bims-mevinf 2023-12-10 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023–12–10
nine papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

HIF-1α promotes virus replication and cytokine storm in H1N1 virus-induced severe pneumonia through cellular metabolic reprogramming.
Zika virus remodelled ER membranes contain proviral factors involved in redox and methylation pathways.
SARS-CoV-2 nucleocapsid protein enhances the level of mitochondrial reactive oxygen species.
The integrated stress response signaling during the persistent HIV infection.
Transcriptome analysis of Huh7 cells upon Chikungunya virus infection and capsid transfection reveals regulation of distinct cellular and metabolic pathways.
Validation of nuclear receptor RORγ isoform 1 as a novel host-directed antiviral target based on the modulation of cholesterol levels.
The glycoprotein 5 of porcine reproductive and respiratory syndrome virus stimulates mitochondrial ROS to facilitate viral replication.
Duck hepatitis A virus type 1 infection induces hepatic metabolite and gut microbiota changes in ducklings.
Carnitine palmitoyl-transferase 1A is potentially involved in bovine herpesvirus 1 productive infection.

Virol Sin. 2023 Nov 30. pii: S1995-820X(23)00142-6. [Epub ahead of print]

HIF-1α promotes virus replication and cytokine storm in H1N1 virus-induced severe pneumonia through cellular metabolic reprogramming.

Xiaoxiao Meng, Yong Zhu, Wenyu Yang, Jiaxiang Zhang, Wei Jin, Rui Tian, Zhengfeng Yang, Ruilan Wang.

  The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine storm. However, the specific mechanisms triggering virus replication and cytokine storm are still not fully elucidated. Here, we identified HIF-1α as one of the major host molecules that facilitates H1N1 virus replication followed by cytokine storm in alveolar epithelial cells. Specifically, HIF-1α protein expression is upregulated after H1N1 infection. Deficiency of HIF-1α attenuates pulmonary injury, viral replication and cytokine storm in vivo. In addition, viral replication and cytokine storm were inhibited after HIF-1α knockdown in vitro. Mechanistically, the invasion of H1N1 virus into alveolar epithelial cells leads to a shift in glucose metabolism to glycolysis, with rapid production of ATP and lactate. Inhibition of glycolysis significantly suppresses viral replication and inflammatory responses. Further analysis revealed that H1N1-induced HIF-1α can promote the expression of hexokinase 2 (HK2), the key enzyme of glycolysis, and then not only provide energy for the rapid replication of H1N1 virus but also produce lactate, which reduces the accumulation of the MAVS/RIG-I complex and inhibits IFN-α/β production. In conclusion, this study demonstrated that the upregulation of HIF-1α by H1N1 infection augments viral replication and cytokine storm by cellular metabolic reprogramming toward glycolysis mainly through upregulation of HK2, providing a theoretical basis for finding potential targets for the treatment of severe pneumonia caused by H1N1 infection.

Keywords:  Glycolysis; H1N1; Hypoxia inducible factor-1α; Severe pneumonia; Virus replication

DOI:  https://doi.org/10.1016/j.virs.2023.11.010
Nat Commun. 2023 Dec 05. 14(1): 8045

Zika virus remodelled ER membranes contain proviral factors involved in redox and methylation pathways.

Solène Denolly, Alexey Stukalov, Uladzimir Barayeu, Alina N Rosinski, Paraskevi Kritsiligkou, Sebastian Joecks, Tobias P Dick, Andreas Pichlmair, Ralf Bartenschlager.

