bims-mevinf 2023-04-30 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023–04–30
eleven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2/ARE Pathway, and Induce Unfolded Protein Response.
The Role of Cytosolic Lipid Droplets in Hepatitis C Virus Replication, Assembly, and Release.
Zika virus-induces metabolic alterations in fetal neuronal progenitors that could influence in neurodevelopment during early pregnancy.
Persistent Coxsackievirus B3 Infection in Pancreatic Ductal Cells In Vitro Downregulates Cellular Polyamine Metabolism.
Early-Phase Drive to the Precursor Pool: Chloroviruses Dive into the Deep End of Nucleotide Metabolism.
Lipid Accumulation in Host Cells Promotes SARS-CoV-2 Replication.
NRF2 Antioxidant Response and Interferon-Stimulated Genes Are Differentially Expressed in Respiratory-Syncytial-Virus- and Rhinovirus-Infected Hospitalized Children.
A platelet lipidomics signature in patients with COVID-19.
Astrovirus replication is dependent on induction of double membrane vesicles through a PI3K-dependent, LC3-independent pathway.
Reticulons promote formation of ER-derived double-membrane vesicles that facilitate SARS-CoV-2 replication.
The Influence of Metabolic Factors in Patients with Chronic Viral Hepatitis C Who Received Oral Antiviral Treatment.

Antioxidants (Basel). 2023 Apr 21. pii: 974. [Epub ahead of print]12(4):

Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2/ARE Pathway, and Induce Unfolded Protein Response.

Olga A Smirnova, Olga N Ivanova, Furkat Mukhtarov, Vladimir T Valuev-Elliston, Artemy P Fedulov, Petr M Rubtsov, Natalia F Zakirova, Sergey N Kochetkov, Birke Bartosch, Alexander V Ivanov.

  Hepatitis delta virus (HDV) is a viroid-like satellite that may co-infect individuals together with hepatitis B virus (HBV), as well as cause superinfection by infecting patients with chronic hepatitis B (CHB). Being a defective virus, HDV requires HBV structural proteins for virion production. Although the virus encodes just two forms of its single antigen, it enhances the progression of liver disease to cirrhosis in CHB patients and increases the incidence of hepatocellular carcinoma. HDV pathogenesis so far has been attributed to virus-induced humoral and cellular immune responses, while other factors have been neglected. Here, we evaluated the impact of the virus on the redox status of hepatocytes, as oxidative stress is believed to contribute to the pathogenesis of various viruses, including HBV and hepatitis C virus (HCV). We show that the overexpression of large HDV antigen (L-HDAg) or autonomous replication of the viral genome in cells leads to increased production of reactive oxygen species (ROS). It also leads to the upregulated expression of NADPH oxidases 1 and 4, cytochrome P450 2E1, and ER oxidoreductin 1α, which have previously been shown to mediate oxidative stress induced by HCV. Both HDV antigens also activated the Nrf2/ARE pathway, which controls the expression of a spectrum of antioxidant enzymes. Finally, HDV and its large antigen also induced endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR). In conclusion, HDV may enhance oxidative and ER stress induced by HBV, thus aggravating HBV-associated pathologies, including inflammation, liver fibrosis, and the development of cirrhosis and hepatocellular carcinoma.

Keywords:  NADPH oxidase; Nrf2; hepatitis delta virus; oxidative stress; unfolded protein response

DOI:  https://doi.org/10.3390/antiox12040974
Biomed Res Int. 2023 ;2023 5156601

The Role of Cytosolic Lipid Droplets in Hepatitis C Virus Replication, Assembly, and Release.

Abdullah A Awadh.

