bims-mevinf 2024-10-20 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024–10–20
eight papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Metabolomic Profiling Reveals Potential of Fatty Acids as Regulators of Stem-like Exhausted CD8 T Cells During Chronic Viral Infection.
Understanding Metabolic Pathway Rewiring by Oncogenic Gamma Herpesvirus.
Inhibition of LPCAT3 exacerbates endoplasmic reticulum stress and HBV replication.
Cholesterol and Cholesterol-Lowering Medications in COVID-19-An Unresolved Matter.
Hepatitis B Virus Increases SphK1-S1P Synthesis by Promoting the Availability of the Transcription Factor USF1.
The tryptophan catabolite or kynurenine pathway in Long COVID disease: A systematic review and meta-analysis.
Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-γ induced IRF1.
Betulonic Acid Inhibits Type-2 Porcine Reproductive and Respiratory Syndrome Virus Replication by Downregulating Cellular ATP Production.

bioRxiv. 2024 Oct 11. pii: 2024.10.07.617124. [Epub ahead of print]

Metabolomic Profiling Reveals Potential of Fatty Acids as Regulators of Stem-like Exhausted CD8 T Cells During Chronic Viral Infection.

Katelynn R Kazane, Lara Labarta-Bajo, Dina R Zangwill, Kalle Liimatta, Fernando Vargas, Kelly C Weldon, Pieter C Dorrestein, Elina I Zúñiga.

Chronic infections drive a CD8 T cell program termed T cell exhaustion, characterized by reduced effector functions. While cell-intrinsic mechanisms underlying CD8 T cell exhaustion have been extensively studied, the impact of the metabolic environment in which exhausted CD8 T cells (Tex) operate remains less clear. Using untargeted metabolomics and the murine lymphocytic choriomeningitis virus infection model we investigated systemic metabolite changes early and late following acute versus chronic viral infections. We identified distinct short-term and persistent metabolite shifts, with the most significant differences occurring transiently during the acute phase of the sustained infection. This included nutrient changes that were independent of viral loads and partially associated with CD8 T cell-induced anorexia and lipolysis. One remarkable observation was the elevation of medium- and long-chain fatty acid (FA) and acylcarnitines during the early phase after chronic infection. During this time, virus-specific CD8 T cells from chronically infected mice exhibited increased lipid accumulation and uptake compared to their counterparts from acute infection, particularly stem-like Tex (Tex STEM ), a subset that generates effector-like Tex INT which directly limit viral replication. Notably, only Tex STEM increased oxidative metabolism and ATP production upon FA exposure. Consistently, short-term reintroduction of FA during late chronic infection exclusively improved Tex STEM mitochondrial fitness, percentages and numbers. This treatment, however, also reduced Tex INT , resulting in compromised viral control. Our study offers a valuable resource for investigating the role of specific metabolites in regulating immune responses during acute and chronic viral infections and highlights the potential of long-chain FA to influence Tex STEM and viral control during a protracted infection.
Significance: This study examines systemic metabolite changes during acute and chronic viral infections. Notably, we identified an early, transient nutrient shift in chronic infection, marked by an increase in medium- and long-chain fatty acid related species. Concomitantly, a virus-specific stem-like T cell population, essential for maintaining other T cells, displayed high lipid avidity and was capable of metabolizing exogenous fatty acids. Administering fatty acids late in chronic infection, when endogenous lipid levels had normalized, expanded this stem-like T cell population and enhanced their mitochondrial fitness. These findings highlight the potential role of fatty acids in regulating stem-like T cells in chronic settings and offer a valuable resource for studying other metabolic signatures in both acute and persistent infections.

DOI: https://doi.org/10.1101/2024.10.07.617124
J Microbiol Biotechnol. 2024 Aug 30. 34(11): 1-10

Understanding Metabolic Pathway Rewiring by Oncogenic Gamma Herpesvirus.

Un Yung Choi, Seung Hyun Lee.

  Gamma herpesviruses, including Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), are key contributors to the development of various cancers through their ability to manipulate host cellular pathways. This review explores the intricate ways these viruses rewire host metabolic pathways to sustain viral persistence and promote tumorigenesis. We look into how EBV and KSHV induce glycolytic reprogramming, alter mitochondrial function, and remodel nucleotide and amino acid metabolism, highlighting the crucial role of lipid metabolism in these oncogenic processes. By understanding these metabolic alterations, which confer proliferative and survival advantages to the virus-infected cells, we can identify potential therapeutic targets and develop innovative treatment strategies for gamma herpesvirus-associated malignancies. Ultimately, this review underscores the critical role of metabolic reprogramming in gamma herpesvirus oncogenesis and its implications for precision medicine in combating virus-driven cancers.

