bims-mevinf 2024-08-04 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024–08–04
eleven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Unlocking Secrets: Lipid Metabolism and Lipid Droplet Crucial Roles in SARS-CoV-2 Infection and the Immune Response.
G6PD deficiency mediated impairment of iNOS and lysosomal acidification affecting phagocytotic clearance in microglia in response to SARS-CoV-2.
Hepatic macrophage niche: a bridge between HBV-mediated metabolic changes with intrahepatic inflammation.
Autophagy promotes replication of Bombyx mori Nucleopolyhedrovirus in insect cells.
In vitro and in vivo evaluation of thapsigargin as an antiviral agent against transmissible gastroenteritis virus.
Differential short-term and long-term metabolic and cytokine responses to infection of severe fever with thrombocytopenia syndrome virus.
Coordination of oxysterol binding protein 1 and VAP-A/B modulates the generation of cholesterol and viral inclusion bodies to promote grass carp reovirus replication.
Scavenging H2O2 of plant host by saliva catalase of leafhopper vector benefits viral transmission.
A New Methodology for the Oxygen Measurement in Lung Tissue of an Aged Ferret Model Proves Hypoxia during COVID-19.
Statins enhance extracellular release of hepatitis C virus particles through ERK5 activation.
SLC38A9 regulates SARS-CoV-2 viral entry.

J Leukoc Biol. 2024 Aug 01. pii: qiae170. [Epub ahead of print]

Unlocking Secrets: Lipid Metabolism and Lipid Droplet Crucial Roles in SARS-CoV-2 Infection and the Immune Response.

Vinicius Cardoso Soares, Suelen Silva Gomes Dias, Julia Cunha Santos, Patrícia T Bozza.

  Lipid droplets (LD) are crucial for maintaining lipid and energy homeostasis within cells. LDs are highly dynamic organelles that present a phospholipid monolayer rich in neutral lipids. Additionally, LDs are associated with structural and non-structural proteins, rapidly mobilizing lipids for various biological processes. Lipids play a pivotal role during viral infection, participating during viral membrane fusion, viral replication, and assembly, endocytosis, and exocytosis. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection often induces LD accumulation, which is used as a source of energy for the replicative process. These findings suggest that LDs are a hallmark of viral infection, including SARS-CoV-2 infection. Moreover, LD participates in the inflammatory process and cell signaling, activating pathways related to innate immunity and cell death. Accumulating evidence demonstrates that LD induction by SARS-CoV-2 is a highly coordinated process, aiding replication and evading the immune system, and may contribute to the different cell death process observed in various studies. Nevertheless, recent research in the field of LDs suggests these organelles according to the pathogen and infection conditions may also play roles in immune and inflammatory responses, protecting the host against viral infection. Understanding how SARS-CoV-2 influences LD biogenesis is crucial for developing novel drugs or repurposing existing ones. By targeting host lipid metabolic pathways exploited by the virus, it is possible to impact viral replication and inflammatory responses. This review seeks to discuss and analyze the role of LDs during SARS-CoV-2 infection, specifically emphasizing their involvement in viral replication and the inflammatory response.

Keywords:  Inflammation; Lipid droplet; Lipid metabolism; SARS-CoV-2

DOI:  https://doi.org/10.1093/jleuko/qiae170
Biochim Biophys Acta Mol Basis Dis. 2024 Jul 27. pii: S0925-4439(24)00437-X. [Epub ahead of print]1870(7): 167444

G6PD deficiency mediated impairment of iNOS and lysosomal acidification affecting phagocytotic clearance in microglia in response to SARS-CoV-2.

Abir Mondal, Subrata Munan, Isha Saxena, Soumyadeep Mukherjee, Prince Upadhyay, Nutan Gupta, Waseem Dar, Animesh Samanta, Shailja Singh, Soumya Pati.

