection induced significant swelling and fragmentation of the Golgi apparatus in A549 cells, indicating the presence of GAS. Among the analyzed GAS response pathways, TFE3 was significantly activated during AIV infection, while HSP47 was activated early in the infection process, and CREB3-ARF4 remained inactive. The blockade of the TFE3 pathway effectively inhibited AIV replication in A549 cells and attenuated AIV virulence in mice. Additionally, activation of the TFE3 pathway promoted endosome acidification and upregulated transcription levels of glycosylation enzymes, facilitating AIV replication. These findings highlight the crucial role of the TFE3 pathway in mediating GAS response during AIV infection, shedding light on its significance in viral replication.

DOI: https://doi.org/10.1371/journal.ppat.1012748
Antiviral Res. 2024 Dec 07. pii: S0166-3542(24)00265-1. [Epub ahead of print] 106054

Negative regulation of SREBP-1/FAS signalling molecules activates the RIG-1/TBK1-mediated IFN-I pathway to inhibit BVDV replication.

Shanshan Liu, An Luo, Taolin Que, Yuxin Liang, Yuxin Song, Tianyi Liu, Jing Li, Nan Li, Zechen Zhang, Yu Liu, Zecai Zhang, Yulong Zhou, Xue Wang, Zhanbo Zhu.

  For many viruses, controlling the process of infection is largely dependent on the enzymes of the fatty acid synthesis (FAS) pathway. An appealing therapeutic target in antiviral research is fatty acid synthetase (FASN), a crucial enzyme in the FAS pathway. Bovine viral diarrhea, caused by the Bovine viral diarrhea virus (BVDV), is a significant viral infectious disease posing a substantial threat to global animal husbandry. Our study revealed that BVDV infection not only upregulates the expression of FAS-related enzymes in BT cells and the blood, liver, and spleen of mice but also markedly enhances the accumulation of lipid droplets, free fatty acids, and triglycerides. The FAS pathway plays a pivotal role throughout the entire BVDV replication cycle. Additionally, administration of the FASN inhibitor C75 and Acetyl CoA carboxylase-1 (ACC-1) inhibitor TOFA significantly reduced the viral content in both serum and organs of BVDV-infected mice, exhibiting inhibitory effects across diverse viral strains. Intriguingly, We found that RIG-1/TBK1-mediated IFN-I signaling inhibits SREBP-1/FAS and reduces BVDV replication. Conversely, targeting a few essential enzymes of SREBP-1/FAS also activates IFN-I signaling. More importantly, FASN inhibitor led to heightened expression of ISGs in mouse spleens by activating the RIG-1/TBK-1 pathway. These findings highlight that FASN inhibitors inhibit BVDV replication through the activation of the RIG-1/TBK-1 pathway to induce ISGs, and offering a novel therapeutic approach for combating BVDV. Thus, it is crucial to negatively regulate SREBP-1/FAS signaling molecules in order to create novel antiviral drugs that are safe, effective, and broad-spectrum.

Keywords:  Antiviral drugs; Bovine viral diarrhea virus; IFN-I; ISGs; fatty acid synthetase

DOI:  https://doi.org/10.1016/j.antiviral.2024.106054
Front Immunol. 2024 ;15 1466870

Endoplasmic reticulum stress triggers unfolded protein response as an antiviral strategy of teleost erythrocytes.

Maria Salvador-Mira, Ester Sanchez-Cordoba, Manuel Solivella, Ivan Nombela, Sara Puente-Marin, Veronica Chico, Luis Perez, Ana Joaquina Perez-Berna, Maria Del Mar Ortega-Villaizan.

   Introduction: Fish nucleated red blood cells (RBCs), also known as erythrocytes, play a crucial role in maintaining immune system balance by modulating protein expression in response to various stimuli, including viral attack. This study explores the intriguing behavior of rainbow trout RBCs when faced with the viral hemorrhagic septicemia virus (VHSV), focusing on the endoplasmic reticulum (ER) stress and the unfolded protein response (UPR).
Methods: Rainbow trout RBCs were Ficoll-purified and exposed to ultraviolet (UV)-inactivated VHSV or live VHSV at different multiplicities of infection (MOIs). Using cryo-soft X-ray tomography (cryo-SXT), we uncovered structural and cellular modifications in RBCs exposed to UV-inactivated VHSV. Moreover, RBCs were treated with 4-phenylbutyric acid (4-PBA), an ER stress inhibitor, to investigate its effect on viral replication. Quantitative real-time PCR was also used to analyze the expression of genes related to the UPR and other related cellular pathways.
Results and discussion: Beyond their antiviral response, RBCs undergo notable intracellular changes to combat the virus. Cryo-SXT highlighted a significant increase in the ER volume. This increase is associated with ER stress and the activation of the UPR pathway. Interestingly, VHSV replication levels augmented in RBCs under ER-stress inhibition by 4-PBA treatment, suggesting that rainbow trout RBCs tune up ER stress to control viral replication. Therefore, our findings suggested the induction of ER stress and subsequent activation UPR signaling in the antiviral response of RBCs to VHSV. The results open a new line of investigation to uncover additional mechanisms that may become novel cellular targets for the development of RBC-targeted antiviral strategies.