Keywords:  EBV; KSHV; Metabolic reprogramming; metabolic therapeutics; oncogenic virus

DOI:  https://doi.org/10.4014/jmb.2407.07039
Int Immunopharmacol. 2024 Oct 17. pii: S1567-5769(24)01859-9. [Epub ahead of print]143(Pt 2): 113337

Inhibition of LPCAT3 exacerbates endoplasmic reticulum stress and HBV replication.

Shiya Shi, He Zhang, Pengjun Jiang, Yanjie Zhou, Yalan Zhu, Tianyu Feng, Chengxia Xie, He He, Jie Chen.

   BACKGROUND: Altered phospholipid metabolism plays a key role in changing the immune microenvironment and severely affecting T-cell function. LPCAT3 is one of the vital enzymes regulating phospholipid metabolism. This study aims to verify the effect of LPCAT3 on HBV replication in vitro and the chronic progression of hepatitis B infection based on the results of lipidomic.
METHODS: Untargeted lipidomic analysis was employed to scrutinize discrepancies in lipid metabolites between 40 HBV-infected patients and those who spontaneously cleared the virus. Subsequently, enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunospot assay (ELISPOT), western blotting (WB) and quantitative polymerase chain reaction (qPCR) were utilized to investigate LPCAT3 expression and assess HBV replication and endoplasmic reticulum stress (ERS).
RESULTS: A comparative analysis between HBV-infected patients and those experiencing spontaneous clearance revealed significant disparities in 24 lipid metabolites. Among these, phosphatidylcholine (PC) and lysophosphatidylcholine (LPC), constituting half (12/24) of the identified metabolites, were identified as substrates and products of LPCAT3. In vitro studies demonstrated that inhibiting LPCAT3 led to elevated expression levels of hepatitis B surface antigen (HBsAg), HBV-DNA, and interferon-γ (IFN-γ) (P < 0.05), indicative of heightened HBV replication. Furthermore, LPCAT3 inhibition significantly upregulated the expression of genes associated with ERS (P < 0.05).
CONCLUSIONS: Inhibiting LPCAT3 significantly correlates with HBV replication and induces inflammation by enhancing ERS. We hypothesize that LPCAT3 serves as a potential biomarker for hepatitis B virus replication and chronic progression. Furthermore, these findings elucidate the malignant progression of HBV infection from the standpoint of lipid metabolism, offering a novel insight for subsequent mechanistic exploration or therapeutic studies.
LAY SUMMARY: LPCAT3 inhibition enhances endoplasmic reticulum stress and HBV replication by altering the membrane phospholipid composition and promotes chronic hepatitis B progression.

Keywords:  Endoplasmic reticulum stress; HBV; LPCAT3; Lipid metabolism

DOI:  https://doi.org/10.1016/j.intimp.2024.113337
Int J Mol Sci. 2024 Sep 29. pii: 10489. [Epub ahead of print]25(19):

Cholesterol and Cholesterol-Lowering Medications in COVID-19-An Unresolved Matter.

Thomas Grewal, Mai Khanh Linh Nguyen, Christa Buechler.

  Infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 2019 (COVID-19), a disease with very heterogeneous symptoms. Dyslipidaemia is prevalent in at least 20% of Europeans, and dyslipidaemia before SARS-CoV-2 infection increases the risk for severe COVID-19 and mortality by 139%. Many reports described reduced serum cholesterol levels in virus-infected patients, in particular in those with severe disease. The liver is the major organ for lipid homeostasis and hepatic dysfunction appears to occur in one in five patients infected with SARS-CoV-2. Thus, SARS-CoV-2 infection, COVID-19 disease severity and liver injury may be related to impaired cholesterol homeostasis. These observations prompted efforts to assess the therapeutic opportunities of cholesterol-lowering medications to reduce COVID-19 severity. The majority of studies implicate statins to have beneficial effects on disease severity and outcome in COVID-19. Proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies have also shown potential to protect against COVID-19. This review describes the relationship between systemic cholesterol levels, liver injury and COVID-19 disease severity. The potential effects of statins and PCSK9 in COVID-19 are summarised. Finally, the relationship between cholesterol and lung function, the first organ to be affected by SARS-CoV-2, is described.

