bims-mevinf 2024-03-17 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024‒03‒17
eleven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

UMP-CMP kinase 2 inhibits ZIKV replication through activation of type I IFN signaling pathway.
Oxidative stress governs mosquito innate immune signalling to reduce chikungunya virus infection in Aedes-derived cells.
Lipidomics reveals the significance and mechanism of the cellular ceramide metabolism for rotavirus replication.
Metabolic regulation of type I interferon production.
Metabolic signatures of acute respiratory distress syndrome: COVID VS non-COVID.
2-Bromopalmitate depletes lipid droplets to inhibit viral replication.
Enteric coronavirus PDCoV evokes a non-Warburg effect by hijacking pyruvic acid as a metabolic hub.
Modulations of Homeostatic ACE2, CD147, GRP78 Pathways Correlate with Vascular and Endothelial Performance Markers during Pulmonary SARS-CoV-2 Infection.
Metabolic Deficiencies Underlie Plasmacytoid Dendritic Cell Exhaustion After Viral Infection.
RNA-Seq time-course analysis of neural precursor cell transcriptome in response to herpes simplex Virus-1 infection.
Essential functions of Inositol hexakisphosphate (IP6) in Murine Leukemia Virus replication.

J Med Virol. 2024 Mar;96(3): e29533

UMP-CMP kinase 2 inhibits ZIKV replication through activation of type I IFN signaling pathway.

Ya Zhu, Qi Tan, Yaoqiang Shi, Qingyuan Li, Shilin Li, Wenxian Wen, He Xie, Bin Li, Xiaoqiong Duan, Limin Chen.

  Cytidine/uridine monophosphate kinase 2 (UMP-CMP kinase 2, CMPK2) has been reported as an antiviral interferon-stimulated gene (ISG). We previously observed that the expression of CMPK2 was significantly upregulated after Zika Virus (ZIKV) infection in A549 cells. However, the association and the underlying mechanisms between CMPK2 induction and ZIKV replication remain to be determined. We investigated the induction of CMPK2 during ZIKV infection and the effect of CMPK2 on ZIKV replication in A549, U251, Vero, IFNAR-deficient U5A and its parental 2fTGH cells, Huh7 and its RIG-I-deficient derivatives Huh7.5.1 cells. The activation status of Jak-STAT signaling pathway was determined by detecting the phosphorylation level of STAT1, the activity of interferon stimulated response element (ISRE) and the expression of several interferon stimulated genes (ISGs). We found that ZIKV infection induced CMPK2 expression through an IFNAR and RIG-I dependent manner. Overexpression of CMPK2 inhibited while CMPK2 knockdown promoted ZIKV replication in A549 and U251 cells. Mechanically, we found that CMPK2 overexpression increased IFNβ expression and activated Jak/STAT signaling pathway as shown by the increased level of p-STAT1, enhanced activity of ISRE, and the upregulated expression of downstream ISGs. These findings suggest that ZIKV infection induced CMPK2 expression, which inhibited ZIKV replication and serves as a positive feedback regulator for IFN-Jak/STAT pathway.

Keywords:  CMPK2; Jak/STAT signaling pathway; ZIKV

DOI:  https://doi.org/10.1002/jmv.29533
J Gen Virol. 2024 Mar;105(3):

Oxidative stress governs mosquito innate immune signalling to reduce chikungunya virus infection in Aedes-derived cells.

Divya Mehta, Sakshi Chaudhary, Sujatha Sunil.

  Arboviruses such as chikungunya, dengue and zika viruses cause debilitating diseases in humans. The principal vector species that transmits these viruses is the Aedes mosquito. Lack of substantial knowledge of the vector species hinders the advancement of strategies for controlling the spread of arboviruses. To supplement our information on mosquitoes' responses to virus infection, we utilized Aedes aegypti-derived Aag2 cells to study changes at the transcriptional level during infection with chikungunya virus (CHIKV). We observed that genes belonging to the redox pathway were significantly differentially regulated. Upon quantifying reactive oxygen species (ROS) in the cells during viral infection, we further discovered that ROS levels are considerably higher during the early hours of infection; however, as the infection progresses, an increase in antioxidant gene expression suppresses the oxidative stress in cells. Our study also suggests that ROS is a critical regulator of viral replication in cells and inhibits intracellular and extracellular viral replication by promoting the Rel2-mediated Imd immune signalling pathway. In conclusion, our study provides evidence for a regulatory role of oxidative stress in infected Aedes-derived cells.