  The glucose-6-phosphate dehydrogenase (G6PD) deficiency is X-linked and is the most common enzymatic deficiency disorder globally. It is a crucial enzyme for the pentose phosphate pathway and produces NADPH, which plays a vital role in regulating the oxidative stress of many cell types. The deficiency of G6PD primarily causes hemolytic anemia under oxidative stress triggered by food, drugs, or infection. G6PD-deficient patients infected with SARS-CoV-2 showed an increase in hemolysis and thrombosis. Patients also exhibited prolonged COVID-19 symptoms, ventilation support, neurological impacts, and high mortality. However, the mechanism of COVID-19 severity in G6PD deficient patients and its neurological manifestation is still ambiguous. Here, using a CRISPR-edited G6PD deficient human microglia cell culture model, we observed a significant reduction in NADPH level and an increase in basal reactive oxygen species (ROS) in microglia. Interestingly, the deficiency of the G6PD-NAPDH axis impairs induced nitric oxide synthase (iNOS) mediated nitric oxide (NO) production, which plays a fundamental role in inhibiting viral replication. Surprisingly, we also observed that the deficiency of the G6PD-NADPH axis reduced lysosomal acidification and free radical production, further abrogating the lysosomal clearance of viral particles. Thus, impairment of NO production, lysosomal functions, and redox dysregulation in G6PD deficient microglia altered innate immune response, promoting the severity of SARS-CoV-2 pathogenesis.

Keywords:  G6PD deficiency; Lysosomes; Microglia; Nitric oxide; SARS-CoV-2

DOI:  https://doi.org/10.1016/j.bbadis.2024.167444
Front Immunol. 2024 ;15 1414594

Hepatic macrophage niche: a bridge between HBV-mediated metabolic changes with intrahepatic inflammation.

Jun Wang, Hongzhou Lu, Qian Li.

  Hepatitis B Virus (HBV) is a stealthy and insidious pathogen capable of inducing chronic necro-inflammatory liver disease and hepatocellular carcinoma (HCC), resulting in over one million deaths worldwide per year. The traditional understanding of Chronic Hepatitis B (CHB) progression has focused on the complex interplay among ongoing virus replication, aberrant immune responses, and liver pathogenesis. However, the dynamic progression and crucial factors involved in the transition from HBV infection to immune activation and intrahepatic inflammation remain elusive. Recent insights have illuminated HBV's exploitation of the sodium taurocholate co-transporting polypeptide (NTCP) and manipulation of the cholesterol transport system shared between macrophages and hepatocytes for viral entry. These discoveries deepen our understanding of HBV as a virus that hijacks hepatocyte metabolism. Moreover, hepatic niche macrophages exhibit significant phenotypic and functional diversity, zonal characteristics, and play essential roles, either in maintaining liver homeostasis or contributing to the pathogenesis of chronic liver diseases. Therefore, we underscore recent revelations concerning the importance of hepatic niche macrophages in the context of viral hepatitis. This review particularly emphasizes the significant role of HBV-induced metabolic changes in hepatic macrophages as a key factor in the transition from viral infection to immune activation, ultimately culminating in liver inflammation. These metabolic alterations in hepatic macrophages offer promising targets for therapeutic interventions and serve as valuable early warning indicators, shedding light on the disease progression.

Keywords:  HBV; hepatic macrophage niches; lipid metabolism (fatty acids); liver inflammation; metabolism

DOI:  https://doi.org/10.3389/fimmu.2024.1414594
Int J Biol Macromol. 2024 Jul 30. pii: S0141-8130(24)05130-4. [Epub ahead of print] 134325

Autophagy promotes replication of Bombyx mori Nucleopolyhedrovirus in insect cells.

Shigang Fei, Junming Xia, Nasir Mehmood, Yeyuan Wang, Min Feng, Jingchen Sun.

  BmNPV is a pathogen that infects silkworms exclusively. Although the interaction between BmNPV and the silkworm has been widely noticed and studied, its specific mechanism has still not been elucidated. In this study, we investigated whether BmNPV infection induces the onset of host cell autophagy to enhance viral replication. We observed a significant increase in double- or single-membrane vesicles and an accumulation of enhanced green fluorescent protein eGFP-ATG8 spots in virus-infected cells 72 h after BmNPV infection, accompanied by a conversion of ATG8 to ATG8-PE. In addition, we observed changes in the mitochondrial morphology of BmN cells after BmNPV infection by transmission electron microscopy. By detecting the mitochondrial membrane potential, we found that BmNPV infection resulted in the decrease of mitochondrial membrane potential, and that eGFP-ATG8 was able to co-localise with mitochondria after virus infection of the cells. Moreover, the use of drugs to regulate the occurrence of autophagy affects the replication of cellular BmNPV. Our data demonstrates that BmNPV infection induces host cell autophagy and leads to cellular mitochondrial damage, which in turn may lead to mitochondrial autophagy, and that BmNPV-induced host autophagy promotes its replication in cells. These findings will provide clues for further understanding of host-virus interactions.

