bims-mevinf Biomed News
on Metabolism in viral infections
Issue of 2024–04–28
ten papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology
  1. Hepatitis B virus and hepatitis C virus affect mitochondrial function through different metabolic pathways, explaining virus-specific clinical features of chronic hepatitis.
  2. Lipid Droplets: Formation, Degradation, and Their Role in Cellular Responses to Flavivirus Infections.
  3. Metabolomics captures the differential metabolites in the replication pathway of snakehead vesiculovirus regulated by glutamine.
  4. Porcine epidemic diarrhea virus E protein induces formation of stress granules and attenuates protein translation through activation of the PERK/eIF2α signaling pathway.
  5. Redox Homeostasis Alteration Is Restored through Melatonin Treatment in COVID-19 Patients: A Preliminary Study.
  6. Commensal bacteria inhibit viral infections via a tryptophan metabolite.
  7. The IRE1α-XBP1 arm of the unfolded protein response is a host factor activated in SARS-CoV-2 infection.
  8. PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2.
  9. Significance of nitrosative stress and glycoxidation products in the diagnosis of COVID-19.
  10. Lipid Profile and Cardiovascular Risk Modification after Hepatitis C Virus Eradication.
  1. J Infect Dis. 2024 Apr 24. pii: jiae210. [Epub ahead of print]
    Hepatitis B virus and hepatitis C virus affect mitochondrial function through different metabolic pathways, explaining virus-specific clinical features of chronic hepatitis.
    Sakthi Priya Selvamani, Anis Khan, Enoch S E Tay, Matthew Garvey, Harout Ajoyan, Eve Diefenbach, Brian S Gloss, Thomas Tu, Jacob George, Mark W Douglas.
       BACKGROUND: Hepatitis C virus (HCV) and hepatitis B virus (HBV) cause chronic hepatitis with important clinical differences. HCV causes hepatic steatosis and insulin resistance, while HBV confers increased risk of liver cancer. We hypothesised these differences may be due to virus-specific effects on mitochondrial function.
    METHODS: Seahorse technology was utilised to investigate effects of virus infection on mitochondrial function. Cell based assays were used to measure mitochondrial membrane potential and quantify pyruvate and lactate. Mass spectrometry was performed on mitochondria isolated from HBV expressing, HCV infected and control cells cultured with isotope-labelled amino acids, to identify proteins with different abundance. Altered expression of key mitochondrial proteins was confirmed by real time PCR and western blot.
    RESULTS: Reduced mitochondrial function and ATP production were observed with HCV infection and HBV expression. HCV impairs glycolysis and reduces expression of genes regulating fatty acid oxidation, promoting lipid accumulation. HBV causes lactate accumulation by increasing expression of lactate dehydrogenase A, which converts pyruvate to lactate. In HBV expressing cells there was marked enrichment of pyruvate dehydrogenase kinase, inhibiting conversion of pyruvate to acetyl-CoA and thereby reducing its availability for mitochondrial oxidative phosphorylation.
    CONCLUSIONS: HCV and HBV impair mitochondrial function and reduce ATP production. HCV reduces acetyl-CoA availability for energy production by impairing fatty acid oxidation, causing lipid accumulation and hepatic steatosis. HBV has no effect on fatty oxidation but reduces acetyl-CoA availability by disrupting pyruvate metabolism. This promotes lactic acidosis and oxidative stress, increasing the risk of disease progression and liver cancer.
    Keywords:  hepatitis B virus; hepatitis C virus; hepatocellular carcinoma; liver cancer; metabolism; mitochondria; steatosis
    DOI:  https://doi.org/10.1093/infdis/jiae210
  2. Microorganisms. 2024 Mar 24. pii: 647. [Epub ahead of print]12(4):
    Lipid Droplets: Formation, Degradation, and Their Role in Cellular Responses to Flavivirus Infections.
    James Z Hsia, Dongxiao Liu, LaPrecious Haynes, Ruth Cruz-Cosme, Qiyi Tang.