Keywords:  Aag2 cells; Aedes aegypti; chikungunya virus; reactive oxygen species; transcriptomic analysis

DOI:  https://doi.org/10.1099/jgv.0.001966
J Virol. 2024 Mar 15. e0006424

Lipidomics reveals the significance and mechanism of the cellular ceramide metabolism for rotavirus replication.

Ran Tao, Xi Cheng, Laqiang Gu, Jinzhu Zhou, Xuejiao Zhu, Xuehan Zhang, Rongli Guo, Wei Wang, Bin Li.

  As one of the most important causative agents of severe gastroenteritis in children, piglets, and other young animals, species A rotaviruses have adversely impacted both human health and the global swine industry. Vaccines against rotaviruses (RVs) are insufficiently effective, and no specific treatment is available. To understand the relationships between porcine RV (PoRV) infection and enterocytes in terms of the cellular lipid metabolism, we performed an untargeted liquid chromatography mass spectrometry (LC-MS) lipidomics analysis of PoRV-infected IPEC-J2 cells. Herein, a total of 451 lipids (263 upregulated lipids and 188 downregulated lipids), spanning sphingolipid, glycerolipid, and glycerophospholipids, were significantly altered compared with the mock-infected group. Interestingly, almost all the ceramides among these lipids were upregulated during PoRV infection. LC-MS analysis was used to validated the lipidomics data and demonstrated that PoRV replication increased the levels of long-chain ceramides (C16-ceramide, C18-ceramide, and C24-ceramide) in cells. Furthermore, we found that these long-chain ceramides markedly inhibited PoRV infection and that their antiviral actions were exerted in the replication stage of PoRV infection. Moreover, downregulation of endogenous ceramides with the ceramide metabolic inhibitors enhanced PoRV propagation. Increasing the levels of ceramides by the addition of C6-ceramide strikingly suppressed the replication of diverse RV strains. We further found that the treatment with an apoptotic inhibitor could reverse the antiviral activity of ceramide against PoRV replication, demonstrating that ceramide restricted RV infection by inducing apoptosis. Altogether, this study revealed that ceramides played an antiviral role against RV infection, providing potential approaches for the development of antiviral therapies.IMPORTANCERotaviruses (RVs) are among the most important zoonosis viruses, which mainly infected enterocytes of the intestinal epithelium causing diarrhea in children and the young of many mammalian and avian species. Lipids play an essential role in viral infection. A comprehensive understanding of the interaction between RV and lipid metabolism in the enterocytes will be helpful to control RV infection. Here, we mapped changes in enterocyte lipids following porcine RV (PoRV) infection using an untargeted lipidomics approach. We found that PoRV infection altered the metabolism of various lipid species, especially ceramides (derivatives of the sphingosine). We further demonstrated that PoRV infection increased the accumulation of ceramides and that ceramides exerted antiviral effects on RV replication by inducing apoptosis. Our findings fill a gap in understanding the alterations of lipid metabolism in RV-infected enterocytes and highlight the antiviral effects of ceramides on RV infection, suggesting potential approaches to control RV infection.

Keywords:  apoptosis; ceramide; inhibition; lipidomics; rotavirus; viral replication

DOI:  https://doi.org/10.1128/jvi.00064-24
Immunol Rev. 2024 Mar 11.

Metabolic regulation of type I interferon production.

Shane M O'Carroll, Fiona D R Henkel, Luke A J O'Neill.

  Over the past decade, there has been a surge in discoveries of how metabolic pathways regulate immune cell function in health and disease, establishing the field of immunometabolism. Specifically, pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and those involving lipid metabolism have been implicated in regulating immune cell function. Viral infections cause immunometabolic changes which lead to antiviral immunity, but little is known about how metabolic changes regulate interferon responses. Interferons are critical cytokines in host defense, rapidly induced upon pathogen recognition, but are also involved in autoimmune diseases. This review summarizes how metabolic change impacts interferon production. We describe how glycolysis, lipid metabolism (specifically involving eicosanoids and cholesterol), and the TCA cycle-linked intermediates itaconate and fumarate impact type I interferons. Targeting these metabolic changes presents new therapeutic possibilities to modulate type I interferons during host defense or autoimmune disorders.

Keywords:  Immunometabolism; interferons; macrophage; metabolism

DOI:  https://doi.org/10.1111/imr.13318
Am J Physiol Lung Cell Mol Physiol. 2024 Mar 12.

Metabolic signatures of acute respiratory distress syndrome: COVID VS non-COVID.

