bims-mevinf 2024-03-03 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024–03–03
seven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Metabolites that feed upper glycolytic branches support glucose independent human cytomegalovirus replication.
Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology.
Influenza A virus propagation requires the activation of the unfolded protein response and the accumulation of insoluble protein aggregates.
Oncolytic Newcastle disease virus induced degradation of YAP through E3 ubiquitin ligase PRKN to exacerbate ferroptosis in tumor cells.
The cGAS-STING pathway in viral infections: a promising link between inflammation, oxidative stress and autophagy.
Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia.
People living with HIV display increased anti-apolipoprotein A1 auto-antibodies, inflammation, and kynurenine metabolites: a case-control study.

bioRxiv. 2024 Feb 12. pii: 2024.02.12.579992. [Epub ahead of print]

Metabolites that feed upper glycolytic branches support glucose independent human cytomegalovirus replication.

Rebekah L Mokry, John G Purdy.

The broad tissue distribution and cell tropism of human cytomegalovirus indicates that the virus successfully replicates in tissues with various nutrient environments. HCMV requires and reprograms central carbon metabolism for viral replication. However, many studies focus on reprogramming of metabolism in high nutrient conditions that do not recapitulate physiological nutrient environments in the body. In this study, we investigate how HCMV successfully replicates when nutrients are suboptimal. We limited glucose following HCMV infection to determine how glucose supports virus replication and how nutrients potentially present in the physiological environment contribute to successful glucose independent HCMV replication. Glucose is required for HCMV viral genome synthesis, viral protein production and glycosylation, and virus production. However, supplement of glucose-free cultures with uridine, ribose, or UDP-GlcNAc-metabolites that support upper glycolytic branches-resulted in partially restored viral genome synthesis and subsequent partial restoration of viral protein levels. Low levels of virus production were also restored. Supplementing lower glycolysis in glucose-free cultures using pyruvate had no effect on virus replication. These results indicate nutrients that support upper glycolytic branches like the pentose phosphate pathway and hexosamine pathway can compensate for glucose during HCMV replication to support low levels of virus production. More broadly, our findings suggest that HCMV could successfully replicate in diverse metabolic niches, including those in the body with low levels of glucose, through alternative nutrient usage.
IMPORTANCE: The metabolic environment is a determinant in the ability of a virus to successfully replicate. HCMV has broad cell tropism and replicates in various tissues that have diverse and/or limiting metabolic environments. We know that HCMV reprograms host central carbon metabolism to support viral replication, but we have little understanding of HCMV replication in diverse metabolic niches as most studies use high nutrient culture media. Here, we show that glucose limitation suppresses virus production through loss of viral genome synthesis and viral protein glycosylation. However, nutrient compensation by uridine, ribose, and UDP-GlcNAc, metabolites that fuel upper glycolytic branches such as the non-oxidative pentose phosphate pathway support low levels of glucose-independent virus production. Our work indicates that metabolite compensation may facilitate HCMV replication in nutrient limited niches in the body.

DOI: https://doi.org/10.1101/2024.02.12.579992
iScience. 2024 Mar 15. 27(3): 109088

Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology.

Sneha Singh, Robert E Wright, Shailendra Giri, Vaithilingaraja Arumugaswami, Ashok Kumar.

  Zika virus (ZIKV) infection during pregnancy causes severe neurological and ocular abnormalities in infants, yet no vaccine or antivirals are available. Our transcriptomic analysis of ZIKV-infected retinal pigment epithelial (RPE) cells revealed alterations in the cholesterol pathway. Thus, we investigated the functional roles of ATP binding cassette transporter G1 (ABCG1) and sterol response element binding protein 2 (SREPB-2), two key players in cholesterol metabolism, during ocular ZIKV infection. Our in vitro data showed that increased ABCG1 activity via liver X receptors (LXRs), reduced ZIKV replication, while ABCG1 knockdown increased replication with elevated intracellular cholesterol. Conversely, inhibiting SREBP-2 or its knockdown reduced ZIKV replication by lowering cholesterol levels. In vivo, LXR agonist or SREBP-2 inhibitor treatment mitigated ZIKV-induced chorioretinal lesions in mice, concomitant with decreased expression of inflammatory mediators and increased activation of antiviral response genes. In summary, our study identifies ABCG1's antiviral role and SREBP-2's proviral effects in ocular ZIKV infection, offering cholesterol metabolism as a potential target to develop antiviral therapies.