      Lipid droplets (LDs) are cellular organelles derived from the endoplasmic reticulum (ER), serving as lipid storage sites crucial for maintaining cellular lipid homeostasis. Recent attention has been drawn to their roles in viral replication and their interactions with viruses. However, the precise biological functions of LDs in viral replication and pathogenesis remain incompletely understood. To elucidate the interaction between LDs and viruses, it is imperative to comprehend the biogenesis of LDs and their dynamic interactions with other organelles. In this review, we explore the intricate pathways involved in LD biogenies within the cytoplasm, encompassing the uptake of fatty acid from nutrients facilitated by CD36-mediated membranous protein (FABP/FATP)-FA complexes, and FA synthesis via glycolysis in the cytoplasm and the TCL cycle in mitochondria. While LD biogenesis primarily occurs in the ER, matured LDs are intricately linked to multiple organelles. Viral infections can lead to diverse consequences in terms of LD status within cells post-infection, potentially involving the breakdown of LDs through the activation of lipophagy. However, the exact mechanisms underlying LD destruction or accumulation by viruses remain elusive. The significance of LDs in viral replication renders them effective targets for developing broad-spectrum antivirals. Moreover, considering that reducing neutral lipids in LDs is a strategy for anti-obesity treatment, LD depletion may not pose harm to cells. This presents LDs as promising antiviral targets for developing therapeutics that are minimally or non-toxic to the host.
    Keywords:  Zika virus; antiviral; dengue virus; endoplasmic reticulum; fatty acid; flaviviruses; hepatitis C virus; lipid droplet; lipid droplet biogenesis; lipid droplet contact; lipophagy; orthoflaviviruses
    DOI:  https://doi.org/10.3390/microorganisms12040647
  3. Dis Aquat Organ. 2024 Apr 25. 158 101-114
    Metabolomics captures the differential metabolites in the replication pathway of snakehead vesiculovirus regulated by glutamine.
    Binbin Sun, Yulei Zhang, Keping Chen, Lindan Sun.
      Snakehead vesiculovirus (SHVV) is a negative-sense single-stranded RNA virus that infects snakehead fish. This virus leads to illness and mortality, causing significant economic losses in the snakehead aquaculture industry. The replication and spread of SHVV in cells, which requires glutamine as a nitrogen source, is accompanied by alterations in intracellular metabolites. However, the metabolic mechanisms underlying the inhibition of viral replication by glutamine deficiency are poorly understood. This study utilized liquid chromatography-mass spectrometry to measure the differential metabolites between the channel catfish Parasilurus asotus ovary cell line infected with SHVV under glutamine-containing and glutamine-deprived conditions. Results showed that the absence of glutamine regulated 4 distinct metabolic pathways and influenced 9 differential metabolites. The differential metabolites PS(16:0/16:0), 5,10-methylene-THF, and PS(18:0/18:1(9Z)) were involved in amino acid metabolism. In the nuclear metabolism functional pathway, differential metabolites of guanosine were observed. In the carbohydrate metabolism pathway, differential metabolites of UDP-d-galacturonate were detected. In the signal transduction pathway, differential metabolites of SM(d18:1/20:0), SM(d18:1/22:1(13Z)), SM(d18:1/24:1(15 Z)), and sphinganine were found. Among them, PS(18:0/18:1(9Z)), PS(16:0/16:0), and UDP-d-galacturonate were involved in the synthesis of phosphatidylserine and glycoprotein. The compound 5,10-methylene-THF provided raw materials for virus replication, and guanosine and sphingosine are related to virus virulence. The differential metabolites may collectively participate in the replication, packaging, and proliferation of SHVV under glutamine deficiency. This study provides new insights and potential metabolic targets for combating SHVV infection in aquaculture through metabolomics approaches.
    Keywords:  Glutamine-deprived; Metabolomics; Snakehead fish; Snakehead vesiculovirus; Ultra-high-performance liquid chromatography
    DOI:  https://doi.org/10.3354/dao03786
  4. Vet Microbiol. 2024 Apr 16. pii: S0378-1135(24)00117-2. [Epub ahead of print]293 110095
    Porcine epidemic diarrhea virus E protein induces formation of stress granules and attenuates protein translation through activation of the PERK/eIF2α signaling pathway.
    Liang Zheng, Ying Yang, Yifeng Han, Jiawen Yu, Zhijun Wu, Matthew Kay, Wenlong Xia, Zhibao Chen, Jinzhu Ma, Xiaoge Yang, Liwei Yin, Xiaojuan Xu, Hua Zhang.