Xiangming Ji, Hong-Long Ji.

  Acute respiratory distress syndrome (ARDS) is a fatal pulmonary disorder characterized by severe hypoxia and inflammation. Systemic and pulmonary infections are a leading cause of ARDS. The common respiratory pathogens include bacteria and virus, including Pseudomonas aeruginosa, Streptococcus aureus, Enterobacter species, coronavirus, influenza, and herpesviruses. COVID-19-associated ARDS is a new etiologic phenotype of the disease. The pathogenesis of ARDS caused by bacteria and viruses differs in host immune responses and lung mesenchymal injury. We postulate that both systemic and lung metabolomics of ARDS induced by virus may differ from those infected by other pathogens. This review aims to compare the metabolic signatures in blood and lung specimens. Both common and SARS-CoV-2-specific metabolomic signatures were comprehensively reviewed. The differences in metabolic profiles between COVID-19 and other etiology-associated ARDS may uncover new biomarkers, pathogenic mechanisms, druggable targets, and differential diagnosis.

Keywords:  Acute respiratory distress syndrome (ARDS); COVID-19; lipidomics; metabolomics

DOI:  https://doi.org/10.1152/ajplung.00266.2023
J Virol. 2024 Mar 15. e0017124

2-Bromopalmitate depletes lipid droplets to inhibit viral replication.

Dongxiao Liu, Ruth Cruz-Cosme, Yong Wu, Julian Leibowitz, Qiyi Tang.

  The global impact of emerging viral infections emphasizes the urgent need for effective broad-spectrum antivirals. The cellular organelle, lipid droplet (LD), is utilized by many types of viruses for replication, but its reduction does not affect cell survival. Therefore, LD is a potential target for developing broad-spectrum antivirals. In this study, we found that 2-bromopalmitate (2 BP), a previously defined palmitoylation inhibitor, depletes LD across all studied cell lines and exerts remarkable antiviral effects on different coronaviruses. We comprehensively utilized 2 BP, alongside other palmitoylation inhibitors such as cerulenin and 2-fluoro palmitic acid (2-FPA), as well as the enhancer palmostatin B and evaluated their impact on LD and the replication of human coronaviruses (hCoV-229E, hCoV-Oc43) and murine hepatitis virus (MHV-A59) at non-cytotoxic concentrations. While cerulenin and 2-FPA exhibited moderate inhibition of viral replication, 2 BP exhibited a much stronger suppressive effect on MHV-A59 replication, although they share similar inhibitory effects on palmitoylation. As expected, palmostatin B significantly enhanced viral replication, it failed to rescue the inhibitory effects of 2 BP, whereas it effectively counteracted the effects of cerulenin and 2-FPA. This suggests that the mechanism that 2 BP used to inhibit viral replication is beyond palmitoylation inhibition. Further investigations unveil that 2 BP uniquely depletes LDs, a phenomenon not exhibited by 2-FPA and cerulenin. Importantly, the depletion of LDs was closely associated with the inhibition of viral replication because the addition of oleic acid to 2 BP significantly rescued LD depletion and its inhibitory effects on MHV-A59. Our findings indicate that the inhibitory effects of 2 BP on viral replication primarily stem from LD disruption rather than palmitoylation inhibition. Intriguingly, fatty acid (FA) assays demonstrated that 2 BP reduces the FA level in mitochondria while concurrently increasing FA levels in the cytoplasm. These results highlight the crucial role of LDs in viral replication and uncover a novel biological activity of 2 BP. These insights contribute to the development of broad-spectrum antiviral strategies.IMPORTANCE: In our study, we conducted a comparative investigation into the antiviral effects of palmitoylation inhibitors including 2-bromopalmitate (2-BP), 2-fluoro palmitic acid (2-FPA), and cerulenin. Surprisingly, we discovered that 2-BP has superior inhibitory effects on viral replication compared to 2-FPA and cerulenin. However, their inhibitory effects on palmitoylation were the same. Intrigued by this finding, we delved deeper into the underlying mechanism of 2-BP's potent antiviral activity, and we unveiled a novel biological activity of 2-BP: depletion of lipid droplets (LDs). Importantly, we also highlighted the crucial role of LDs in viral replication. Our insights shed new light on the antiviral mechanism of LD depletion paving the way for the development of broad-spectrum antiviral strategies by targeting LDs.