Keywords:  Molecular biology; Virology

DOI:  https://doi.org/10.1016/j.isci.2024.109088
iScience. 2024 Mar 15. 27(3): 109100

Influenza A virus propagation requires the activation of the unfolded protein response and the accumulation of insoluble protein aggregates.

Mariana Marques, Bruno Ramos, Hélio Albuquerque, Marisa Pereira, Diana Roberta Ribeiro, Alexandre Nunes, Jéssica Sarabando, Daniela Brás, Ana Rita Ferreira, Rui Vitorino, Maria João Amorim, Artur M S Silva, Ana Raquel Soares, Daniela Ribeiro.

  Influenza A virus (IAV) employs multiple strategies to manipulate cellular mechanisms and support proper virion formation and propagation. In this study, we performed a detailed analysis of the interplay between IAV and the host cells' proteostasis throughout the entire infectious cycle. We reveal that IAV infection activates the inositol requiring enzyme 1 (IRE1) branch of the unfolded protein response, and that this activation is important for an efficient infection. We further observed the accumulation of virus-induced insoluble protein aggregates, containing both viral and host proteins, associated with a dysregulation of the host cell RNA metabolism. Our data indicate that this accumulation is important for IAV propagation and favors the final steps of the infection cycle, more specifically the virion assembly. These findings reveal additional mechanisms by which IAV disrupts host proteostasis and uncovers new cellular targets that can be explored for the development of host-directed antiviral strategies.

Keywords:  Virology

DOI:  https://doi.org/10.1016/j.isci.2024.109100
J Virol. 2024 Feb 27. e0189723

Oncolytic Newcastle disease virus induced degradation of YAP through E3 ubiquitin ligase PRKN to exacerbate ferroptosis in tumor cells.

Yifan Sun, Lanlan Tang, Xianjin Kan, Lei Tan, Cuiping Song, Xusheng Qiu, Ying Liao, Venugopal Nair, Chan Ding, Xiufan Liu, Yingjie Sun.

  Ferroptosis, a form of programmed cell death characterized by iron-dependent lipid peroxidation, has recently gained considerable attention in the field of cancer therapy. There is significant crosstalk between ferroptosis and several classical signaling pathways, such as the Hippo pathway, which suppresses abnormal growth and is frequently aberrant in tumor tissues. Yes-associated protein 1 (YAP), the core effector molecule of the Hippo pathway, is abnormally expressed and activated in a variety of malignant tumor tissues. We previously proved that the oncolytic Newcastle disease virus (NDV) activated ferroptosis to kill tumor cells. NDV has been used in tumor therapy; however, its oncolytic mechanism is not completely understood. In this study, we demonstrated that NDV exacerbated ferroptosis in tumor cells by inducing ubiquitin-mediated degradation of YAP at Lys90 through E3 ubiquitin ligase parkin (PRKN). Blocking YAP degradation suppressed NDV-induced ferroptosis by suppressing the expression of Zrt/Irt-like protein 14 (ZIP14), a metal ion transporter that regulates iron uptake. These findings demonstrate that NDV exacerbated ferroptosis in tumor cells by inducing YAP degradation. Our study provides new insights into the mechanism of NDV-induced ferroptosis and highlights the critical role that oncolytic viruses play in the treatment of drug-resistant cancers.IMPORTANCEThe oncolytic Newcastle disease virus (NDV) is being developed for use in cancer treatment; however, its oncolytic mechanism is still not completely understood. The Hippo pathway, which is a tumor suppressor pathway, is frequently dysregulated in tumor tissues due to aberrant yes-associated protein 1 (YAP) activation. In this study, we have demonstrated that NDV degrades YAP to induce ferroptosis and promote virus replication in tumor cells. Notably, NDV was found to induce ubiquitin-mediated degradation of YAP at Lys90 through E3 ubiquitin ligase parkin (PRKN). Our study reveals a new mechanism by which NDV induces ferroptosis and provides new insights into NDV as an oncolytic agent for cancer treatment.

Keywords:  Hippo pathway; Newcastle disease virus; ferroptosis; oncolytic viruses

DOI:  https://doi.org/10.1128/jvi.01897-23
Front Immunol. 2024 ;15 1352479

The cGAS-STING pathway in viral infections: a promising link between inflammation, oxidative stress and autophagy.

Kunli Zhang, Qiuyan Huang, Xinming Li, Ziqiao Zhao, Chun Hong, Zeyi Sun, Bo Deng, Chunling Li, Jianfeng Zhang, Sutian Wang.

