bims-mevinf 2024-09-15 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024–09–15
eight papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Multi-omics analysis reveals the impact of influenza a virus host adaptation on immune signatures in pig tracheal tissue.
Novel Clinical, Immunological, and Metabolic Features Associated with Persistent Post-Acute COVID-19 Syndrome.
Emergence of dysfunctional neutrophils with a defect in arginase-1 release in severe COVID-19.
RNA-Seq Analysis of Glycolysis Regulation of Avian Leukosis Virus Subgroup J Replication.
Regulation of Hepatitis B Virus Replication by Modulating Endoplasmic Reticulum Stress (ER-Stress).
HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV.
Unraveling the relevance of SARS-Cov-2 infection and ferroptosis within the heart of COVID-19 patients.
SARS-CoV-2 envelope protein alters calcium signaling via SERCA interactions.

Front Immunol. 2024 ;15 1432743

Multi-omics analysis reveals the impact of influenza a virus host adaptation on immune signatures in pig tracheal tissue.

Helena Aagaard Laybourn, Chrysillis Hellemann Polhaus, Charlotte Kristensen, Betina Lyngfeldt Henriksen, Yaolei Zhang, Louise Brogaard, Cathrine Agnete Larsen, Ramona Trebbien, Lars Erik Larsen, Konstantinos Kalogeropoulos, Ulrich Auf dem Keller, Kerstin Skovgaard.

   Introduction: Influenza A virus (IAV) infection is a global respiratory disease, which annually leads to 3-5 million cases of severe illness, resulting in 290,000-650,000 deaths. Additionally, during the past century, four global IAV pandemics have claimed millions of human lives. The epithelial lining of the trachea plays a vital role during IAV infection, both as point of viral entry and replication as well as in the antiviral immune response. Tracheal tissue is generally inaccessible from human patients, which makes animal models crucial for the study of the tracheal host immune response.
Method: In this study, pigs were inoculated with swine- or human-adapted H1N1 IAV to gain insight into how host adaptation of IAV shapes the innate immune response during infection. In-depth multi-omics analysis (global proteomics and RNA sequencing) of the host response in upper and lower tracheal tissue was conducted, and results were validated by microfluidic qPCR. Additionally, a subset of samples was selected for histopathological examination.
Results: A classical innate antiviral immune response was induced in both upper and lower trachea after infection with either swine- or human-adapted IAV with upregulation of genes and higher abundance of proteins associated with viral infection and recognition, accompanied by a significant induction of interferon stimulated genes with corresponding higher proteins concentrations. Infection with the swine-adapted virus induced a much stronger immune response compared to infection with a human-adapted IAV strain in the lower trachea, which could be a consequence of a higher viral load and a higher degree of inflammation.
Discussion: Central components of the JAK-STAT pathway, apoptosis, pyrimidine metabolism, and the cytoskeleton were significantly altered depending on infection with swine- or human-adapted virus and might be relevant mechanisms in relation to antiviral immunity against putative zoonotic IAV. Based on our findings, we hypothesize that during host adaptation, IAV evolve to modulate important host cell elements to favor viral infectivity and replication.

Keywords:  RNA-Seq; global proteomics; host adaptation; host metabolism; immune regulation; influenza A virus

DOI:  https://doi.org/10.3389/fimmu.2024.1432743
Int J Mol Sci. 2024 Sep 06. pii: 9661. [Epub ahead of print]25(17):

Novel Clinical, Immunological, and Metabolic Features Associated with Persistent Post-Acute COVID-19 Syndrome.

Karina Santana-de Anda, Jiram Torres-Ruiz, Nancy R Mejía-Domínguez, Beatriz Alcalá-Carmona, José L Maravillas-Montero, José Carlos Páez-Franco, Ana Sofía Vargas-Castro, Jaquelin Lira-Luna, Emmanuel A Camacho-Morán, Guillermo Juarez-Vega, David Meza-Sánchez, Carlos Núñez-Álvarez, Marina Rull-Gabayet, Diana Gómez-Martín.