Zika virus (ZIKV) has emerged as a global health issue, yet neither antiviral therapy nor a vaccine are available. ZIKV is an enveloped RNA virus, replicating in the cytoplasm in close association with ER membranes. Here, we isolate ER membranes from ZIKV-infected cells and determine their proteome. Forty-six host cell factors are enriched in ZIKV remodeled membranes, several of these having a role in redox and methylation pathways. Four proteins are characterized in detail: thioredoxin reductase 1 (TXNRD1) contributing to folding of disulfide bond containing proteins and modulating ZIKV secretion; aldo-keto reductase family 1 member C3 (AKR1C3), regulating capsid protein abundance and thus, ZIKV assembly; biliverdin reductase B (BLVRB) involved in ZIKV induced lipid peroxidation and increasing stability of viral transmembrane proteins; adenosylhomocysteinase (AHCY) indirectly promoting m6A methylation of ZIKV RNA by decreasing the level of S- adenosyl homocysteine and thus, immune evasion. These results highlight the involvement of redox and methylation enzymes in the ZIKV life cycle and their accumulation at virally remodeled ER membranes.

DOI: https://doi.org/10.1038/s41467-023-43665-6
J Med Virol. 2023 Dec;95(12): e29270

SARS-CoV-2 nucleocapsid protein enhances the level of mitochondrial reactive oxygen species.

Haiyun Yu, Lu Yang, Zhennan Han, Xiaoyu Zhou, Zihan Zhang, Tianli Sun, Fang Zheng, Jingzhi Yang, Fei Guan, Jungang Xie, Chaohong Liu.

  Coronavirus disease 2019 (COVID-19) pathogenesis is influenced by reactive oxygen species (ROS). Nevertheless, the precise mechanisms implicated remain poorly understood. The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the main driver for this condition, is a structural protein indispensable for viral replication and assembly, and its role in ROS production has not been reported. This study shows that SARS-CoV-2 N protein expression enhances mitochondrial ROS level. Bulk RNA-sequencing suggests of aberrant redox state of the electron transport chain. Accordingly, this protein hinders ATP production but simultaneously augments the activity of complexes I and III, and most mitochondrially encoded complex I and III proteins are upregulated by it. Mechanistically, N protein of SARS-CoV-2 shows significant mitochondrial localization. It interacts with mitochondrial transcription components and stabilizes them. Moreover, it also impairs the activity of antioxidant enzymes with or without detectable interaction.

Keywords:  ROS; SARS-CoV-2; interaction; mitochondria; nucleocapsid

DOI:  https://doi.org/10.1002/jmv.29270
iScience. 2023 Dec 15. 26(12): 108418

The integrated stress response signaling during the persistent HIV infection.

Erica A Mendes, Yuyang Tang, Guochun Jiang.

  Human immunodeficiency virus-1 (HIV) infection is a chronic disease under antiretroviral therapy (ART), during which active HIV replication is effectively suppressed. Stable viral reservoirs are established early in infection and cannot be eradicated in people with HIV (PWH) by ART alone, which features residual immune inflammation with disease-associated secondary comorbidities. Mammalian cells are equipped with integrated stress response (ISR) machinery to detect intrinsic and extrinsic stresses such as heme deficiency, nutrient fluctuation, the accumulation of unfolded proteins, and viral infection. ISR is the part of the innate immunity that defends against pathogen infection or environmental alteration, thereby maintaining homeostasis to avoid diseases. Here, we describe how this machinery responds to the off-target effects of ART and persistent HIV infection in both the peripheral compartments and the brain. The latter may be important for us to better understand the mechanisms of stable HIV reservoirs and HIV-associated neurocognitive disorders.

Keywords:  Cell biology; Virology

DOI:  https://doi.org/10.1016/j.isci.2023.108418
Virology. 2023 Nov 28. pii: S0042-6822(23)00272-6. [Epub ahead of print]589 109953

Transcriptome analysis of Huh7 cells upon Chikungunya virus infection and capsid transfection reveals regulation of distinct cellular and metabolic pathways.

Nitika Gaurav, Shivani Kumar, Siva Raghavendhar, Praveen Kumar Tripathi, Shipra Gupta, Ravi Arya, Ashok Kumar Patel.