Keywords:  2-bromopalmitate; MHV-A59; antiviral; coronavirus; lipid droplet; palmitoylation

DOI:  https://doi.org/10.1128/jvi.00171-24
Redox Biol. 2024 Mar 04. pii: S2213-2317(24)00088-0. [Epub ahead of print]71 103112

Enteric coronavirus PDCoV evokes a non-Warburg effect by hijacking pyruvic acid as a metabolic hub.

Guanning Su, Jiao Liu, Chenrui Duan, Puxian Fang, Liurong Fang, Yanrong Zhou, Shaobo Xiao.

  The Warburg effect, also referred as aerobic glycolysis, is a common metabolic program during viral infection. Through targeted metabolomics combined with biochemical experiments and various cell models, we investigated the central carbon metabolism (CCM) profiles of cells infected with porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus with zoonotic potential. We found that PDCoV infection required glycolysis but decreased glycolytic flux, exhibiting a non-Warburg effect characterized by pyruvic acid accumulation. Mechanistically, PDCoV enhanced pyruvate kinase activity to promote pyruvic acid anabolism, a process that generates pyruvic acid with concomitant ATP production. PDCoV also hijacked pyruvic acid catabolism to increase biosynthesis of non-essential amino acids (NEAAs), suggesting that pyruvic acid is an essential hub for PDCoV to scavenge host energy and metabolites. Furthermore, PDCoV facilitated glutaminolysis to promote the synthesis of NEAA and pyrimidines for optimal proliferation. Our work supports a novel CCM model after viral infection and provides potential anti-PDCoV drug targets.

Keywords:  Antiviral drug target; Central carbon metabolism; Metabolomic; Porcine deltacoronavirus; Pyruvic acid

DOI:  https://doi.org/10.1016/j.redox.2024.103112
Cells. 2024 Feb 29. pii: 432. [Epub ahead of print]13(5):

Modulations of Homeostatic ACE2, CD147, GRP78 Pathways Correlate with Vascular and Endothelial Performance Markers during Pulmonary SARS-CoV-2 Infection.

Annuurun Nisa, Ranjeet Kumar, Santhamani Ramasamy, Afsal Kolloli, Judith Olejnik, Sallieu Jalloh, Suryaram Gummuluru, Selvakumar Subbian, Yuri Bushkin.

  The pathologic consequences of Coronavirus Disease-2019 (COVID-19) include elevated inflammation and dysregulated vascular functions associated with thrombosis. In general, disruption of vascular homeostasis and ensuing prothrombotic events are driven by activated platelets, monocytes, and macrophages, which form aggregates (thrombi) attached to the endothelium lining of vessel walls. However, molecular pathways underpinning the pathological interactions between myeloid cells and endothelium during COVID-19 remain undefined. Here, we tested the hypothesis that modulations in the expression of cellular receptors angiotensin-converting enzyme 2 (ACE2), CD147, and glucose-regulated protein 78 (GRP78), which are involved in homeostasis and endothelial performance, are the hallmark responses induced by SARS-CoV-2 infection. Cultured macrophages and lungs of hamster model systems were used to test this hypothesis. The results indicate that while macrophages and endothelial cells are less likely to support SARS-CoV-2 proliferation, these cells may readily respond to inflammatory stimuli generated by the infected lung epithelium. SARS-CoV-2 induced modulations of tested cellular receptors correlated with corresponding changes in the mRNA expression of coagulation cascade regulators and endothelial integrity components in infected hamster lungs. Among these markers, tissue factor (TF) had the best correlation for prothrombotic events during SARS-CoV-2 infection. Furthermore, the single-molecule fluorescence in situ hybridization (smFISH) method alone was sufficient to determine the peak and resolution phases of SARS-CoV-2 infection and enabled screening for cellular markers co-expressed with the virus. These findings suggest possible molecular pathways for exploration of novel drugs capable of blocking the prothrombotic shift events that exacerbate COVID-19 pathophysiology and control the disease.

Keywords:  ACE2; CD147; COVID-19; GRP78; hamster; single-molecule FISH; thrombosis; vascular dysfunction

DOI:  https://doi.org/10.3390/cells13050432
bioRxiv. 2024 Mar 03. pii: 2024.02.28.582551. [Epub ahead of print]

Metabolic Deficiencies Underlie Plasmacytoid Dendritic Cell Exhaustion After Viral Infection.