The hepatitis C virus (HCV) causes chronic hepatitis by establishing a persistent infection. Patients with chronic hepatitis frequently develop hepatic cirrhosis, which can lead to liver cancer-the progressive liver damage results from the host's immune response to the unresolved infection. The HCV replication process, including the entry, replication, assembly, and release stages, while the virus circulates in the bloodstream, it is intricately linked to the host's lipid metabolism, including the dynamic of the cytosolic lipid droplets (cLDs). This review article depicts how this interaction regulates viral cell tropism and aids immune evasion by coining viral particle characteristics. cLDs are intracellular organelles that store most of the cytoplasmic components of neutral lipids and are assumed to play an increasingly important role in the pathophysiology of lipid metabolism and host-virus interactions. cLDs are involved in the replication of several clinically significant viruses, where viruses alter the lipidomic profiles of host cells to improve viral life cycles. cLDs are involved in almost every phase of the HCV life cycle. Indeed, pharmacological modulators of cholesterol synthesis and intracellular trafficking, lipoprotein maturation, and lipid signaling molecules inhibit the assembly of HCV virions. Likewise, small-molecule inhibitors of cLD-regulating proteins inhibit HCV replication. Thus, addressing the molecular architecture of HCV replication will aid in elucidating its pathogenesis and devising preventive interventions that impede persistent infection and prevent disease progression. This is possible via repurposing the available therapeutic agents that alter cLDs metabolism. This review highlights the role of cLD in HCV replication.

DOI: https://doi.org/10.1155/2023/5156601
Biol Open. 2023 Apr 15. pii: bio059889. [Epub ahead of print]12(4):

Zika virus-induces metabolic alterations in fetal neuronal progenitors that could influence in neurodevelopment during early pregnancy.

Javier Gilbert-Jaramillo, Ujang Purnama, Zoltán Molnár, William S James.

  Cortical development consists of an orchestrated process in which progenitor cells exhibit distinct fate restrictions regulated by time-dependent activation of energetic pathways. Thus, the hijacking of cellular metabolism by Zika virus (ZIKV) to support its replication may contribute to damage in the developing fetal brain. Here, we showed that ZIKV replicates differently in two glycolytically distinct pools of cortical progenitors derived from human induced pluripotent stem cells (hiPSCs), which resemble the metabolic patterns of quiescence (early hi-NPCs) and immature brain cells (late hi-NPCs) in the forebrain. This differential replication alters the transcription of metabolic genes in both pools of cortical progenitors but solely upregulates the glycolytic capacity of early hi-NPCs. Analysis using Imagestream® revealed that, during early stages of ZIKV replication, in early hi-NPCs there is an increase in lipid droplet abundance and size. This stage of ZIKV replication significantly reduced the mitochondrial distribution in both early and late hi-NPCs. During later stages of ZIKV replication, late hi-NPCs show reduced mitochondrial size and abundance. The finding that there are alterations of cellular metabolism during ZIKV infection which are specific to pools of cortical progenitors at different stages of maturation may help to explain the differences in brain damage over each trimester.

Keywords:  Fetal neurodevelopment; Metabolism; Neurometabolism; Neuronal progenitors; ZIKV; Zika virus

DOI:  https://doi.org/10.1242/bio.059889
mSphere. 2023 Apr 25. e0003623

Persistent Coxsackievirus B3 Infection in Pancreatic Ductal Cells In Vitro Downregulates Cellular Polyamine Metabolism.

Vincent Mastrodomenico, Natalie J LoMascolo, Mason R Firpo, Maria Del Mar Villanueva Guzman, Adam Zaporowski, Bryan C Mounce.

  Picornaviruses infect a wide variety of cell types in vitro, with rapid replication kinetics and pronounced cytopathic effect. Coxsackievirus B3 (CVB3) can also establish a persistent infection in vivo that can lead to pathology, including dilated cardiomyopathy and myocarditis. One model system to study persistent infection is the pancreatic ductal cell line PANC-1, which CVB3 infects and is maintained indefinitely. We have characterized this model for CVB3 infection to study persistent infection for over 6 months. We find that CVB3 rapidly replicates within PANC-1 cells without robust cytopathic effect, and after 1 month in culture, titers stabilize. We find that infection does not significantly affect cellular viability. Persistent virus reverts to lytic infection when transferred to Huh7 or Vero cells. We find that persistent CVB3 adapts to PANC-1 cells via mutation of its capsid proteins and, curiously, the viral polymerase (3Dpol) to generate a high-fidelity polymerase. Persistent infection is associated with reduced cleavage of eIF4G, reduced plaque size, and decreasing particle infectivity. We further find that polyamine metabolism is altered in persistently infected cells, with the rate-limiting enzyme ornithine decarboxylase (ODC1) reduced in translation. We further find that targeting polyamine synthesis reduces persistent infection without affecting the viability of the PANC-1 cells. Finally, we find that viral fidelity is essential to maintaining CVB3 infection, and targeting viral fidelity reduces persistent virus infection. Together, these data highlight a novel role for polyamines and fidelity in persistent CVB3 infection and suggest avenues for therapeutic development to target persistent infection. IMPORTANCE Enteroviruses are significant human pathogens that can cause severe disease, including cardiomyopathies. Viruses like coxsackievirus B3 (CVB3) can cause tissue damage by lytically infecting cells; however, CVB3 can also persistently infect, which has been associated with several pathologies. Studying persistent infection in vitro is challenging, as CVB3 lytically infects most cellular model systems. Here, we show that CVB3 establishes persistent infection in pancreatic ductal cells in vitro, similar to prior studies on other coxsackieviruses. We also show that this infection results in adaptation of the virus to these cells, as well as changes to cellular metabolism of polyamines.

