bims-mevinf 2024-03-10 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024–03–10
ten papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Integrated Metabolomic and transcriptomic analyses reveal deoxycholic acid promotes transmissible gastroenteritis virus infection by inhibiting phosphorylation of NF-κB and STAT3.
Modulation of nucleotide metabolism by picornaviruses.
PI3K/AKT mediated De novo fatty acid synthesis regulates RIG-1/MDA-5-dependent type I IFN responses in BVDV-infected CD8+T cells.
PMI-controlled mannose metabolism and glycosylation determines tissue tolerance and virus fitness.
Editorial: Host-cell pathways modulated by influenza virus infection: new insight into pathogenetic mechanisms and cell-targeted antiviral strategies.
Fatty acid oxidation fuels natural killer cell responses against infection and cancer.
The role of pyroptosis in viral infection.
Shotgun metagenomics and systemic targeted metabolomics highlight indole-3-propionic acid as a protective gut microbial metabolite against influenza infection.
Heme oxygenase-1 is an equid alphaherpesvirus 8 replication restriction host protein and suppresses viral replication via the PKCβ/ERK1/ERK2 and NO/cGMP/PKG pathway.
Non-cytopathic bovine viral diarrhea virus (BVDV) inhibits innate immune responses via induction of mitophagy.

BMC Genomics. 2024 Mar 04. 25(1): 239

Integrated Metabolomic and transcriptomic analyses reveal deoxycholic acid promotes transmissible gastroenteritis virus infection by inhibiting phosphorylation of NF-κB and STAT3.

Yajing Zhou, Chao Xu, Shanshen Gu, Yeyi Xiao, Shenglong Wu, Haifei Wang, Wenbin Bao.

   BACKGROUND: Acute diarrhea, dehydration and death in piglets are all symptoms of transmissible gastroenteritis virus (TGEV), which results in significant financial losses in the pig industry. It is important to understand the pathogenesis and identify new antiviral targets by revealing the metabolic interactions between TGEV and host cells.
RESULTS: We performed metabolomic and transcriptomic analyses of swine testicular cells infected with TGEV. A total of 1339 differential metabolites and 206 differentially expressed genes were detected post TEGV infection. The differentially expressed genes were significantly enriched in the HIF-1 signaling pathway and PI3K-Akt signaling. Integrated analysis of differentially expressed genes and differential metabolites indicated that they were significantly enriched in the metabolic processes such as nucleotide metabolism, biosynthesis of cofactors and purine metabolism. In addition, the results showed that most of the detected metabolites involved in the bile secretion was downregulated during TGEV infection. Furthermore, exogenous addition of key metabolite deoxycholic acid (DCA) significantly enhanced TGEV replication by NF-κB and STAT3 signal pathways.
CONCLUSIONS: We identified a significant metabolite, DCA, related to TGEV replication. It added TGEV replication in host cells by inhibiting phosphorylation of NF-κB and STAT3. This study provided novel insights into the metabolomic and transcriptomic alterations related to TGEV infection and revealed potential molecular and metabolic targets for the regulation of TGEV infection.

Keywords:  Deoxycholic acid; Metabolomics; TGEV; Transcriptomics; Virus replication

DOI:  https://doi.org/10.1186/s12864-024-10167-8
PLoS Pathog. 2024 Mar;20(3): e1012036

Modulation of nucleotide metabolism by picornaviruses.

Lonneke V Nouwen, Martijn Breeuwsma, Esther A Zaal, Chris H A van de Lest, Inge Buitendijk, Marleen Zwaagstra, Pascal Balić, Dmitri V Filippov, Celia R Berkers, Frank J M van Kuppeveld.

Viruses actively reprogram the metabolism of the host to ensure the availability of sufficient building blocks for virus replication and spreading. However, relatively little is known about how picornaviruses-a large family of small, non-enveloped positive-strand RNA viruses-modulate cellular metabolism for their own benefit. Here, we studied the modulation of host metabolism by coxsackievirus B3 (CVB3), a member of the enterovirus genus, and encephalomyocarditis virus (EMCV), a member of the cardiovirus genus, using steady-state as well as 13C-glucose tracing metabolomics. We demonstrate that both CVB3 and EMCV increase the levels of pyrimidine and purine metabolites and provide evidence that this increase is mediated through degradation of nucleic acids and nucleotide recycling, rather than upregulation of de novo synthesis. Finally, by integrating our metabolomics data with a previously acquired phosphoproteomics dataset of CVB3-infected cells, we identify alterations in phosphorylation status of key enzymes involved in nucleotide metabolism, providing insight into the regulation of nucleotide metabolism during infection.