  The coronavirus disease 2019 (COVID-19) survivors are frequently observed to present persistent symptoms constituting what has been called "post-acute COVID-19 syndrome" (PACS) or "long COVID-19". Some clinical risk factors have been identified to be associated with PACS development; however, specific mechanisms responsible for PACS pathology remain unknown. This study investigates clinical, immunological, and metabolomic risk factors associated with post-acute COVID-19 syndrome (PACS) in 51 patients, assessed 7-19 months after acute infection. Among the participants, 62.7% were male and 37.2% were female, with an average age of 47.8 years. At the follow-up, 37.2% met the criteria for PACS, revealing significant differences in immunological and metabolomic profiles at the time of acute infection. Patients with PACS were characterized by elevated levels of mature low-density granulocytes (LDGs), interleukin-8 (IL-8), pyruvate, pseudouridine, and cystine. Baseline multivariate analysis showed increased pyruvate and decreased alpha tocopherol levels. At follow-up, there was a decrease in absolute B lymphocytes and an increase in non-classical monocytes and 3-hydroxyisovaleric acid levels. These findings suggest that specific immunological and metabolomic markers during acute infection can help identify patients at higher risk of developing persistent PACS.

Keywords:  B cells; chemokines; metabolomics; monocytes; neutrophils; persistent PACS

DOI:  https://doi.org/10.3390/ijms25179661
JCI Insight. 2024 Sep 10. pii: e171659. [Epub ahead of print]9(17):

Emergence of dysfunctional neutrophils with a defect in arginase-1 release in severe COVID-19.

Amrita Dwivedi, Aisling Ui Mhaonaigh, Makala Carroll, Bahareh Khosravi, Isabella Batten, Robert Seán Ballantine, Stuart Hendricken Phelan, Laura O'Doherty, Angel Mary George, Jacklyn Sui, Heike C Hawerkamp, Padraic G Fallon, Elnè Noppe, Sabina Mason, Niall Conlon, Clíona Ni Cheallaigh, Conor M Finlay, Mark A Little, On Behalf Of The St James's And Tallaght Trinity Allied Researchers Sttar Bioresource.

  Neutrophilia occurs in patients infected with SARS-CoV-2 (COVID-19) and is predictive of poor outcomes. Here, we link heterogenous neutrophil populations to disease severity in COVID-19. We identified neutrophils with features of cellular aging and immunosuppressive capacity in mild COVID-19 and features of neutrophil immaturity and activation in severe disease. The low-density neutrophil (LDN) number in circulating blood correlated with COVID-19 severity. Many of the divergent neutrophil phenotypes in COVID-19 were overrepresented in the LDN fraction and were less detectable in normal-density neutrophils. Functionally, neutrophils from patients with severe COVID-19 displayed defects in neutrophil extracellular trap formation and reactive oxygen species production. Soluble factors secreted by neutrophils from these patients inhibited T cell proliferation. Neutrophils from patients with severe COVID-19 had increased expression of arginase-1 protein, a feature that was retained in convalescent patients. Despite this increase in intracellular expression, there was a reduction in arginase-1 release by neutrophils into serum and culture supernatants. Furthermore, neutrophil-mediated T cell suppression was independent of arginase-1. Our results indicate the presence of dysfunctional, activated, and immature neutrophils in severe COVID-19.

Keywords:  COVID-19; Immunology; Neutrophils

DOI:  https://doi.org/10.1172/jci.insight.171659
Animals (Basel). 2024 Aug 28. pii: 2500. [Epub ahead of print]14(17):

RNA-Seq Analysis of Glycolysis Regulation of Avian Leukosis Virus Subgroup J Replication.

Ting Yang, Lingling Qiu, Shihao Chen, Zhixiu Wang, Yong Jiang, Hao Bai, Yulin Bi, Guobin Chang.

  Avian Leukosis virus (ALV) is a widely spread virus that causes major economic losses to the global poultry industry. This study aims to investigate the effect of glycolysis on the replication of the ALV-J virus and identify the key circular RNAs that regulate the replication of the ALV-J virus. We found that glucose uptake, pyruvate content, and lactate content in DF1 cells were increased after ALV-J infection. Moreover, inhibiting the glycolysis of ALV-J-infected DF1 cells reduced the replication of the ALV-J virus. To further study the mechanism of glycolysis in the replication of the ALV-J virus, we performed RNA-seq on ALV-J-infected and ALV-J-infected cells treated with glycolysis inhibition. RNA-seq results show that a total of 10,375 circular RNAs (circRNAs) were identified, of which the main types were exonic circular RNAs, and 28 circRNAs were differentially expressed between ALV-J-infected and ALV-J-infected cells treated with glycolysis inhibition. Then, we performed functional enrichment analysis of differentially expressed circRNA source and target genes. Functional enrichment analysis indicated that some circRNAs might be involved in regulating the replication of the ALV-J virus by influencing some pathways like glycolysis/gluconeogenesis, the NOD-like receptor signaling pathway, MAPK signaling pathway, p53 signaling pathway, Toll-like receptor signaling pathway, Insulin signaling pathway, and Apoptosis. This study revealed the effect of glycolysis on the replication of the ALV-J virus in DF1 cells and its possible regulatory mechanism, which provided a basis for understanding the factors influencing the replication of the ALV-J virus and reducing the rate of infection of the ALV-J virus in poultry.