Keywords:  LDL receptor; albumin; aminotransferase; statin

DOI:  https://doi.org/10.3390/ijms251910489
J Immunol. 2024 Oct 14. pii: ji2400088. [Epub ahead of print]

Hepatitis B Virus Increases SphK1-S1P Synthesis by Promoting the Availability of the Transcription Factor USF1.

Lu Zhang, Ya-Hui Song, Juan Liu, Yin-Xia Zhao, Ruo-Ran Zhou, Jun-Chi Xu, Jun He, You-Li Lu, Wen-Juan Gan, Xing-Sheng Lu, Min Li, Peng Zhou, Lin Wang, Qing-Zhen Han.

Hepatitis B virus (HBV) is the most common chronic viral infection globally, affecting ∼360 million people and causing about 1 million deaths annually due to end-stage liver disease or hepatocellular carcinoma. Current antiviral treatments rarely achieve a functional cure for chronic hepatitis B, highlighting the need for improved monitoring and intervention strategies. This study explores the role of the sphingosine kinase 1 (SphK1)-sphingosine-1-phosphate (S1P) axis in HBV-related liver injury. We investigated the association between serum S1P concentration and HBV DNA levels in chronic hepatitis B patients, finding a significant positive correlation. Additionally, SphK1 was elevated in liver tissues of HBV-positive hepatocellular carcinoma patients, particularly in HBsAg-positive regions. HBV infection models in HepG2-sodium taurocholate cotransporting polypeptide cells confirmed that HBV enhances SphK1 expression and S1P production. Inhibition of HBV replication through antiviral agents and the CRISPR-Cas9 system reduced SphK1 and S1P levels. Further, we identified the transcription factor USF1 as a key regulator of SphK1 expression during HBV infection. USF1 binds to the SphK1 promoter, increasing its transcriptional activity, and is upregulated in response to HBV infection. In vivo studies in mice demonstrated that HBV exposure promotes the expression of USF1 and SphK1-S1P. These findings suggest that the SphK1-S1P axis, regulated by HBV-induced USF1, could serve as a potential biomarker and therapeutic target for HBV-related liver injury.

DOI: https://doi.org/10.4049/jimmunol.2400088
Neuroscience. 2024 Oct 16. pii: S0306-4522(24)00532-3. [Epub ahead of print]

The tryptophan catabolite or kynurenine pathway in Long COVID disease: A systematic review and meta-analysis.

Abbas F Almulla, Yanin Thipakorn, Bo Zhou, Aristo Vojdani, Rossitsa Paunova, Michael Maes.

   BACKGROUND: Recent studies confirm the involvement of activated immune-inflammatory responses and increased oxidative and nitrosative stress in Long COVID (LC) disease. However, the influence of these pathways on the metabolism of tryptophan (TRP) through the TRP catabolite (TRYCAT) pathway and their mediating effects on LC pathophysiology, has not been fully explored.
OBJECTIVE: This meta-analysis investigates peripheral TRP and TRYCAT levels and the TRYCAT pathway in patients with LC disease.
METHOD: This review utilized systematic searches of PubMed, Google Scholar, and SciFinder, including 14 full-text articles and 1,167 participants, consisting of 480 patients with LC and 687 normal controls.
RESULTS: The results indicated a significant increase in the kynurenine (KYN)/TRP ratio, with a large effect size (standardized mean difference, SMD = 0.755; confidence intervals, CI: 0.119;1.392), in LC patients compared to normal controls. Additionally, LC patients exhibited a significant decrease in TRP levels (SMD = -0.520, CI: -0.793; -0.246) and an increase in KYN levels after imputing missing studies (SMD = 1.176, CI: 0.474; 1.877), suggesting activation of the Indoleamine 2,3-dioxygenase (IDO) enzyme and upregulation of the TRYCAT pathway. No significant elevation in TRYCAT-related neurotoxicity, kynurenic acid (KA)/KYN and 3-hydroxykynurenine (3-HK)/KYN ratios were observed in LC patients compared to normal controls.
CONCLUSION: The current findings indicate that an activated TRYCAT pathway, characterized by decreased TRP levels and maybe elevated KYN levels, plays a significant role in the pathophysiology of LC.