Trever T Greene, Yeara Jo, Monica Macal, Ziyan Fang, Fawziyah S Khatri, Alicia L Codrington, Katelynn R Kazane, Carolina Chiale, Elizabeth Akbulut, Shobha Swaminathan, Yu Fujita, Patricia Fitzgerald-Bocarsly, Thekla Cordes, Christian Metallo, David A Scott, Elina I Zuniga.

Type I Interferons (IFN-I) are central to host protection against viral infections 1 . While any cell can produce IFN-I, Plasmacytoid Dendritic Cells (pDCs) make greater quantities and more varieties of these cytokines than any other cell type 2 . However, following an initial burst of IFN- I, pDCs lose their exceptional IFN-I production capacity and become "exhausted", a phenotype that associates with enhanced susceptibility to secondary infections 3-5 . Despite this apparent cost for the host, pDC exhaustion is conserved across multiple species and viral infections, but the underlying mechanisms and the potential evolutionary advantages are not well understood. Here we characterize pDC exhaustion and demonstrate that it is associated with a reduced capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a novel positive regulator of pDC IFN-I production in mice and humans, show that LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following a viral infection, and demonstrate that preservation of LDHB expression is sufficient to partially restore exhausted pDC function in vitro and in vivo . Furthermore, restoring LDHB in vivo in exhausted pDCs increased IFNAR dependent infection- associated pathology. Therefore, our work identifies a novel and conserved mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved but previously unexplained phenomenon of pDC exhaustion.

DOI: https://doi.org/10.1101/2024.02.28.582551
J Neurovirol. 2024 Mar 13.

RNA-Seq time-course analysis of neural precursor cell transcriptome in response to herpes simplex Virus-1 infection.

Joel A Wood, Srilakshmi Chaparala, Cecilia Bantang, Ansuman Chattopadhyay, Maribeth A Wesesky, Paul R Kinchington, Vishwajit L Nimgaonkar, David C Bloom, Leonardo D'Aiuto.

  The neurogenic niches within the central nervous system serve as essential reservoirs for neural precursor cells (NPCs), playing a crucial role in neurogenesis. However, these NPCs are particularly vulnerable to infection by the herpes simplex virus 1 (HSV-1). In the present study, we investigated the changes in the transcriptome of NPCs in response to HSV-1 infection using bulk RNA-Seq, compared to those of uninfected samples, at different time points post infection and in the presence or absence of antivirals. The results showed that NPCs upon HSV-1 infection undergo a significant dysregulation of genes playing a crucial role in aspects of neurogenesis, including genes affecting NPC proliferation, migration, and differentiation. Our analysis revealed that the CREB signaling, which plays a crucial role in the regulation of neurogenesis and memory consolidation, was the most consistantly downregulated pathway, even in the presence of antivirals. Additionally, cholesterol biosynthesis was significantly downregulated in HSV-1-infected NPCs. The findings from this study, for the first time, offer insights into the intricate molecular mechanisms that underlie the neurogenesis impairment associated with HSV-1 infection.

Keywords:  (hiPSCs); Herpes simplex virus (HSV); Human induced pluripotent stem cells; Neural precursor cells; Neurospheres; RNA-Seq; Time-course analysis

DOI:  https://doi.org/10.1007/s13365-024-01198-8
bioRxiv. 2024 Feb 27. pii: 2024.02.27.581940. [Epub ahead of print]

Essential functions of Inositol hexakisphosphate (IP6) in Murine Leukemia Virus replication.

Banhi Biswas, Kin Kui Lai, Harrison Bracey, Siddhartha A K Datta, Demetria Harvin, Gregory A Sowd, Christopher Aiken, Alan Rein.

We have investigated the function of inositol hexakisphosphate (IP6) and inositol pentakisphosphate (IP5) in the replication of murine leukemia virus (MLV). While IP6 is known to be critical for the life cycle of HIV-1, its significance in MLV remains unexplored. We find that IP6 is indeed important for MLV replication. It significantly enhances endogenous reverse transcription (ERT) in MLV. Additionally, a pelleting-based assay reveals that IP6 can stabilize MLV cores, thereby facilitating ERT. We find that IP5 and IP6 are packaged in MLV particles. However, unlike HIV-1, MLV depends upon the presence of IP6 and IP5 in target cells for successful infection. This IP6/5 requirement for infection is reflected in impaired reverse transcription observed in IP6/5-deficient cell lines. In summary, our findings demonstrate the importance of capsid stabilization by IP6/5 in the replication of diverse retroviruses; we suggest possible reasons for the differences from HIV-1 that we observed in MLV.

DOI: https://doi.org/10.1101/2024.02.27.581940