bims-mevinf 2023-06-18 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023–06–18
eight papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

The unfolded protein response components IRE1α and XBP1 promote human coronavirus infection.
Zika virus infection induces expression of NRF2 and antioxidant systems in trophoblast cells.
PI3K/Akt/Nrf2 mediated cellular signaling and virus-host interactions: latest updates on the potential therapeutic management of SARS-CoV-2 infection.
HCV Core Protein-ISX Axis Promotes Chronic Liver Disease Progression via Metabolic Remodeling and Immune Suppression.
Cytokine storm in individuals with severe COVID-19 decreases endothelial cell antioxidant defense via Downregulation of the Nrf2 transcriptional factor.
HIV-1 activates oxidative phosphorylation in infected CD4 T cells in a human tonsil explant model.
Transcriptomic Profiling Reveals Intense Host-Pathogen Dispute Compromising Homeostasis during Acute Rift Valley Fever Virus Infection.
Amniotic fluid metabolomics identifies impairment of glycerophospholipid and amino acid metabolism during congenital Zika syndrome development.

mBio. 2023 Jun 12. e0054023

The unfolded protein response components IRE1α and XBP1 promote human coronavirus infection.

Jessica M Oda, Andreas B den Hartigh, Shoen M Jackson, Ana R Tronco, Susan L Fink.

  The cellular processes that support human coronavirus replication and contribute to the pathogenesis of severe disease remain incompletely understood. Many viruses, including coronaviruses, cause endoplasmic reticulum (ER) stress during infection. IRE1α is a component of the cellular response to ER stress that initiates non-conventional splicing of XBP1 mRNA. Spliced XBP1 encodes a transcription factor that induces the expression of ER-related targets. Activation of the IRE1α-XBP1 pathway occurs in association with risk factors for severe human coronavirus infection. In this study, we found that the human coronaviruses HCoV-OC43 (human coronavirus OC43) and SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) both robustly activate the IRE1α-XBP1 branch of the unfolded protein response in cultured cells. Using IRE1α nuclease inhibitors and genetic knockdown of IRE1α and XBP1, we found that these host factors are required for optimal replication of both viruses. Our data suggest that IRE1α supports infection downstream of initial viral attachment and entry. In addition, we found that ER stress-inducing conditions are sufficient to enhance human coronavirus replication. Furthermore, we found markedly increased XBP1 in circulation in human patients with severe coronavirus disease 2019 (COVID-19). Together, these results demonstrate the importance of IRE1α and XBP1 for human coronavirus infection.IMPORTANCEThere is a critical need to understand the cellular processes co-opted during human coronavirus replication, with an emphasis on identifying mechanisms underlying severe disease and potential therapeutic targets. Here, we demonstrate that the host proteins IRE1α and XBP1 are required for robust infection by the human coronaviruses, SARS-CoV-2 and HCoV-OC43. IRE1α and XBP1 participate in the cellular response to ER stress and are activated during conditions that predispose to severe COVID-19. We found enhanced viral replication with exogenous IRE1α activation, and evidence that this pathway is activated in humans during severe COVID-19. Together, these results demonstrate the importance of IRE1α and XBP1 for human coronavirus infection.

Keywords:  ER stress; HCoV-OC43; IRE1α; SARS-CoV-2; XBP1; coronavirus; endoplasmic reticulum; unfolded protein response

DOI:  https://doi.org/10.1128/mbio.00540-23
Virus Genes. 2023 Jun 16.

Zika virus infection induces expression of NRF2 and antioxidant systems in trophoblast cells.

Manuel Adrián Velázquez Cervantes, Julio Angel Vázquez Martinez, Luis Didider Gonzalez García, Orestes Lopez Ortega, Haruki Arevalo Romero, Araceli Montoya Estrada, Macario Martínez Castillo, Arturo Flores Pliego, Guadalupe León Reyes, Addy Cecilia Helguera Repetto, Julio García Cordero, Moisés León Juárez.

  The nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a critical role in the xenobiotic and stress responses. During viral infection, NRF2 can modulate the host metabolism and innate immunity; however, the most common activity of NRF2 in viral diseases is controlling reactive oxygen species (ROS). The Zika virus (ZIKV) is involved in a vertical infection in pregnancy, with reported fetal health consequences. However, the possibility that ZIKV regulates NRF2 expression in placental trophoblasts has not been investigated. In this report, we evaluated the upregulation of NRF2 and antioxidant enzymes in a trophoblast-like cell. These findings could help us understand the antioxidant mechanism underlying the ZIKV infection in the placenta during pregnancy.