  Chikungunya virus (CHIKV) causes persistent arthritis and neurological problems imposing a huge burden globally. The present study aims to understand the interaction mechanism of Chikungunya virus and CHIKV-capsid in Huh7 cells. The RNA-sequencing and qRT-PCR method was used for the transcript and gene profiles of CHIKV virus and CHIKV capsid alone. Transcriptional analysis showed capsid induced 1114 and 956 differentially expressed genes (DEGs) to be upregulated and downregulated respectively, while in virus, 933 genes were upregulated and 956 were downregulated. Total 202 DEGs were common in both capsid and virus; and nine were validated using qRT-PCR. Identified DEGs were found to be associated with metabolic pathways such as Diabetes, cardiac disease, and visual impairment. Further, knock-down study on one of the DEGs (MafA) responsible for insulin regulation showed low viral proteins expression suggesting a reduction in virus-infection. Thus, the study provides insight into the interplay of the virus-host factors assisting virus replication.

Keywords:  Capsid protein; Cellular pathways; Chikungunya; Host-virus interplay; Huh7 cells; RNA sequencing

DOI:  https://doi.org/10.1016/j.virol.2023.109953
Antiviral Res. 2023 Dec 04. pii: S0166-3542(23)00247-4. [Epub ahead of print] 105769

Validation of nuclear receptor RORγ isoform 1 as a novel host-directed antiviral target based on the modulation of cholesterol levels.

Christina Wangen, Andrea Raithel, Julia Tillmanns, Christian Gege, Alexandra Herrmann, Daniel Vitt, Hella Kohlhof, Manfred Marschall, Friedrich Hahn.

  Currently, the clinically approved repertoire of antiviral drugs predominantly comprises direct-acting antivirals (DAAs). However, the use of DAAs is frequently limited by adverse effects, restriction to individual virus species, or the induction of viral drug resistance. These issues will likely be resolved by the introduction of host-directed antivirals (HDAs) targeting cellular proteins crucial for viral replication. However, experiences with the development of antiviral HDAs and clinical applications are still in their infancy. With the present study, we explored the human nuclear receptor and transcription factor RORγ isoform 1 (RORγ1), a member of the retinoic acid receptor-related orphan receptor (ROR) family, as a putative target of antiviral HDAs. To this end, cell culture models were used to investigate major viral human pathogens, i.e. the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human cytomegalovirus (HCMV), varicella zoster virus (VZV) and human immunodeficiency virus 1 (HIV-1). Our results demonstrated (i) an antiviral activity of the clinically relevant RORγ modulators cedirogant and others, (ii) that isoform RORγ1 acts as the responsible determinant and drug target in the analyzed cell culture-based models, (iii) a selectivity of the antiviral effect for RORγ1 over related receptors RORα and RORβ, (iv) a late-phase inhibition exerted by cedirogant in HCMV replication and (v) a mechanistic link to the cellular cholesterol biosynthesis. Combined, the data highlight this novel RORγ-specific antiviral targeting concept and the developmental potential of RORγ-directed small molecules.

Keywords:  Host-directed antiviral targeting; Major viral human pathogens; Metabolic restriction of virus replication; Novel drug targeting options; RORγ2/t modulator cedirogant; Transcriptional regulation of cholesterol biosynthesis

DOI:  https://doi.org/10.1016/j.antiviral.2023.105769
mBio. 2023 Dec 04. e0265123

The glycoprotein 5 of porcine reproductive and respiratory syndrome virus stimulates mitochondrial ROS to facilitate viral replication.

Shuang Zhang, Lei Zeng, Bing-Qian Su, Guo-Yu Yang, Jiang Wang, Sheng-Li Ming, Bei-Bei Chu.

   IMPORTANCE: Porcine reproductive and respiratory syndrome virus (PRRSV) presents a significant economic concern for the global swine industry due to its connection to serious production losses and increased mortality rates. There is currently no specific treatment for PRRSV. Previously, we had uncovered that PRRSV-activated lipophagy to facilitate viral replication. However, the precise mechanism that PRRSV used to trigger autophagy remained unclear. Here, we found that PRRSV GP5 enhanced mitochondrial Ca2+ uptake from ER by promoting ER-mitochondria contact, resulting in mROS release. Elevated mROS induced autophagy, which alleviated NLRP3 inflammasome activation for optimal viral replication. Our study shed light on a novel mechanism revealing how PRRSV exploits mROS to facilitate viral replication.