DOI: https://doi.org/10.1371/journal.ppat.1012036
Vet Microbiol. 2024 Feb 28. pii: S0378-1135(24)00056-7. [Epub ahead of print]291 110034

PI3K/AKT mediated De novo fatty acid synthesis regulates RIG-1/MDA-5-dependent type I IFN responses in BVDV-infected CD8+T cells.

Shan-Shan Liu, Tong-Tong Bai, Tao-Lin Que, An Luo, Yu-Xin Liang, Yu-Xin Song, Tian-Yi Liu, Jin-Wei Chen, Jing Li, Nan Li, Ze-Chen Zhang, Nan-Nan Chen, Yu Liu, Ze-Cai Zhang, Yu-Long Zhou, Xue Wang, Zhan-Bo Zhu.

  Bovine viral diarrhea virus (BVDV) has caused massive economic losses in the cattle business worldwide. Fatty acid synthase (FASN), a key enzyme of the fatty acid synthesis (FAS) pathway, has been shown to support virus replication. To investigate the role of fatty acids (FAs) in BVDV infection, we infected CD8+T lymphocytes obtained from healthy cattle with BVDV in vitro. During early cytopathic (CP) and noncytopathic (NCP) BVDV infection in CD8+ T cells, there is an increase in de novo lipid biosynthesis, resulting in elevated levels of free fatty acids (FFAs) and triglycerides (TG). BVDV infection promotes de novo lipid biosynthesis in a dose-dependent manner. Treatment with the FASN inhibitor C75 significantly reduces the phosphorylation of PI3K and AKT in BVDV-infected CD8+ T cells, while inhibition of PI3K with LY294002 decreases FASN expression. Both CP and NCP BVDV strains promote de novo fatty acid synthesis by activating the PI3K/AKT pathway. Further investigation shows that pharmacological inhibitors targeting FASN and PI3K concurrently reduce FFAs, TG levels, and ATP production, effectively inhibiting BVDV replication. Conversely, the in vitro supplementation of oleic acid (OA) to replace fatty acids successfully restored BVDV replication, underscoring the impact of abnormal de novo fatty acid metabolism on BVDV replication. Intriguingly, during BVDV infection of CD8+T cells, the use of FASN inhibitors prompted the production of IFN-α and IFN-β, as well as the expression of interferon-stimulated genes (ISGs). Moreover, FASN inhibitors induce TBK-1 phosphorylation through the activation of RIG-1 and MDA-5, subsequently activating IRF-3 and ultimately enhancing the IFN-1 response. In conclusion, our study demonstrates that BVDV infection activates the PI3K/AKT pathway to boost de novo fatty acid synthesis, and inhibition of FASN suppresses BVDV replication by activating the RIG-1/MDA-5-dependent IFN response.

Keywords:  Bovine viral diarrhea virus; De novo fatty acid synthesis; FASN; IFN-I; PI3K/AKT pathway

DOI:  https://doi.org/10.1016/j.vetmic.2024.110034
Nat Commun. 2024 Mar 08. 15(1): 2144

PMI-controlled mannose metabolism and glycosylation determines tissue tolerance and virus fitness.

Ronghui Liang, Zi-Wei Ye, Zhenzhi Qin, Yubin Xie, Xiaomeng Yang, Haoran Sun, Qiaohui Du, Peng Luo, Kaiming Tang, Bodan Hu, Jianli Cao, Xavier Hoi-Leong Wong, Guang-Sheng Ling, Hin Chu, Jiangang Shen, Feifei Yin, Dong-Yan Jin, Jasper Fuk-Woo Chan, Kwok-Yung Yuen, Shuofeng Yuan.

Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered immunometabolic response cascade and reduces tissue damage. Safe and inexpensive D-mannose can compete with glucose for the same transporter and hexokinase. Such competitions suppress glycolysis, reduce mitochondrial reactive-oxygen-species and succinate-mediated hypoxia-inducible factor-1α, and thus reduce virus-induced proinflammatory cytokine production. The combinatorial treatment by D-mannose and antiviral monotherapy exhibits in vivo synergy despite delayed antiviral treatment in mouse model of virus infections. Phosphomannose isomerase (PMI) knockout cells are viable, whereas addition of D-mannose to the PMI knockout cells blocks cell proliferation, indicating that PMI activity determines the beneficial effect of D-mannose. PMI inhibition suppress a panel of virus replication via affecting host and viral surface protein glycosylation. However, D-mannose does not suppress PMI activity or virus fitness. Taken together, PMI-centered therapeutic strategy clears virus infection while D-mannose treatment reprograms glycolysis for control of collateral damage.