      Porcine epidemic diarrhea virus (PEDV) envelope protein (E) has been characterized as an important structural protein that plays critical roles in the interplay with its host to affect the virus life cycle. Stress granules (SGs) are host translationally silent ribonucleoproteins, which are mainly induced by the phosphorylation of eIF2α in the PERK/eIF2α signaling pathway. Our previous study found that PEDV E protein caused endoplasmic reticulum stress response (ERS)-mediated suppression of antiviral proteins' translation. However, the link and the underlying mechanism by which PEDV induces SGs formation and suppresses host translation remain elusive. In this study, our results showed that PEDV E protein significantly elevated the expression of GRP78, CANX, and phosphorylation of PERK and eIF2α, indicating that the PERK/eIF2α branch of ERS was activated. PEDV E protein localized to the ER and aggregated into puncta to reconstruct ER structure, and further induced SGs formation, which has been caused through upregulating the G3BP1 expression level. In addition, a significant global translational stall and endogenous protein translation attenuation were detected in the presence of E protein overexpression, but the global mRNA transcriptional level remained unchanged, suggesting that the shutoff of protein translation was associated with the translation, not with the transcription process. Collectively, this study demonstrates that PERK/eIF2α activation is required for SGs formation and protein translation stall. This study is beneficial for us to better understand the mechanism by which PEDV E suppresses host protein synthesis, and provides us a new insight into the host translation regulation during virus infection.
    Keywords:  E protein; PERK/eIF2α signaling; Porcine epidemic diarrhea virus; Stress granules; Translation attenuation
    DOI:  https://doi.org/10.1016/j.vetmic.2024.110095
  5. Int J Mol Sci. 2024 Apr 21. pii: 4543. [Epub ahead of print]25(8):
    Redox Homeostasis Alteration Is Restored through Melatonin Treatment in COVID-19 Patients: A Preliminary Study.
    María Elena Soto, Israel Pérez-Torres, Linaloe Manzano-Pech, Adrían Palacios-Chavarría, Rafael Ricardo Valdez-Vázquez, Verónica Guarner-Lans, Elizabeth Soria-Castro, Eulises Díaz-Díaz, Vicente Castrejón-Tellez.
      Type II pneumocytes are the target of the SARS-CoV-2 virus, which alters their redox homeostasis to increase reactive oxygen species (ROS). Melatonin (MT) has antioxidant proprieties and protects mitochondrial function. In this study, we evaluated whether treatment with MT compensated for the redox homeostasis alteration in serum from COVID-19 patients. We determined oxidative stress (OS) markers such as carbonyls, glutathione (GSH), total antioxidant capacity (TAC), thiols, nitrites (NO2-), lipid peroxidation (LPO), and thiol groups in serum. We also studied the enzymatic activities of glutathione peroxidase (GPx), glutathione-S-transferase (GST), reductase (GR), thioredoxin reductase (TrxR), extracellular superoxide dismutase (ecSOD) and peroxidases. There were significant increases in LPO and carbonyl quantities (p ≤ 0.03) and decreases in TAC and the quantities of NO2-, thiols, and GSH (p < 0.001) in COVID-19 patients. The activities of the antioxidant enzymes such as ecSOD, TrxR, GPx, GST, GR, and peroxidases were decreased (p ≤ 0.04) after the MT treatment. The treatment with MT favored the activity of the antioxidant enzymes that contributed to an increase in TAC and restored the lost redox homeostasis. MT also modulated glucose homeostasis, functioning as a glycolytic agent, and inhibited the Warburg effect. Thus, MT restores the redox homeostasis that is altered in COVID-19 patients and can be used as adjuvant therapy in SARS-CoV-2 infection.
    Keywords:  COVID-19; SARS-CoV-2; antioxidant enzymes; melatonin; oxidative stress; redox homeostasis
    DOI:  https://doi.org/10.3390/ijms25084543
  6. bioRxiv. 2024 Apr 21. pii: 2024.04.21.589969. [Epub ahead of print]
    Commensal bacteria inhibit viral infections via a tryptophan metabolite.
    Danting Jiang, Nicole Soo, Chin Yee Tan, Sedem Dankwa, Hsuan-Yuan Wang, Barbara S Theriot, Amir Ardeshir, Nazema Y Siddiqui, Koen K A Van Rompay, Kristina De Paris, Sallie R Permar, Ria Goswami, Neeraj K Surana.
      There is growing appreciation that commensal bacteria impact the outcome of viral infections, though the specific bacteria and their underlying mechanisms remain poorly understood. Studying a simian-human immunodeficiency virus (SHIV)-challenged cohort of pediatric nonhuman primates, we bioinformatically associated Lactobacillus gasseri and the bacterial family Lachnospiraceae with enhanced resistance to infection. We experimentally validated these findings by demonstrating two different Lachnospiraceae isolates, Clostridium immunis and Ruminococcus gnavus, inhibited HIV replication in vitro and ex vivo. Given the link between tryptophan catabolism and HIV disease severity, we found that an isogenic mutant of C. immunis that lacks the aromatic amino acid aminotransferase (ArAT) gene, which is key to metabolizing tryptophan into 3-indolelactic acid (ILA), no longer inhibits HIV infection. Intriguingly, we confirmed that a second commensal bacterium also inhibited HIV in an ArAT-dependent manner, thus establishing the generalizability of this finding. In addition, we found that purified ILA inhibited HIV infection by agonizing the aryl hydrocarbon receptor (AhR). Given that the AhR has been implicated in the control of multiple viral infections, we demonstrated that C. immunis also inhibited human cytomegalovirus (HCMV) infection in an ArAT-dependent manner. Importantly, metagenomic analysis of individuals at-risk for HIV revealed that those who ultimately acquired HIV had a lower fecal abundance of the bacterial ArAT gene compared to individuals who did not, which indicates our findings translate to humans. Taken together, our results provide mechanistic insights into how commensal bacteria decrease susceptibility to viral infections. Moreover, we have defined a microbiota-driven antiviral pathway that offers the potential for novel therapeutic strategies targeting a broad spectrum of viral pathogens.