Keywords:  ER-mitochondria contacts; IP3R; NLRP3 inflammasome; PRRSV; VDAC1; autophagy

DOI:  https://doi.org/10.1128/mbio.02651-23
Poult Sci. 2023 Nov 05. pii: S0032-5791(23)00784-8. [Epub ahead of print]103(2): 103265

Duck hepatitis A virus type 1 infection induces hepatic metabolite and gut microbiota changes in ducklings.

Hui Yan, Guige Xu, Lei Bei, Shijin Jiang, Ruihua Zhang.

  Duck hepatitis A virus type 1 (DHAV-1) can cause severe liver damage in infected ducklings and is a fatal and contagious pathogen that endangers the Chinese duck industry. The objective of this study was to explore the correlation mechanism of liver metabolism-gut microbiota in DHAV-1 infection. Briefly, liquid chromatography-mass spectrometry and 16S rDNA sequencing combined with multivariate statistical analysis were used to evaluate the effects of DHAV-1 infection on liver metabolism, gut microbiota regulation, and other potential mechanisms in ducklings. In DHAV-1-infected ducklings at 72 h postinfection, changes were found in metabolites associated with key metabolic pathways such as lipid metabolism, sugar metabolism, and nucleotide metabolism, which participated in signaling networks and ultimately affecting the function of the liver. The abundance and composition of gut microbiota were also changed, and gut microbiota is significantly involved in lipid metabolism in the liver. The evident correlation between gut microbiota and liver metabolites indicates that DHAV-host gut microbiome interactions play important roles in the development of duck viral hepatitis (DVH).

Keywords:  16S rDNA; DHAV-1; LC-MS; gut microbiota; liver metabolomics

DOI:  https://doi.org/10.1016/j.psj.2023.103265
Vet Microbiol. 2023 Nov 30. pii: S0378-1135(23)00286-9. [Epub ahead of print]288 109932

Carnitine palmitoyl-transferase 1A is potentially involved in bovine herpesvirus 1 productive infection.

Hao Yang, Wenyuan Gu, Junqing Ni, Yabin Ma, Shitao Li, Donna Neumann, Xiuyan Ding, Liqian Zhu.

  Bovine herpesvirus 1(BoHV-1) is an important bovine pathogen that causes great economic loss to cattle farms worldwide. The virus-productive infection in bovine kidney (MDBK) cells results in ATP depletion. The mechanisms are not well understood. Mitochondrial fatty acid β-oxidation (FAO) is an important energy source in many tissues with high energy demand. Since carnitine palmitoyl-transferase 1 A (CPT1A) is the rate-limiting enzyme of FAO, we investigated the interactions between virus-productive infection and CPT1A signaling. Here, we found that virus-productive infection at the later stage significantly decreased CPT1A protein levels in all the detected cells, including MDBK, A549, and Neuro-2A cells, differentially altered the accumulation of CPT1A proteins in the nucleus and cytosol, and re-localized the protein in the nucleus. Etomoxir (ETO), an irreversible inhibitor of CPT1A, inhibited viral replication and partially interfered with the ability of BoHV-1 to alter CPT1A accumulation in the nucleus but not in the cytosol. Furthermore, ETO consistently reduced RNA levels of two viral regulatory proteins (bICP0 and bICP22) and protein expression of virion-associated proteins during productive infection, further supporting the important roles of CPT1A signaling in BoHV-1 productive infection. These data, for the first time, suggest that CPT1A is potentially involved in BoHV-1 productive infection.

Keywords:  BoHV-1; CPT1A; Etomoxir; β-oxidation

DOI:  https://doi.org/10.1016/j.vetmic.2023.109932