Keywords:  Autophagy; BmNPV; Mitochondrial membrane; Silkworm

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.134325
Vet Res. 2024 Aug 02. 55(1): 97

In vitro and in vivo evaluation of thapsigargin as an antiviral agent against transmissible gastroenteritis virus.

Yang Li, Yuanyuan Liu, Yunhang Zhang, Chen Tan, Yifei Cai, Yue Zhang, Jianing Chen, Yuguang Fu, Guangliang Liu.

  Swine enteric coronaviruses (SeCoVs) pose a significant threat to the global pig industry, but no effective drugs are available for treatment. Previous research has demonstrated that thapsigargin (TG), an ER stress inducer, has broad-spectrum antiviral effects on human coronaviruses. In this study, we investigated the impact of TG on transmissible gastroenteritis virus (TGEV) infection using cell lines, porcine intestinal organoid models, and piglets. The results showed that TG effectively inhibited TGEV replication both in vitro and ex vivo. Furthermore, animal experiments demonstrated that oral administration of TG inhibited TGEV infection in neonatal piglets and relieved TGEV-associated tissue injury. Transcriptome analyses revealed that TG improved the expression of the ER-associated protein degradation (ERAD) component and influenced the biological processes related to secretion, nutrient responses, and epithelial cell differentiation in the intestinal epithelium. Collectively, these results suggest that TG is a potential novel oral antiviral drug for the clinical treatment of TGEV infection, even for infections caused by other SeCoVs.

Keywords:  ERS; TGEV; antiviral drug; intestinal organoids; thapsigargin

DOI:  https://doi.org/10.1186/s13567-024-01359-x
Metabolomics. 2024 Jul 27. 20(4): 84

Differential short-term and long-term metabolic and cytokine responses to infection of severe fever with thrombocytopenia syndrome virus.

Zhiyi Zhang, Yafei Hu, Xiang Zheng, Cairong Chen, Yishuang Zhao, Haijiang Lin, Na He.

   INTRODUCTION: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus (SFTSV), which has a wide geographic distribution. The primary clinical manifestations of SFTS are fever and thrombocytopenia, with multiorgan failure being the leading cause of death. While most patients recover with treatment, little is known about the potential long-term metabolic effects of SFTSV infection.
OBJECTIVES: This study aimed to shed light on dysregulated metabolic pathways and cytokine responses following SFTSV infection, which pose significant risks to the short-term and long-term health of affected individuals.
METHODS: Fourteen laboratory-confirmed clinical SFTS cases and thirty-eight healthy controls including 18 SFTSV IgG-positive and 20 IgG-negative individuals were recruited from Taizhou city of Zhejiang province, Eastern China. Inclusion criteria of healthy controls included residing in the study area for at least one year, absence of fever or other symptoms in the past two weeks, and no history of SFTS diagnosis. Ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to obtain the relative abundance of plasma metabolites. Short-term metabolites refer to transient alterations present only during SFTSV infection, while long-term metabolites persistently deviate from normal levels even after recovery from SFTSV infection. Additionally, the concentrations of 12 cytokines were quantified through fluorescence intensity measurements. Differential metabolites were screened using orthogonal projections to latent structures discriminant analysis (OPLS-DA) and the Wilcoxon rank test. Metabolic pathway analysis was performed using MetaboAnalyst. Between-group differences of metabolites and cytokines were examined using the Wilcoxon rank test. Correlation matrices between identified metabolites and cytokines were analyzed using Spearman's method.
RESULTS AND CONCLUSIONS: We screened 122 long-term metabolites and 108 short-term metabolites by analytical comparisons and analyzed their correlations with 12 cytokines. Glycerophospholipid metabolism (GPL) was identified as a significant short-term metabolic pathway suggesting that the activation of GPL might be linked to the self-replication of SFTSV, whereas pentose phosphate pathway and alanine, aspartate, and glutamate metabolism were indicated as significant long-term metabolic pathways playing a role in combating long-standing oxidative stress in the patients. Furthermore, our study suggests a new perspective that α-ketoglutarate could serve as a dietary supplement to protect recovering SFTS patients.

Keywords:  Cytokines; Metabolic pathway; Metabolomics; SFTSV

DOI:  https://doi.org/10.1007/s11306-024-02150-x
Front Immunol. 2024 ;15 1419321

Coordination of oxysterol binding protein 1 and VAP-A/B modulates the generation of cholesterol and viral inclusion bodies to promote grass carp reovirus replication.

Jia Qi Li, Jie Zhang, Yang Chen, Tao Le, Ming Xian Chang.