Keywords:  VHSV; cryo-soft X-ray tomography; endoplasmic reticulum stress; erythrocytes; fish; rainbow trout; red blood cells; virus

DOI:  https://doi.org/10.3389/fimmu.2024.1466870
J Proteome Res. 2024 Dec 10.

Multiomics Analyses Reveal that Fatty Acid Metabolism and TCA Cycle Contribute to the Achievement of Functional Cure in Chronic Hepatitis B.

Kun Lin, Rongxian Qiu, Songhang Wu, Yongbin Zeng, Tianbin Chen, Zhen Xun, Ni Lin, Can Liu, Qishui Ou, Ya Fu.

  Peg-IFNα is one of the current therapeutic strategies for Hepatitis B virus (HBV) seroclearance. Nevertheless, the underlying mechanisms are not yet adequately understood. The objective of this study was to explore the potential mechanisms using multiomics approach. For the first time, we revealed the transcriptomic, proteomic, and metabolomic characterizations of Peg-IFNα-induced HBsAg seroclearance. We found that Peg-IFNα caused significant changes during the treatment. Patients who achieved HBsAg seroclearance were characterized as having decreased transcriptional activity of genes involved in fatty acid metabolism and the glycolysis/gluconeogenesis pathway, with up-regulated expression of fatty acid degradation-related proteins. Consistently, mitochondrial TCA cycle metabolites, including citric, isocitric, and malic acids, were significantly elevated in patients who achieved HBsAg seroclearance. We also observed up-regulated transcriptional activity of NK cell-mediated cytotoxicity, positive regulation of B cell activation, immunoglobulin production, and T cell receptor complex in functional-cured patients. Conversely, the metabolites associated with unsaturated fatty acid biosynthesis were increased in HBsAg persistent patients, and the transcriptional activity of immunoglobulin production and T cell receptor complex was down-regulated after 48 weeks of Peg-IFNα treatment. Our findings provided valuable resources to better understand the process of HBsAg seroclearance and shed new light on the pathways to facilitate higher functional cure rates for CHB.

Keywords:  HBV; HBsAg seroclearance; Peg-IFNα; chronic hepatitis B; citrate cycle (TCA cycle); fatty acid metabolism; functional cure; immunity; multiomics; therapy

DOI:  https://doi.org/10.1021/acs.jproteome.4c00747
Poult Sci. 2024 Nov 27. pii: S0032-5791(24)01179-9. [Epub ahead of print]104(1): 104601

Matrine relieved DHAV-1-induced hepatocyte excessive interferon and pyroptosis by activating mitophagy.

Weiran Wang, Xiang Fu, Bolin Gu, Mengxin Hu, Jiaguo Liu.

  Duck hepatitis A virus type 1 (DHAV-1) is a significant pathogen affecting ducklings, capable of causing rapid mortality and adversely impacting the development of the duck industry. Matrine, the primary active ingredient in various Chinese herbal medicines, has demonstrated antiviral and anti-inflammatory properties. Nevertheless, the effects and mechanisms of action of matrine against DHAV-1 infection remain unclear. This research investigates the effects of matrine on DHAV-1 infection and elucidates the mechanisms involved. We found that matrine mitigated the excessive retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling response, pyroptosis, and mitochondrial damage induced by DHAV-1 in duckling livers and duck embryonic hepatocytes (DEHs). Additionally‌, by incorporating the autophagy inhibitor chloroquine, we observed that the effects of matrine on the regulation of excessive interferon (IFN) production, pyroptosis, mitochondrial damage, and oxidative stress were reversed. Overall, matrine inhibited excessive IFN production and pyroptosis by promoting mitophagy, suggesting that matrine may act as a possible therapeutic agent for addressing DHAV-1 infection and other viral hepatitis.

Keywords:  DHAV-1; Matrine; Mitophagy; Pyroptosis; RLR signaling

DOI:  https://doi.org/10.1016/j.psj.2024.104601
Trends Cell Biol. 2024 Dec 11. pii: S0962-8924(24)00248-4. [Epub ahead of print]

Peroxisomes are underappreciated organelles hijacked by viruses.

Marie Villares, Lucile Espert, Coralie F Daussy.

  Peroxisomes are cellular organelles that are crucial for metabolism, stress responses, and healthy aging. They have recently come to be considered as important mediators of the immune response during viral infections. Consequently, various viruses target peroxisomes for the purpose of hijacking either their biogenesis or their functions, as a means of replicating efficiently, making this a compelling research area. Despite their known connections with mitochondria, which have been the object of considerable research on account of their role in the innate immune response, less is known about peroxisomes in this context. In this review, we explore the evolving understanding of the role of peroxisomes, highlighting recent findings on how they are exploited by viruses to modulate their replication cycle.

Keywords:  immune response; peroxisome; viral replication

DOI:  https://doi.org/10.1016/j.tcb.2024.11.006