  The host defence responses play vital roles in viral infection and are regulated by complex interactive networks. The host immune system recognizes viral pathogens through the interaction of pattern-recognition receptors (PRRs) with pathogen-associated molecular patterns (PAMPs). As a PRR mainly in the cytoplasm, cyclic GMP-AMP synthase (cGAS) senses and binds virus DNA and subsequently activates stimulator of interferon genes (STING) to trigger a series of intracellular signalling cascades to defend against invading pathogenic microorganisms. Integrated omic and functional analyses identify the cGAS-STING pathway regulating various host cellular responses and controlling viral infections. Aside from its most common function in regulating inflammation and type I interferon, a growing body of evidence suggests that the cGAS-STING signalling axis is closely associated with a series of cellular responses, such as oxidative stress, autophagy, and endoplasmic reticulum stress, which have major impacts on physiological homeostasis. Interestingly, these host cellular responses play dual roles in the regulation of the cGAS-STING signalling axis and the clearance of viruses. Here, we outline recent insights into cGAS-STING in regulating type I interferon, inflammation, oxidative stress, autophagy and endoplasmic reticulum stress and discuss their interactions with viral infections. A detailed understanding of the cGAS-STING-mediated potential antiviral effects contributes to revealing the pathogenesis of certain viruses and sheds light on effective solutions for antiviral therapy.

Keywords:  autophagy; cGAS-STING; inflammation; innate immune; oxidative stress; viral infection; virus-host interaction

DOI:  https://doi.org/10.3389/fimmu.2024.1352479
Crit Care. 2024 Feb 27. 28(1): 63

Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia.

*ARBs CORONA I. Investigators

   RATIONALE: Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair.
OBJECTIVE: To map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis.
METHODS: We analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC-MS/MS and DI-MS/MS analytical platforms.
RESULTS: Distinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms.
CONCLUSION: Different metabolic phenotypes characterize ARDS associated with different viral and bacterial infections.

Keywords:  Acute respiratory distress syndrome; H1N1; Metabolomics; Pneumonia; SARS-CoV-2

DOI:  https://doi.org/10.1186/s13054-024-04843-0
Front Cardiovasc Med. 2024 ;11 1343361

People living with HIV display increased anti-apolipoprotein A1 auto-antibodies, inflammation, and kynurenine metabolites: a case-control study.

Miguel A Frias, Sabrina Pagano, Nasim Bararpour, Jonathan Sidibé, Festus Kamau, Vanessa Fétaud-Lapierre, Peter Hudson, Aurélien Thomas, Sandrine Lecour, Hans Strijdom, Nicolas Vuilleumier.

   Objective: This study aimed to study the relationship between auto-antibodies against apolipoprotein A1 (anti-apoA1 IgG), human immunodeficiency virus (HIV) infection, anti-retroviral therapy (ART), and the tryptophan pathways in HIV-related cardiovascular disease.
Design: This case-control study conducted in South Africa consisted of control volunteers (n = 50), people living with HIV (PLWH) on ART (n = 50), and untreated PLWH (n = 44). Cardiovascular risk scores were determined, vascular measures were performed, and an extensive biochemical characterisation (routine, metabolomic, and inflammatory systemic profiles) was performed.
Methods: Anti-apoA1 IgG levels were assessed by an in-house ELISA. Inflammatory biomarkers were measured with the Meso Scale Discovery® platform, and kynurenine pathway metabolites were assessed using targeted metabolomic profiling conducted by liquid chromatography-multiple reaction monitoring/mass spectrometry (LC-MRM/MS).
Results: Cardiovascular risk scores and vascular measures exhibited similarities across the three groups, while important differences were observed in systemic inflammatory and tryptophan pathways. Anti-apoA1 IgG seropositivity rates were 15%, 40%, and 70% in control volunteers, PLWH ART-treated, and PLWH ART-naïve, respectively. Circulating anti-apoA1 IgG levels were significantly negatively associated with CD4+ cell counts and positively associated with viremia and pro-inflammatory biomarkers (IFNγ, TNFα, MIPα, ICAM-1, VCAM-1). While circulating anti-apoA1 IgG levels were associated with increased levels of kynurenine in both control volunteers and PLWH, the kynurenine/tryptophan ratio was significantly increased in PLWH ART-treated.
Conclusion: HIV infection increases the humoral response against apoA1, which is associated with established HIV severity criteria and kynurenine pathway activation.

Keywords:  HIV; anti-apolipoprotein A1 auto-antibodies; anti-retroviral therapy; autoimmunity; cardiovascular disease; kynurenine pathway metabolites

DOI:  https://doi.org/10.3389/fcvm.2024.1343361