Keywords:  coxsackievirus; enterovirus; pancreatic ductal cells; persistence; polyamines

DOI:  https://doi.org/10.1128/msphere.00036-23
Viruses. 2023 Mar 31. pii: 911. [Epub ahead of print]15(4):

Early-Phase Drive to the Precursor Pool: Chloroviruses Dive into the Deep End of Nucleotide Metabolism.

David D Dunigan, Irina V Agarkova, Ahmed Esmael, Sophie Alvarez, James L Van Etten.

  Viruses face many challenges on their road to successful replication, and they meet those challenges by reprogramming the intracellular environment. Two major issues challenging Paramecium bursaria chlorella virus 1 (PBCV-1, genus Chlorovirus, family Phycodnaviridae) at the level of DNA replication are (i) the host cell has a DNA G+C content of 66%, while the virus is 40%; and (ii) the initial quantity of DNA in the haploid host cell is approximately 50 fg, yet the virus will make approximately 350 fg of DNA within hours of infection to produce approximately 1000 virions per cell. Thus, the quality and quantity of DNA (and RNA) would seem to restrict replication efficiency, with the looming problem of viral DNA synthesis beginning in only 60-90 min. Our analysis includes (i) genomics and functional annotation to determine gene augmentation and complementation of the nucleotide biosynthesis pathway by the virus, (ii) transcriptional profiling of these genes, and (iii) metabolomics of nucleotide intermediates. The studies indicate that PBCV-1 reprograms the pyrimidine biosynthesis pathway to rebalance the intracellular nucleotide pools both qualitatively and quantitatively, prior to viral DNA amplification, and reflects the genomes of the progeny virus, providing a successful road to virus infection.

Keywords:  algae; augmenting/auxiliary metabolic genes; chlorovirus; genome-to-phenome; giant virus; metabolic reprogramming; nucleotide biosynthesis; pyrimidine biosynthesis; virus

DOI:  https://doi.org/10.3390/v15040911
Viruses. 2023 Apr 21. pii: 1026. [Epub ahead of print]15(4):

Lipid Accumulation in Host Cells Promotes SARS-CoV-2 Replication.

Tatjana Seitz, Christian Setz, Pia Rauch, Ulrich Schubert, Claus Hellerbrand.

  Coronavirus disease-19 (COVID-19) is still affecting the lives of people around the globe and remains a major public health threat. Lipid levels in the host cells have been shown to promote SARS-CoV-2 replication, and since the start of COVID-19 pandemic, several studies have linked obesity and other components of the metabolic syndrome with severity of illness, as well as mortality in patients with COVID-19. The aim of this study was to obtain insights into the pathophysiological mechanisms of these associations. First, we established an in vitro model simulating high fatty acid levels and showed that this situation induced the uptake of fatty acids and triglyceride accumulation in human Calu-3 lung cells. Importantly, we found that lipid accumulation significantly enhanced the replication of SARS-CoV-2 Wuhan type or the variant of concern, Delta, in Calu-3 cells. In summary, these findings indicate that hyperlipidemia as found in patients with obesity promotes viral replication and herewith the disease course of COVID-19.

Keywords:  COVID-19; SARS-CoV-2; coronavirus; fatty acid; hyperlipidemia; obesity; variant of concern delta

DOI:  https://doi.org/10.3390/v15041026
Pathogens. 2023 Apr 09. pii: 577. [Epub ahead of print]12(4):

NRF2 Antioxidant Response and Interferon-Stimulated Genes Are Differentially Expressed in Respiratory-Syncytial-Virus- and Rhinovirus-Infected Hospitalized Children.