Keywords:  Oxidative stress; Placenta; ROS; Trophoblast; Zika virus

DOI:  https://doi.org/10.1007/s11262-023-02014-x
Front Mol Biosci. 2023 ;10 1158133

PI3K/Akt/Nrf2 mediated cellular signaling and virus-host interactions: latest updates on the potential therapeutic management of SARS-CoV-2 infection.

V S Lekshmi, Kumari Asha, Melvin Sanicas, Abhila Asi, U M Arya, Binod Kumar.

  The emergence and re-emergence of viral diseases, which cause significant global mortality and morbidity, are the major concerns of this decade. Of these, current research is focused majorly on the etiological agent of the COVID-19 pandemic, SARS-CoV-2. Understanding the host response and metabolic changes during viral infection may provide better therapeutic targets for the proper management of pathophysiological conditions associated with SARS-CoV-2 infection. We have achieved control over most emerging viral diseases; however, a lack of understanding of the underlying molecular events prevents us from exploring novel therapeutic targets, leaving us forced to witness re-emerging viral infections. SARS-CoV-2 infection is usually accompanied by oxidative stress, which leads to an overactive immune response, the release of inflammatory cytokines, increasing lipid production, and also alterations in the endothelial and mitochondrial functions. PI3K/Akt signaling pathway confers protection against oxidative injury by various cell survival mechanisms including Nrf2-ARE mediated antioxidant transcriptional response. SARS-CoV-2 is also reported to hijack this pathway for its survival within host and few studies have suggested the role of antioxidants in modulating the Nrf2 pathway to manage disease severity. This review highlights the interrelated pathophysiological conditions associated with SARS-CoV-2 infection and the host survival mechanisms mediated by PI3K/Akt/Nrf2 signaling pathways that can help ameliorate the severity of the disease and provide effective antiviral targets against SARS-CoV-2.

Keywords:  COVID-19; Coronavirus; Nrf2; PI3K/Akt pathway; SARS-CoV-2; inflammation; oxidative stress; pandemic

DOI:  https://doi.org/10.3389/fmolb.2023.1158133
Adv Sci (Weinh). 2023 Jun 14. e2300644

HCV Core Protein-ISX Axis Promotes Chronic Liver Disease Progression via Metabolic Remodeling and Immune Suppression.

Li-Ting Wang, Shen-Nien Wang, Shyh-Shin Chiou, Jhih-Peng Tsai, Chee-Yin Chai, Li-Wen Tseng, Jin-Ching Lee, Ming-Hong Lin, Shau-Ku Huang, Shih-Hsien Hsu.

  Chronic hepatitis C virus (HCV) infection is an important public health issue. However, knowledge on how the virus remodels the metabolic and immune response toward hepatic pathologic environment is limited. The transcriptomic and multiple evidences reveal that the HCV core protein-intestine-specific homeobox (ISX) axis promotes a spectrum of metabolic, fibrogenic, and immune modulators (e.g., kynurenine, PD-L1, and B7-2), regulating HCV-infection relevant pathogenic phenotype in vitro and in vivo. In a transgenic mice model, the HCV core protein-ISX axis enhance metabolic disturbance (particularly lipid and glucose metabolism) and immune suppression, and finally, chronic liver fibrosis in a high-fat diet (HFD)-induced disease model. Mechanistically, cells with HCV JFH-1 replicons upregulate ISX and, consequently, the expressions of metabolic, fibrosis progenitor, and immune modulators via core protein-induced nuclear factor-κB signaling. Conversely, cells with specific ISX shRNAi inhibit HCV core protein-induced metabolic disturbance and immune suppression. Clinically, the HCV core level is significantly correlated with ISX, IDOs, PD-L1, and B7-2 levels in HCC patients with HCV infection. Therefore, it highlights the significance of HCV core protein-ISX axis as an important mechanism in the development of HCV-induced chronic liver disease and can be a specific therapeutic target clinically.

Keywords:  HCV core protein; ISX; immune suppression; metabolic dysregulation; programmed death-ligand 1 (PD-L1)

DOI:  https://doi.org/10.1002/advs.202300644
Am J Physiol Heart Circ Physiol. 2023 Jun 16.