DOI: https://doi.org/10.1038/s41467-024-46415-4
Front Cell Infect Microbiol. 2024 ;14 1372896

Editorial: Host-cell pathways modulated by influenza virus infection: new insight into pathogenetic mechanisms and cell-targeted antiviral strategies.

Marta De Angelis, Paola Checconi, David Olagnier.



Keywords:  host-cell targeted therapy; host-virus interactions; inflammation; influenza virus; oxidative stress

DOI:  https://doi.org/10.3389/fcimb.2024.1372896
Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2319254121

Fatty acid oxidation fuels natural killer cell responses against infection and cancer.

Sam Sheppard, Katja Srpan, Wendy Lin, Mariah Lee, Rebecca B Delconte, Mark Owyong, Peter Carmeliet, Daniel M Davis, Joao B Xavier, Katharine C Hsu, Joseph C Sun.

  Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.

Keywords:  NK cells; T cells; cancer; metabolism; virus infection

DOI:  https://doi.org/10.1073/pnas.2319254121
Arch Virol. 2024 Mar 08. 169(3): 69

The role of pyroptosis in viral infection.

Zhen Zhao, Yan Zhang, Bing Luo.

Pyroptosis, also known as inflammatory necrosis, is a form of programmed cell death, which is an important natural immune response. Pyroptosis plays a major role in combating pathogenic infections. The mechanism of pyroptosis is distinct from other forms of cell death and is characterized by its dependence on inflammatory caspases (mainly caspases 1, 4, 5, and 11). Activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory vesicles is involved in caspase-1 activation and cleavage, which in turn triggers cleavage and multimerization of multiple gasdermin family members, including gasdermin-D (GSDMD). This further leads to cell perforation and cellular distension, causing cell membrane rupture, resulting in a massive efflux of cell contents, which triggers inflammatory reactions. In recent years, detailed study of viral diseases, has demonstrated that pyroptosis is closely associated with the development of viral diseases. This article focuses on the mechanism of pyroptosis and the connection between pyroptosis and viral infection.

DOI: https://doi.org/10.1007/s00705-024-05978-9
Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2325067

Shotgun metagenomics and systemic targeted metabolomics highlight indole-3-propionic acid as a protective gut microbial metabolite against influenza infection.

Séverine Heumel, Vinícius de Rezende Rodovalho, Charlotte Urien, Florian Specque, Patrícia Brito Rodrigues, Cyril Robil, Lou Delval, Valentin Sencio, Amandine Descat, Lucie Deruyter, Stéphanie Ferreira, Marina Gomes Machado, Adeline Barthelemy, Fabiola Silva Angulo, Joel T Haas, Jean François Goosens, Isabelle Wolowczuk, Corinne Grangette, Yves Rouillé, Ghjuvan Grimaud, Marie Lenski, Benjamin Hennart, Marco Aurélio Ramirez Vinolo, François Trottein.

  The gut-to-lung axis is critical during respiratory infections, including influenza A virus (IAV) infection. In the present study, we used high-resolution shotgun metagenomics and targeted metabolomic analysis to characterize influenza-associated changes in the composition and metabolism of the mouse gut microbiota. We observed several taxonomic-level changes on day (D)7 post-infection, including a marked reduction in the abundance of members of the Lactobacillaceae and Bifidobacteriaceae families, and an increase in the abundance of Akkermansia muciniphila. On D14, perturbation persisted in some species. Functional scale analysis of metagenomic data revealed transient changes in several metabolic pathways, particularly those leading to the production of short-chain fatty acids (SCFAs), polyamines, and tryptophan metabolites. Quantitative targeted metabolomics analysis of the serum revealed changes in specific classes of gut microbiota metabolites, including SCFAs, trimethylamine, polyamines, and indole-containing tryptophan metabolites. A marked decrease in indole-3-propionic acid (IPA) blood level was observed on D7. Changes in microbiota-associated metabolites correlated with changes in taxon abundance and disease marker levels. In particular, IPA was positively correlated with some Lactobacillaceae and Bifidobacteriaceae species (Limosilactobacillus reuteri, Lactobacillus animalis) and negatively correlated with Bacteroidales bacterium M7, viral load, and inflammation markers. IPA supplementation in diseased animals reduced viral load and lowered local (lung) and systemic inflammation. Treatment of mice with antibiotics targeting IPA-producing bacteria before infection enhanced viral load and lung inflammation, an effect inhibited by IPA supplementation. The results of this integrated metagenomic-metabolomic analysis highlighted IPA as an important contributor to influenza outcomes and a potential biomarker of disease severity.