Leonardo Sorrentino, Walter Toscanelli, Matteo Fracella, Marta De Angelis, Federica Frasca, Carolina Scagnolari, Laura Petrarca, Raffaella Nenna, Fabio Midulla, Anna Teresa Palamara, Lucia Nencioni, Alessandra Pierangeli.

  Respiratory diseases caused by respiratory syncytial virus (RSV) and human rhinovirus (HRV) are frequent causes of the hospitalization of children; nonetheless, RSV is responsible for the most severe and life-threatening illnesses. Viral infection triggers an inflammatory response, activating interferon (IFN)-mediated responses, including IFN-stimulated genes (ISG) expression with antiviral and immunomodulatory activities. In parallel, the reactive oxygen species (ROS) production activates nuclear factor erythroid 2-related factor 2 (NRF2), whose antioxidant activity can reduce inflammation by interacting with the NF-kB pathway and the IFN response. To clarify how the interplay of IFN and NRF2 may impact on clinical severity, we enrolled children hospitalized for bronchiolitis and pneumonia, and measured gene expression of type-I and III IFNs, of several ISGs, of NRF2 and antioxidant-related genes, i.e., glucose-6-phosphate dehydrogenase (G6PD), heme oxygenase 1 (HO1), and NAD(P)H dehydrogenase [Quinone] 1 (NQO1) in RSV- (RSV-A N = 33 and RSV-B N = 30) and HRV (N = 22)-positive respiratory samples. NRF2 and HO1 expression is significantly elevated in children with HRV infection compared to RSV (p = 0.012 and p = 0.007, respectively), whereas ISG15 and ISG56 expression is higher in RSV-infected children (p = 0.016 and p = 0.049, respectively). Children admitted to a pediatric intensive care unit (PICU) had reduced NRF2 expression (p = 0.002). These data suggest, for the first time, that lower activation of the NRF2 antioxidant response in RSV-infected infants may contribute to bronchiolitis severity.

Keywords:  NRF2; antioxidant response; human rhinovirus; interferon; respiratory syncytial virus

DOI:  https://doi.org/10.3390/pathogens12040577
Platelets. 2023 Dec;34(1): 2200847

A platelet lipidomics signature in patients with COVID-19.

Laura Goracci, Eleonora Petito, Alessandra Di Veroli, Emanuela Falcinelli, Caterina Bencivenga, Elisa Giglio, Cecilia Becattini, Edoardo De Robertis, Gaetano Vaudo, Paolo Gresele.

  Ischemic cardiovascular and venous thromboembolic events are a frequent cause of death in severe COVID-19 patients. Platelet activation plays a key role in these complications, however platelet lipidomics have not been studied yet. The aim of our pilot investigation was to perform a preliminary study of platelet lipidomics in COVID-19 patients compared to healthy subjects. Lipid extraction and identification of ultrapurified platelets from eight hospitalized COVID-19 patients and eight age- and sex-matched healthy controls showed a lipidomic pattern almost completely separating COVID-19 patients from healthy controls. In particular, a significant decrease of ether phospholipids and increased levels of ganglioside GM3 were observed in platelets from COVID-19 patients. In conclusion, our study shows for the first time that platelets from COVID-19 patients display a different lipidomics signature distinguishing them from healthy controls, and suggests that altered platelet lipid metabolism may play a role in viral spreading and in the thrombotic complications of COVID-19.

Keywords:  COVID-19; Platelet lipidomics

DOI:  https://doi.org/10.1080/09537104.2023.2200847
bioRxiv. 2023 Apr 12. pii: 2023.04.11.536492. [Epub ahead of print]

Astrovirus replication is dependent on induction of double membrane vesicles through a PI3K-dependent, LC3-independent pathway.

Theresa Bub, Virginia Hargest, Shaoyuan Tan, Maria Smith, Ana Vazquez-Pagan, Tim Flerlage, Pamela H Brigleb, Victoria Meliopoulos, Brett Lindenbach, Valerie Cortez, Jeremy Chase Crawford, Stacey Schultz-Cherry.