  Similar to other RNA viruses, grass carp reovirus, the causative agent of the hemorrhagic disease, replicates in cytoplasmic viral inclusion bodies (VIBs), orchestrated by host proteins and lipids. The host pathways that facilitate the formation and function of GCRV VIBs are poorly understood. This work demonstrates that GCRV manipulates grass carp oxysterol binding protein 1 (named as gcOSBP1) and vesicle-associated membrane protein-associated protein A/B (named as gcVAP-A/B), 3 components of cholesterol transport pathway, to generate VIBs. By siRNA-mediated knockdown, we demonstrate that gcOSBP1 is an essential host factor for GCRV replication. We reveal that the nonstructural proteins NS80 and NS38 of GCRV interact with gcOSBP1, and that the gcOSBP1 is recruited by NS38 and NS80 for promoting the generation of VIBs. gcOSBP1 increases the expression of gcVAP-A/B and promotes the accumulation of intracellular cholesterol. gcOSBP1 also interacts with gcVAP-A/B for forming gcOSBP1-gcVAP-A/B complexes, which contribute to enhance the accumulation of intracellular cholesterol and gcOSBP1-mediated generation of VIBs. Inhibiting cholesterol accumulation by lovastatin can completely abolish the effects of gcOSBP1 and/or gcVAP-A/B in promoting GCRV infection, suggesting that cholesterol accumulation is vital for gcOSBP1- and/or gcVAP-A/B-mediated GCRV replication. Thus, our results, which highlight that gcOSBP1 functions in the replication of GCRV via its interaction with essential viral proteins for forming VIBs and with host gcVAP-A/B, provide key molecular targets for obtaining anti-hemorrhagic disease grass carp via gene editing technology.

Keywords:  VAP-A/B; cholesterol; grass carp OSBP1; grass carp reovirus; viral inclusion bodies

DOI:  https://doi.org/10.3389/fimmu.2024.1419321
New Phytol. 2024 Jul 29.

Scavenging H2O2 of plant host by saliva catalase of leafhopper vector benefits viral transmission.

Hongxiang Zhang, Yunhua Chi, Siyu Chen, Xinwei Lv, Dongsheng Jia, Qian Chen, Taiyun Wei.

  Catalase (CAT) is the main reactive oxygen species (ROS)-scavenging enzyme in plants and insects. However, it remains elusive whether and how insect saliva CAT suppresses ROS-mediated plant defense, thereby promoting initial virus transmission by insect vectors. Here, we investigated how leafhopper Recilia dorsalis catalase (RdCAT) was secreted from insect salivary glands into rice phloem, and how it was perceived by rice chaperone NO CATALASE ACTIVITY1 (OsNCA1) to scavenge excessive H2O2 during insect-to-plant virus transmission. We found that the interaction of OsNCA1 with RdCAT activated its enzymatic activity to decompose H2O2 in rice plants during leafhopper feeding. However, initial insect feeding did not significantly change rice CATs transcripts. Knockout of OsNCA1 in transgenic lines decreased leafhopper feeding-activated CAT activity and caused higher H2O2 accumulation. A devastating rice reovirus activated RdCAT expression and promoted the cosecretion of virions and RdCAT into leafhopper salivary cavities and ultimately into the phloem. Virus-mediated increase of RdCAT secretion suppressed excessive H2O2, thereby promoting host attractiveness to insect vectors and initial virus transmission. Our findings provide insights into how insect saliva CAT is secreted and perceived by plant chaperones to suppress the early H2O2 burst during insect feeding, thereby facilitating viral transmission.

Keywords:  H2O2; catalase; leafhopper; rice; saliva proteins; viral transmission

DOI:  https://doi.org/10.1111/nph.19988
Am J Respir Cell Mol Biol. 2024 Aug;71(2): 146-153

A New Methodology for the Oxygen Measurement in Lung Tissue of an Aged Ferret Model Proves Hypoxia during COVID-19.

Katrin Wirz, Claudia Schulz, Franz Söbbeler, Federico Armando, Georg Beythien, Ingo Gerhauser, Nicole de Buhr, Veronika Pilchová, Christian Meyer Zu Natrup, Wolfgang Baumgärtner, Sabine Kästner, Maren von Köckritz-Blickwede.