    DOI:  https://doi.org/10.1101/2024.04.21.589969
  7. Biochim Biophys Acta Mol Basis Dis. 2024 Apr 20. pii: S0925-4439(24)00182-0. [Epub ahead of print]1870(5): 167193
    The IRE1α-XBP1 arm of the unfolded protein response is a host factor activated in SARS-CoV-2 infection.
    Jose Javier Fernández, Arturo Marín, Romel Rosales, Rebekah Penrice-Randal, Petra Mlcochova, Yolanda Alvarez, Fernando Villalón-Letelier, Soner Yildiz, Enrique Pérez, Raveen Rathnasinghe, Anastasija Cupic, Thomas Kehrer, Melissa B Uccellini, Sara Alonso, Fernando Martínez, Briana Lynn McGovern, Jordan J Clark, Parul Sharma, Yolanda Bayón, Andrés Alonso, Randy A Albrecht, Kris M White, Michael Schotsaert, Lisa Miorin, James P Stewart, Julian A Hiscox, Ravindra K Gupta, Nerea Irigoyen, Adolfo García-Sastre, Mariano Sánchez Crespo, Nieves Fernández.
      SARS-CoV-2 infection can cause severe pneumonia, wherein exacerbated inflammation plays a major role. This is reminiscent of the process commonly termed cytokine storm, a condition dependent on a disproportionated production of cytokines. This state involves the activation of the innate immune response by viral patterns and coincides with the biosynthesis of the biomass required for viral replication, which may overwhelm the capacity of the endoplasmic reticulum and drive the unfolded protein response (UPR). The UPR is a signal transduction pathway composed of three branches that is initiated by a set of sensors: inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). These sensors control adaptive processes, including the transcriptional regulation of proinflammatory cytokines. Based on this background, the role of the UPR in SARS-CoV-2 replication and the ensuing inflammatory response was investigated using in vivo and in vitro models of infection. Mice and Syrian hamsters infected with SARS-CoV-2 showed a sole activation of the Ire1α-Xbp1 arm of the UPR associated with a robust production of proinflammatory cytokines. Human lung epithelial cells showed the dependence of viral replication on the expression of UPR-target proteins branching on the IRE1α-XBP1 arm and to a lower extent on the PERK route. Likewise, activation of the IRE1α-XBP1 branch by Spike (S) proteins from different variants of concern was a uniform finding. These results show that the IRE1α-XBP1 system enhances viral replication and cytokine expression and may represent a potential therapeutic target in SARS-CoV-2 severe pneumonia.
    Keywords:  COVID-19; Cytokines; Fluvoxamine; Pneumonia; TLR; Transcription factors; Unfolded protein response; Variants of concern; Viral sepsis
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167193
  8. bioRxiv. 2024 Apr 17. pii: 2024.04.15.589676. [Epub ahead of print]
    PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2.
    Marwah Karim, Manjari Mishra, Chieh-Wen Lo, Sirle Saul, Halise Busra Cagirici, Do Hoang Nhu Tran, Aditi Agrawal, Luca Ghita, Amrita Ojha, Michael P East, Karen Anbro Gammeltoft, Malaya Kumar Sahoo, Gary L Johnson, Soumita Das, Dirk Jochmans, Courtney A Cohen, Judith Gottwein, John Dye, Norma Neff, Benjamin A Pinsky, Tuomo Laitinen, Tatu Pantsar, Antti Poso, Fabio Zanini, Steven De Jonghe, Christopher R M Asquith, Shirit Einav.