Keywords:  Influenza; disease severity; gut microbiota; indole-3-propionic acid; metabolomics; shotgun metagenomics

DOI:  https://doi.org/10.1080/19490976.2024.2325067
Microbiol Spectr. 2024 Mar 05. e0322023

Heme oxygenase-1 is an equid alphaherpesvirus 8 replication restriction host protein and suppresses viral replication via the PKCβ/ERK1/ERK2 and NO/cGMP/PKG pathway.

Tongtong Wang, Shuwen Li, Xinyao Hu, Yiqing Geng, Li Chen, Wenqiang Liu, Juan Zhao, Wenxia Tian, Changfa Wang, Yubao Li, Liangliang Li.

  Equid alphaherpesvirus 8 (EqHV-8) is one of the most economically important viruses that is known to cause severe respiratory disease, abortion, and neurological syndromes in equines. However, no effective vaccines or therapeutic agents are available to control EqHV-8 infection. Heme oxygenase-1 (HO-1) is an antioxidant defense enzyme that displays significant cytoprotective effects against different viral infections. However, the literature on the function of HO-1 during EqHV-8 infection is little. We explored the effects of HO-1 on EqHV-8 infection and revealed its potential mechanisms. Our results demonstrated that HO-1 induced by cobalt-protoporphyrin (CoPP) or HO-1 overexpression inhibited EqHV-8 replication in susceptible cells. In contrast, HO-1 inhibitor (zinc protoporphyria) or siRNA targeting HO-1 reversed the anti-EqHV-8 activity. Furthermore, biliverdin, a metabolic product of HO-1, mediated the anti-EqHV-8 effect of HO-1 via both the protein kinase C (PKC)β/extracellular signal-regulated kinase (ERK)1/ERK2 and nitric oxide (NO)-dependent cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathways. In addition, CoPP protected the mice by reducing the EqHV-8 infection in the lungs. Altogether, these results indicated that HO-1 can be developed as a promising therapeutic strategy to control EqHV-8 infection.IMPORTANCEEqHV-8 infections have threatened continuously donkey and horse industry worldwide, which induces huge economic losses every year. However, no effective vaccination strategies or drug against EqHV-8 infection until now. Our present study found that one host protien HO-1 restrict EqHV-8 replication in vitro and in vivo. Furthermore, we demonstrate that HO-1 and its metabolite biliverdin suppress EqHV-8 relication via the PKCβ/ERK1/ERK2 and NO/cGMP/PKG pathways. Hence, we believe that HO-1 can be developed as a promising therapeutic strategy to control EqHV-8 infection.

Keywords:  EqHV-8; HO-1; anti-viral effect; biliverdin; mouse model

DOI:  https://doi.org/10.1128/spectrum.03220-23
Vet Res. 2024 Mar 05. 55(1): 27

Non-cytopathic bovine viral diarrhea virus (BVDV) inhibits innate immune responses via induction of mitophagy.

Zhijun Li, Ying Zhang, Bao Zhao, Qinghong Xue, Chunjiang Wang, Siyu Wan, Jingyu Wang, Xiwen Chen, Xuefeng Qi.

  Bovine viral diarrhea virus (BVDV) belongs to the genus Pestivirus within the family Flaviviridae. Mitophagy plays important roles in virus-host interactions. Here, we provide evidence that non-cytopathic (NCP) BVDV shifts the balance of mitochondrial dynamics toward fission and induces mitophagy to inhibit innate immune responses. Mechanistically, NCP BVDV triggers the translocation of dynamin-related protein (Drp1) to mitochondria and stimulates its phosphorylation at Ser616, leading to mitochondrial fission. In parallel, NCP BVDV-induced complete mitophagy via Parkin-dependent pathway contributes to eliminating damaged mitochondria to inhibit MAVS- and mtDNA-cGAS-mediated innate immunity responses, mtROS-mediated inflammatory responses and apoptosis initiation. Importantly, we demonstrate that the LIR motif of ERNS is essential for mitophagy induction. In conclusion, this study is the first to show that NCP BVDV-induced mitophagy plays a central role in promoting cell survival and inhibiting innate immune responses in vitro.

Keywords:  BVDV; MAVS; PINK1-Parkin; cGAS; innate immunity; mitophagy; persistent infection

DOI:  https://doi.org/10.1186/s13567-024-01284-z