Keywords:  ALV-J; CircRNA; glycolysis; virus replication

DOI:  https://doi.org/10.3390/ani14172500
Int J Microbiol. 2024 ;2024 9117453

Regulation of Hepatitis B Virus Replication by Modulating Endoplasmic Reticulum Stress (ER-Stress).

Md Golzar Hossain, Keiji Ueda.

Hepatitis B virus (HBV), resistant to several antiviral drugs due to viral genomic mutations, has been reported, which aggravates chronic infection and leads to hepatocellular carcinoma. Therefore, host cellular factors/signaling modulation might be an alternative way of treatment for drug-resistant HBV. Here, we investigated the viral protein expression, replication, and virion production using endoplasmic reticulum (ER) stress-modulating chemicals, tunicamycin (an ER-stress inducer), and salubrinal (an ER-stress inhibitor). We found that ER-stress could be induced by HBV replication in transfected HepG2 cells as well as by tunicamycin as demonstrated by dual luciferase assay. HBV intracellular core-associated DNA quantified by qPCR has been significantly increased by tunicamycin in transfected HepG2 cells. Inversely, intracellular core associated and extracellular particle DNA has been significantly decreased in a dose-dependent manner in salubrinal-treated HepG2 cells transfected with HBV-replicating plasmid pHBI. Similar results were found in stably HBV-expressing hepatoblastoma (HB611) cells treated with salubrinal. However, increased or decreased ER-stress by tunicamycin or salubrinal treatment, respectively, has been confirmed by expression analysis of grp78 using Western blot. In addition, Western blot results demonstrated that the expression of HBV core protein and large HBsAg is increased and decreased by tunicamycin and salubrinal, respectively. In conclusion, the sal-mediated inhibition of the HBV replication and virion production might be due to the simultaneous reduction of core and large HBsAg expression and maintaining the ER homeostasis. These results of HBV replication regulation by modulation of ER-stress dynamics would be useful for designing/identifying anti-HBV drugs targeting cellular signaling pathways.

DOI: https://doi.org/10.1155/2024/9117453
Brain Behav Immun. 2024 Sep 09. pii: S0889-1591(24)00602-0. [Epub ahead of print]

HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV.

Yan Cheng, Jaekeun Jung, Liyang Guo, Dorela D Shuboni-Mulligan, Jian-Fu Chen, Wenhui Hu, Ming-Lei Guo.

  Chronic HIV infection can dysregulate lipid/cholesterol metabolism in the peripheral system, contributing to the higher incidences of diabetes and atherosclerosis in HIV (+) individuals. Recently, accumulating evidence indicate that HIV proteins can also dysregulate lipid/cholesterol metabolism in the brain and such dysregulation could be linked with the pathogenesis of HIV-associated neurological disorders (HAND)/NeuroHIV. To further characterize the association between lipid/cholesterol metabolism and HAND, we employed HIV-inducible transactivator of transcription (iTAT) and control mice to compare their brain lipid profiles. Our results reveal that HIV-iTAT mice possess dysregulated lipid profiles and have increased numbers of lipid droplets (LDs) accumulation microglia (LDAM) in the brains. HIV protein TAT can upregulate LDs formation through enhancing the lipid/cholesterol synthesis in vitro. Mechanistically, HIV-TAT increases the expression of sterol regulatory element-binding protein 2 (SREBP2) through microRNA-124 downregulation. Cholesterol synthesis inhibition can block HIV-TAT-mediated NLRP3 inflammasome activation and microglial activation in vitro as well as mitigate aging-related behavioral impairment and memory deficiency in HIV-iTAT mice. Taken together, our results indicate an inherent role of lipid metabolism and LDAM in the pathogenesis of NeuroHIV (immunometabolism). These findings suggest that LDAM reversal through modulating lipid/cholesterol metabolism could be a novel therapeutic target for ameliorating NeuroHIV symptoms in chronic HIV (+) individuals.