Human astrovirus is a positive sense, single stranded RNA virus. Astrovirus infection causes gastrointestinal symptoms and can lead to encephalitis in immunocompromised patients. Positive strand RNA viruses typically utilize host intracellular membranes to form replication organelles, which are potential antiviral targets. Many of these replication organelles are double membrane vesicles (DMVs). Here we show that astrovirus infection leads to an increase in DMV formation, and this process is replication-dependent. Our data suggest that astrovirus infection induces rearrangement of endoplasmic reticulum fragments, which may become the origin for DMV formation. Transcriptional data suggested that formation of DMVs during astrovirus infection requires some early components of the autophagy machinery. Results indicate that the upstream class III phosphatidylinositol 3-kinase (PI3K) complex, but not LC3 conjugation machinery, is utilized in DMV formation. Inhibition of the PI3K complex leads to significant reduction in viral replication and release from cells. Elucidating the role of autophagy machinery in DMV formation during astrovirus infection reveals a potential target for therapeutic intervention for immunocompromised patients.
Importance: These studies provide critical new evidence that astrovirus replication requires formation of double membrane vesicles, which utilize class III PI3K, but not LC3 conjugation autophagy machinery for biogenesis. These results are consistent with replication mechanisms for other positive sense RNA viruses. This suggests that targeting PI3K could be a promising therapeutic option for not only astrovirus, but other positive sense RNA virus infections.

DOI: https://doi.org/10.1101/2023.04.11.536492
J Cell Biol. 2023 Jul 03. pii: e202203060. [Epub ahead of print]222(7):

Reticulons promote formation of ER-derived double-membrane vesicles that facilitate SARS-CoV-2 replication.

Jeffrey M Williams, Yu-Jie Chen, Woo Jung Cho, Andrew W Tai, Billy Tsai.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiologic agent for the global COVID-19 pandemic, triggers the formation of endoplasmic reticulum (ER)-derived replication organelles, including double-membrane vesicles (DMVs), in the host cell to support viral replication. Here, we clarify how SARS-CoV-2 hijacks host factors to construct the DMVs. We show that the ER morphogenic proteins reticulon-3 (RTN3) and RTN4 help drive DMV formation, enabling viral replication, which leads to productive infection. Different SARS-CoV-2 variants, including the delta variant, use the RTN-dependent pathway to promote infection. Mechanistically, our results reveal that the membrane-embedded reticulon homology domain (RHD) of the RTNs is sufficient to functionally support viral replication and physically engage NSP3 and NSP4, two viral non-structural membrane proteins known to induce DMV formation. Our findings thus identify the ER morphogenic RTN3 and RTN4 membrane proteins as host factors that help promote the biogenesis of SARS-CoV-2-induced DMVs, which can act as viral replication platforms.

DOI: https://doi.org/10.1083/jcb.202203060
Metabolites. 2023 Apr 17. pii: 571. [Epub ahead of print]13(4):

The Influence of Metabolic Factors in Patients with Chronic Viral Hepatitis C Who Received Oral Antiviral Treatment.

Oana Irina Gavril, Radu Sebastian Gavril, Florin Mitu, Otilia Gavrilescu, Iolanda Valentina Popa, Diana Tatarciuc, Andrei Drugescu, Andrei Catalin Oprescu, Andreea Gherasim, Laura Mihalache, Irina Mihaela Esanu.

  Hepatic diseases pose a significant public health concern. Regardless of the severity of hepatic fibrosis, treatment is recommended for all chronic hepatitis C virus (HCV) subjects. However, fibrosis and steatosis assessment remains crucial for evaluating the prognosis, progression, and hepatic disease monitoring, particularly following the treatment with direct-acting antivirals (DAAs). The aim of our study was to evaluate the impact of metabolic factors and the extent of hepatic fibrosis and fat accumulation in chronic HCV infection subjects. Additionally, another objective was to investigate modifications regarding fibrosis and steatosis three months after a successful sustained viral response (SVR). A total of 100 patients with compensated cirrhosis and chronic hepatitis C (CHC) were included in our study. These patients received treatment with DAA and underwent Fibromax assessment before and three months post SVR. After DAA treatment, a significant decrease was observed in the degree of hepatic fibrosis and hepatic steatosis. This regression was evident three months following the achievement of SVR. Chronic viral hepatitis C may trigger risk factors for metabolic syndromes, such as obesity and type 2 diabetes mellitus. Conclusions: It is crucial to monitor metabolic factors and take timely measures to prevent or treat metabolic syndrome in patients with chronic viral hepatitis C.

Keywords:  chronic hepatitis C virus; metabolic syndrome; sustained viral response

DOI:  https://doi.org/10.3390/metabo13040571