  Oxygen as a key element has a high impact on cellular processes. Infection with a pathogen such as SARS-CoV-2 and after inflammation may lead to hypoxic conditions in tissue that impact cellular responses. To develop optimized translational in vitro models for a better understanding of physiologic and pathophysiologic oxygen conditions, it is a prerequisite to determine oxygen concentrations generated in vivo. Our study objective was the establishment of an invasive method for oxygen measurements using a luminescence-based microsensor to determine the dissolved oxygen in the lung tissue of ferrets as animal models for SARS-CoV-2 research. By way of analogy to humans, aged ferrets are more likely to show clinical signs after SARS-CoV-2 infection than are young animals. To investigate oxygen concentrations during a respiratory viral infection, we intratracheally infected nine aged (3-yr-old) ferrets with SARS-CoV-2. The aged SARS-CoV-2-infected ferrets showed mild to moderate clinical signs associated with prolonged viral RNA shedding until 14 days postinfection. SARS-CoV-2-infected ferrets showed histopathologic lung lesion scores that significantly negatively correlated with oxygen concentrations in lung tissue. At 4 days postinfection, oxygen concentrations in lung tissue were significantly lower (mean percentage O2, 3.89 ≙ ≈ 27.78 mm Hg) than in the negative control group (mean percentage O2, 8.65 ≙ ≈ 61.4 mm Hg). In summary, we succeeded in determining the pathophysiologic oxygen conditions in the lung tissue of aged SARS-CoV-2-infected ferrets.

Keywords:  SARS-CoV-2; animal model; ferret; hypoxia; oxygen measurement

DOI:  https://doi.org/10.1165/rcmb.2024-0005MA
Microbiol Immunol. 2024 Jul 29.

Statins enhance extracellular release of hepatitis C virus particles through ERK5 activation.

Chie Aoki-Utsubo, Masanori Kameoka, Lin Deng, Muhammad Hanafi, Beti Ernawati Dewi, Pratiwi Sudarmono, Takaji Wakita, Hak Hotta.

  Statins, such as lovastatin, have been known to inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Statins were reported to moderately suppress hepatitis C virus (HCV) replication in cultured cells harboring HCV RNA replicons. We report here using an HCV cell culture (HCVcc) system that high concentrations of lovastatin (5-20 μg/mL) markedly enhanced the release of HCV infectious particles (virion) in the culture supernatants by up to 40 times, without enhancing HCV RNA replication, HCV protein synthesis, or HCV virion assembly in the cells. We also found that lovastatin increased the phosphorylation (activation) level of extracellular-signal-regulated kinase 5 (ERK5) in both the infected and uninfected cells in a dose-dependent manner. The lovastatin-mediated increase of HCV virion release was partially reversed by selective ERK5 inhibitors, BIX02189 and XMD8-92, or by ERK5 knockdown using small interfering RNA (siRNA). Moreover, we demonstrated that other cholesterol-lowering statins, but not dehydrolovastatin that is incapable of inhibiting HMG-CoA reductase and activating ERK5, enhanced HCV virion release to the same extent as observed with lovastatin. These results collectively suggest that statins markedly enhance HCV virion release from infected cells through HMG-CoA reductase inhibition and ERK5 activation.

Keywords:  ERK5 activation; HMG‐CoA reductase inhibition; hepatitis C virus; statin; virion release

DOI:  https://doi.org/10.1111/1348-0421.13166
iScience. 2024 Jul 19. 27(7): 110387

SLC38A9 regulates SARS-CoV-2 viral entry.

Gaurav Datta, Neda Rezagholizadeh, Wendie A Hasler, Nabab Khan, Xuesong Chen.

  SARS-CoV-2 viral entry into host cells depends on the cleavage of spike (S) protein into S1 and S2 proteins. Such proteolytic cleavage by furin results in the exposure of a multibasic motif on S1, which is critical for SARS-CoV-2 viral infection and transmission; however, how such a multibasic motif contributes to the infection of SARS-CoV-2 remains elusive. Here, we demonstrate that the multibasic motif on S1 is critical for its interaction with SLC38A9, an endolysosome-resident arginine sensor. SLC38A9 knockdown prevents S1-induced endolysosome de-acidification and blocks the S protein-mediated entry of pseudo-SARS-CoV-2 in Calu-3, U87MG, Caco-2, and A549 cells. Our findings provide a novel mechanism in regulating SARS-CoV-2 viral entry; S1 present in endolysosome lumen could interact with SLC38A9, which mediates S1-induced endolysosome de-acidification and dysfunction, facilitating the escape of SARS-CoV-2 from endolysosomes and enhancing viral entry.

Keywords:  Molecular biology; Virology

DOI:  https://doi.org/10.1016/j.isci.2024.110387