Cytokine storm in individuals with severe COVID-19 decreases endothelial cell antioxidant defense via Downregulation of the Nrf2 transcriptional factor.

Daniel Rodrigues, Mirele M Resende, Juliano V Alves, Thais F C Fraga-Silva, Ronaldo B Martins, Ligia C B Campos, Daniely F Franscisco, Ariel E S Couto, Vânia L D Bonato, Eurico Arruda, Christiane Becari, Maria Auxiliadora-Martins, Paulo Louzada-Júnior, Rafael M da Costa, Rita C Tostes.

  The cytokine storm in SARS-CoV-2 infection contributes to the onset of inflammation and target organ damage. The endothelium is a key player in COVID-19 pathophysiology and it is an important target for cytokines. Since cytokines trigger oxidative stress and negatively impact endothelial cell function, we sought to determine whether serum derived from severe COVID-19 individuals decreases endothelial cells' main antioxidant defense, i.e. the antioxidant transcriptional factor Nrf2. Human umbilical vein endothelial cells (HUVEC) were incubated with severe COVID-19 serum at different time points and the effects on redox balance and Nrf2 activity were determined. Serum from COVID-19 individuals increased oxidant species, as indicated by higher DHE oxidation, increased protein carbonylation and augmented mitochondrial reactive oxygen species (ROS) generation and dysfunction. COVID-19 serum, in comparison with serum from healthy individuals, induced cell death and diminished nitric oxide (NO) bioavailability. In parallel, Nrf2 nuclear accumulation and the expression of Nrf2-targeted genes were reduced in endothelial cells exposed to serum from COVID-19 individuals. Additionally, these cells exhibited higher expression of Bach-1, a negative regulator of Nrf2 that competes for DNA binding. All events were prevented by Tocilizumab, an IL-6 receptor blocker, indicating that IL-6 is key to the impairment of endothelial antioxidant defense. In conclusion, endothelial dysfunction related to SARS-Cov-2 infection is linked to an IL-6-dependent decrease in the endothelial antioxidant defense. Pharmacological activation of Nrf2 may decrease endothelial cell damage in individuals with severe COVID-19.

Keywords:  COVID-19; Cytokine storm; Endothelial cell; Nrf2; vascular function

DOI:  https://doi.org/10.1152/ajpheart.00096.2023
Front Immunol. 2023 ;14 1172938

HIV-1 activates oxidative phosphorylation in infected CD4 T cells in a human tonsil explant model.

Tracey L Freeman, Connie Zhao, Nadine Schrode, Trinisia Fortune, Sanjana Shroff, Benjamin Tweel, Kristin G Beaumont, Talia H Swartz.

   Introduction: Human immunodeficiency virus type 1 (HIV-1) causes a chronic, incurable infection leading to immune activation and chronic inflammation in people with HIV-1 (PWH), even with virologic suppression on antiretroviral therapy (ART). The role of lymphoid structures as reservoirs for viral latency and immune activation has been implicated in chronic inflammation mechanisms. Still, the specific transcriptomic changes induced by HIV-1 infection in different cell types within lymphoid tissue remain unexplored.
Methods: In this study, we utilized human tonsil explants from healthy human donors and infected them with HIV-1 ex vivo. We performed single-cell RNA sequencing (scRNA-seq) to analyze the cell types represented in the tissue and to investigate the impact of infection on gene expression profiles and inflammatory signaling pathways.
Results: Our analysis revealed that infected CD4+ T cells exhibited upregulation of genes associated with oxidative phosphorylation. Furthermore, macrophages exposed to the virus but uninfected showed increased expression of genes associated with the NLRP3 inflammasome pathway.
Discussion: These findings provide valuable insights into the specific transcriptomic changes induced by HIV-1 infection in different cell types within lymphoid tissue. The activation of oxidative phosphorylation in infected CD4+ T cells and the proinflammatory response in macrophages may contribute to the chronic inflammation observed in PWH despite ART. Understanding these mechanisms is crucial for developing targeted therapeutic strategies to eradicate HIV-1 infection in PWH.

Keywords:  CD4 T cell; HIV-1; NLRP3 inflammasome; bystander cells; macrophage; metabolomics; oxidative phoshorylation; single cell RNA sequencing (scRNA)

DOI:  https://doi.org/10.3389/fimmu.2023.1172938
J Virol. 2023 Jun 12. e0041523

Transcriptomic Profiling Reveals Intense Host-Pathogen Dispute Compromising Homeostasis during Acute Rift Valley Fever Virus Infection.