Keywords:  Cholesterol; HIV-TAT; Microglia; NeuroHIV; SREBP2; miR-124

DOI:  https://doi.org/10.1016/j.bbi.2024.09.011
Heliyon. 2024 Sep 15. 10(17): e36567

Unraveling the relevance of SARS-Cov-2 infection and ferroptosis within the heart of COVID-19 patients.

Amin Alizadeh Saghati, Zahra Sharifi, Mehdi Hatamikhah, Marieh Salimi, Mahmood Talkhabi.

   Background: The coronavirus disease 2019 (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which led to a huge mortality rate and imposed significant costs on the health system, causing severe damage to the cells of different organs such as the heart. However, the exact details and mechanisms behind this damage are not clarified. Therefore, we aimed to identify the cell and molecular mechanism behind the heart damage caused by SARS-Cov-2 infection.
Methods: RNA-seq data for COVID-19 patients' hearts was analyzed to obtain differentially expressed genes (DEGs) and differentially expressed ferroptosis-related genes (DEFRGs). Then, DEFRGs were used for analyzing GO and KEGG enrichment, and perdition of metabolites and drugs. we also constructed a PPI network and identified hub genes and functional modules for the DEFRGs. Subsequently, the hub genes were validated using two independent RNA-seq datasets. Finally, the miRNA-gene interaction networks were predicted in addition to a miRNA-TF co-regulatory network, and important miRNAs and transcription factors (TFs) were highlighted.
Findings: We found ferroptosis transcriptomic alterations within the hearts of COVID-19 patients. The enrichment analyses suggested the involvement of DEFRGs in the citrate cycle pathway, ferroptosis, carbon metabolism, amino acid biosynthesis, and response to oxidative stress. IL6, CDH1, AR, EGR1, SIRT3, GPT2, VDR, PCK2, VDR, and MUC1 were identified as the ferroptosis-related hub genes. The important miRNAs and TFs were miR-124-3P, miR-26b-5p, miR-183-5p, miR-34a-5p and miR-155-5p; EGR1, AR, IL6, HNF4A, SRC, EZH2, PPARA, and VDR.
Conclusion: These results provide a useful context and a cellular snapshot of how ferroptosis affects cardiomyocytes (CMs) in COVID-19 patients' hearts. Besides, suppressing ferroptosis seems to be a beneficial therapeutic approach to mitigate heart damage in COVID-19.

Keywords:  Bioinformatics; COVID-19 heart samples; Ferroptosis; Gene regulatory network; SARS-CoV-2

DOI:  https://doi.org/10.1016/j.heliyon.2024.e36567
Sci Rep. 2024 09 11. 14(1): 21200

SARS-CoV-2 envelope protein alters calcium signaling via SERCA interactions.

Blanka Berta, Hedvig Tordai, Gergely L Lukács, Béla Papp, Ágnes Enyedi, Rita Padányi, Tamás Hegedűs.

  The clinical management of severe COVID-19 cases is not yet well resolved. Therefore, it is important to identify and characterize cell signaling pathways involved in virus pathogenesis that can be targeted therapeutically. Envelope (E) protein is a structural protein of the virus, which is known to be highly expressed in the infected host cell and is a key virulence factor; however, its role is poorly characterized. The E protein is a single-pass transmembrane protein that can assemble into a pentamer forming a viroporin, perturbing Ca2+ homeostasis. Because it is structurally similar to regulins such as, for example, phospholamban, that regulate the sarco/endoplasmic reticulum calcium ATPases (SERCA), we investigated whether the SARS-CoV-2 E protein affects the SERCA system as an exoregulin. Using FRET experiments we demonstrate that E protein can form oligomers with regulins, and thus can alter the monomer/multimer regulin ratio and consequently influence their interactions with SERCAs. We also confirm that a direct interaction between E protein and SERCA2b results in a decrease in SERCA-mediated ER Ca2+ reload. Structural modeling of the complexes indicates an overlapping interaction site for E protein and endogenous regulins. Our results reveal novel links in the host-virus interaction network that play an important role in viral pathogenesis and may provide a new therapeutic target for managing severe inflammatory responses induced by SARS-CoV-2.

Keywords:  COVID-19; Ca2+ signaling; Envelope protein; Regulin; SARS-CoV-2; SERCA

DOI:  https://doi.org/10.1038/s41598-024-71144-5