Keywords:  Biomarkers; Inflammation; Neuroimmune; Neurotoxicity; Oxidative and nitrosative stress

DOI:  https://doi.org/10.1016/j.neuroscience.2024.10.021
bioRxiv. 2024 Oct 11. pii: 2024.10.10.617691. [Epub ahead of print]

Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-γ induced IRF1.

Tyron Chang, Jessica Alvarez, Sruthi Chappidi, Stacey Crockett, Mahsa Sorouri, Robert C Orchard, Dustin C Hancks.

Interferon (IFN) induced activities are critical, early determinants of immune responses and infection outcomes. A key facet of IFN responses is the upregulation of hundreds of mRNAs termed interferon-stimulated genes (ISGs) that activate intrinsic and cell-mediated defenses. While primary interferon signaling is well-delineated, other layers of regulation are less explored but implied by aberrant ISG expression signatures in many diseases in the absence of infection. Consistently, our examination of tonic ISG levels across uninfected human tissues and individuals revealed three ISG subclasses. As tissue identity and many comorbidities with increased virus susceptibility are characterized by differences in metabolism, we characterized ISG responses in cells grown in media known to favor either aerobic glycolysis (glucose) or oxidative phosphorylation (galactose supplementation). While these conditions over time had a varying impact on the expression of ISG RNAs, the differences were typically greater between treatments than between glucose/galactose. Interestingly, extended interferon-priming led to divergent expression of two ISG proteins: upregulation of IRF1 in IFN-γ/glucose and increased IFITM3 in galactose by IFN-α and IFN-γ. In agreement with a hardwired response, glucose/galactose regulation of interferon-γ induced IRF1 is conserved in unrelated mouse and cat cell types. In galactose conditions, proteasome inhibition restored interferon-γ induced IRF1 levels to that of glucose/interferon-γ. Glucose/interferon-γ decreased replication of the model poxvirus vaccinia at low MOI and high MOIs. Vaccinia replication was restored by IRF1 KO. In contrast, but consistent with differential regulation of IRF1 protein by glucose/galactose, WT and IRF1 KO cells in galactose media supported similar levels of vaccinia replication regardless of IFN-γ priming. Also associated with glucose/galactose is a seemingly second block at a very late stage in viral replication which results in reductions in herpes- and poxvirus titers but not viral protein expression. Collectively, these data illustrate a novel layer of regulation for the key ISG protein, IRF1, mediated by glucose/galactose and imply unappreciated subprograms embedded in the interferon response. In principle, such cellular circuitry could rapidly adapt immune responses by sensing changing metabolite levels consumed during viral replication and cell proliferation.

DOI: https://doi.org/10.1101/2024.10.10.617691
Int J Mol Sci. 2024 Sep 26. pii: 10366. [Epub ahead of print]25(19):

Betulonic Acid Inhibits Type-2 Porcine Reproductive and Respiratory Syndrome Virus Replication by Downregulating Cellular ATP Production.

Feixiang Long, Lizhan Su, Mingxin Zhang, Shuhua Wang, Qian Sun, Jinyi Liu, Weisan Chen, Haihong Wang, Jianxin Chen.

  Porcine reproductive and respiratory syndrome (PRRS), caused by PRRS virus (PRRSV) infection, has been a serious threat to the pork industry worldwide and continues to bring significant economic loss. Current vaccination strategies offer limited protection against PRRSV transmission, highlighting the urgent need for novel antiviral approaches. In the present study, we reported for the first time that betulonic acid (BA), a widely available pentacyclic triterpenoids throughout the plant kingdom, exhibited potent inhibition on PRRSV infections in both Marc-145 cells and primary porcine alveolar macrophages (PAMs), with IC50 values ranging from 3.3 µM to 3.7 µM against three different type-2 PRRSV strains. Mechanistically, we showed that PRRSV replication relies on energy supply from cellular ATP production, and BA inhibits PRRSV infection by reducing cellular ATP production. Our findings indicate that controlling host ATP production could be a potential strategy to combat PRRSV infections, and that BA might be a promising therapeutic agent against PRRSV epidemics.

Keywords:  adenosine triphosphate (ATP); anti-PRRSV activity; betulonic acid (BA); porcine reproductive and respiratory syndrome virus (PRRSV)

DOI:  https://doi.org/10.3390/ijms251910366