Erick Bermúdez-Méndez, Paolo Angelino, Lucien van Keulen, Sandra van de Water, Barry Rockx, Gorben P Pijlman, Angela Ciuffi, Jeroen Kortekaas, Paul J Wichgers Schreur.

  Rift Valley fever virus (RVFV) (family Phenuiviridae) can cause severe disease, and outbreaks of this mosquito-borne pathogen pose a significant threat to public and animal health. Yet many molecular aspects of RVFV pathogenesis remain incompletely understood. Natural RVFV infections are acute, characterized by a rapid onset of peak viremia during the first days post-infection, followed by a rapid decline. Although in vitro studies identified a major role of interferon (IFN) responses in counteracting the infection, a comprehensive overview of the specific host factors that play a role in RVFV pathogenesis in vivo is still lacking. Here, the host in vivo transcriptional profiles in the liver and spleen tissues of lambs exposed to RVFV are studied using RNA sequencing (RNA-seq) technology. We validate that IFN-mediated pathways are robustly activated in response to infection. We also link the observed hepatocellular necrosis with severely compromised organ function, which is reflected as a marked downregulation of multiple metabolic enzymes essential for homeostasis. Furthermore, we associate the elevated basal expression of LRP1 in the liver with RVFV tissue tropism. Collectively, the results of this study deepen the knowledge of the in vivo host response during RVFV infection and reveal new insights into the gene regulation networks underlying pathogenesis in a natural host. IMPORTANCE Rift Valley fever virus (RVFV) is a mosquito-transmitted pathogen capable of causing severe disease in animals and humans. Outbreaks of RVFV pose a significant threat to public health and can result in substantial economic losses. Little is known about the molecular basis of RVFV pathogenesis in vivo, particularly in its natural hosts. We employed RNA-seq technology to investigate genome-wide host responses in the liver and spleen of lambs during acute RVFV infection. We show that RVFV infection drastically decreases the expression of metabolic enzymes, which impairs normal liver function. Moreover, we highlight that basal expression levels of the host factor LRP1 may be a determinant of RVFV tissue tropism. This study links the typical pathological phenotype induced by RVFV infection with tissue-specific gene expression profiles, thereby improving our understanding of RVFV pathogenesis.

Keywords:  RNA-seq; Rift Valley fever virus; host-pathogen interactions; pathogenesis

DOI:  https://doi.org/10.1128/jvi.00415-23
Proteomics Clin Appl. 2023 Jun 17. e2300008

Amniotic fluid metabolomics identifies impairment of glycerophospholipid and amino acid metabolism during congenital Zika syndrome development.

Patricia Sosa-Acosta, Geisa P C Evaristo, Joseph A M Evaristo, Gabriel Reis Alves Carneiro, Mauricio Quiñones-Vega, Gustavo Monnerat, Adriana Melo, Patrícia P Garcez, Fábio C S Nogueira, Gilberto B Domont.

   PURPOSE: Our main goal is to identify the alterations in the amniotic fluid (AF) metabolome in Zika virus (ZIKV)-infected patients and their relation to congenital Zika syndrome (CZS) progression.
EXPERIMENTAL DESIGN: We applied an untargeted metabolomics strategy to analyze seven AF of pregnant women: healthy women and ZIKV-infected women bearing non-microcephalic and microcephalic fetuses.
RESULTS: Infected patients were characterized by glycerophospholipid metabolism impairment, which is accentuated in microcephalic phenotypes. Glycerophospholipid decreased concentration in AF can be a consequence of intracellular transport of lipids to the placental or fetal tissues under development. The increased intracellular concentration of lipids can lead to mitochondrial dysfunction and neurodegeneration caused by lipid droplet accumulation. Furthermore, the dysregulation of amino acid metabolism was a molecular fingerprint of microcephalic phenotypes, specifically serine, and proline metabolisms. Both amino acid deficiencies were related to neurodegenerative disorders, intrauterine growth retardation, and placental abnormalities.
CONCLUSIONS AND CLINICAL RELEVANCE: This study enhances our understanding of the development of CZS pathology and sheds light on dysregulated pathways that could be relevant for future studies.

Keywords:  Zika virus; amino acid metabolism; amniotic fluid; congenital Zika syndrome; glycerophospholipid metabolism; metabolomics

DOI:  https://doi.org/10.1002/prca.202300008