      In search for broad-spectrum antivirals, we discovered a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrated selective dual inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target engagement by its clickable analog. Advanced lipidomics revealed alteration of SARS-CoV-2-induced phosphoinositide signature by RMC-113 and linked its antiviral effect with functional PIP4K2C and PIKfyve inhibition. We discovered PIP4K2C's roles in SARS-CoV-2 entry, RNA replication, and assembly/egress, validating it as a druggable antiviral target. Integrating proteomics, single-cell transcriptomics, and functional assays revealed that PIP4K2C binds SARS-CoV-2 nonstructural protein 6 and regulates virus-induced impairment of autophagic flux. Reversing this autophagic flux impairment is a mechanism of antiviral action of RMC-113. These findings reveal virus-induced autophagy regulation via PIP4K2C, an understudied kinase, and propose dual inhibition of PIP4K2C and PIKfyve as a candidate strategy to combat emerging viruses.
    DOI:  https://doi.org/10.1101/2024.04.15.589676
  9. Sci Rep. 2024 Apr 22. 14(1): 9198
    Significance of nitrosative stress and glycoxidation products in the diagnosis of COVID-19.
    Blanka Wolszczak-Biedrzycka, Justyna Dorf, Joanna Matowicka-Karna, Marzena Wojewódzka-Żeleźniakowicz, Piotr Żukowski, Anna Zalewska, Mateusz Maciejczyk.
      Nitrosative stress promotes protein glycoxidation, and both processes can occur during an infection with the SARS-CoV-2 virus. Therefore, the aim of this study was to assess selected nitrosative stress parameters and protein glycoxidation products in COVID-19 patients and convalescents relative to healthy subjects, including in reference to the severity of COVID-19 symptoms. The diagnostic utility of nitrosative stress and protein glycoxidation biomarkers was also evaluated in COVID-19 patients. The study involved 218 patients with COVID-19, 69 convalescents, and 48 healthy subjects. Nitrosative stress parameters (NO, S-nitrosothiols, nitrotyrosine) and protein glycoxidation products (tryptophan, kynurenine, N-formylkynurenine, dityrosine, AGEs) were measured in the blood plasma or serum with the use of colorimetric/fluorometric methods. The levels of NO (p = 0.0480), S-nitrosothiols (p = 0.0004), nitrotyrosine (p = 0.0175), kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan fluorescence was significantly (p < 0.0001) lower in COVID-19 patients than in the control group. Significant differences in the analyzed parameters were observed in different stages of COVID-19. In turn, the concentrations of kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan levels were significantly (p < 0.0001) lower in convalescents than in healthy controls. The ROC analysis revealed that protein glycoxidation products can be useful for diagnosing infections with the SARS-CoV-2 virus because they differentiate COVID-19 patients (KN: sensitivity-91.20%, specificity-92.00%; NFK: sensitivity-92.37%, specificity-92.00%; AGEs: sensitivity-99,02%, specificity-100%) and convalescents (KN: sensitivity-82.22%, specificity-84.00%; NFK: sensitivity-82,86%, specificity-86,00%; DT: sensitivity-100%, specificity-100%; AGE: sensitivity-100%, specificity-100%) from healthy subjects with high sensitivity and specificity. Nitrosative stress and protein glycoxidation are intensified both during and after an infection with the SARS-CoV-2 virus. The levels of redox biomarkers fluctuate in different stages of the disease. Circulating biomarkers of nitrosative stress/protein glycoxidation have potential diagnostic utility in both COVID-19 patients and convalescents.
    Keywords:  COVID-19; Glycoxidation products; MEWS; Nitrosative stress; SARS-CoV-2 virus
    DOI:  https://doi.org/10.1038/s41598-024-59876-w
  10. Pathogens. 2024 Mar 25. pii: 278. [Epub ahead of print]13(4):
    Lipid Profile and Cardiovascular Risk Modification after Hepatitis C Virus Eradication.
    Andrea Pascual-Oliver, Diego Casas-Deza, Carmen Yagüe-Caballero, Jose M Arbones-Mainar, Vanesa Bernal-Monterde.
      The eradication of the hepatitis C virus (HCV) has revolutionized the hepatology paradigm, halting the progression of advanced liver disease in patients with chronic infection and reducing the risk of hepatocarcinoma. In addition, treatment with direct-acting antivirals can reverse the lipid and carbohydrate abnormalities described in HCV patients. Although HCV eradication may reduce the overall risk of vascular events, it is uncertain whether altered lipid profiles increase the risk of cerebrovascular disease in certain patients. We have conducted a review on HCV and lipid and carbohydrate metabolism, as well as new scientific advances, following the advent of direct-acting antivirals.
    Keywords:  cardiovascular disease; chronic hepatitis C virus treatment; direct-acting antiviral treatment; hepatitis C virus; insulin resistance; lipoproteins
    DOI:  https://doi.org/10.3390/pathogens13040278
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