bims-mevinf 2023-11-12 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023–11–12
six papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Modulation of endoplasmic reticulum stress response pathways by respiratory viruses.
Duck Tembusu virus induces incomplete autophagy via the ERK/mTOR and AMPK/mTOR signalling pathways to promote viral replication in neuronal cells.
Molecular Mechanisms Associated with Neurodegeneration of Neurotropic Viral Infection.
Plasma essential fatty acid on hospital admission is a marker of COVID-19 disease severity.
Rotavirus-induced lncRNA SLC7A11-AS1 promotes ferroptosis by targeting cystine/glutamate antiporter xCT (SLC7A11) to facilitate virus infection.
Metabolic reprograming and increased inflammation by cadmium exposure following early-life respiratory syncytial virus infection-the involvement of protein S-palmitoylation.

Crit Rev Microbiol. 2023 Nov 07. 1-19

Modulation of endoplasmic reticulum stress response pathways by respiratory viruses.

Kyle L Macauslane, Cassandra L Pegg, Kirsty R Short, Benjamin L Schulz.

  Acute respiratory infections (ARIs) are amongst the leading causes of death and disability, and the greatest burden of disease impacts children, pregnant women, and the elderly. Respiratory viruses account for the majority of ARIs. The unfolded protein response (UPR) is a host homeostatic defence mechanism primarily activated in response to aberrant endoplasmic reticulum (ER) resident protein accumulation in cell stresses including viral infection. The UPR has been implicated in the pathogenesis of several respiratory diseases, as the respiratory system is particularly vulnerable to chronic and acute activation of the ER stress response pathway. Many respiratory viruses therefore employ strategies to modulate the UPR during infection, with varying effects on the host and the pathogens. Here, we review the specific means by which respiratory viruses affect the host UPR, particularly in association with the high production of viral glycoproteins, and the impact of UPR activation and subversion on viral replication and disease pathogenesis. We further review the activation of UPR in common co-morbidities of ARIs and discuss the therapeutic potential of modulating the UPR in virally induced respiratory diseases.

Keywords:  Respiratory virus infection; coronavirus; glycoproteins; influenza virus; respiratory syncytial virus; unfolded protein response; viral replication; virus-host biology

DOI:  https://doi.org/10.1080/1040841X.2023.2274840
Vet Res. 2023 Nov 07. 54(1): 103

Duck Tembusu virus induces incomplete autophagy via the ERK/mTOR and AMPK/mTOR signalling pathways to promote viral replication in neuronal cells.

Qing Wang, Yaqian Jiang, Guangbin Bao, Weiping Yao, Qing Yang, Shuyue Chen, Guijun Wang.

  Duck Tembusu virus (DTMUV) is a neurotropic virus in the genus Flavivirus that causes massive economic losses to the poultry industry in China and neighbouring countries. Autophagy is pivotal in cellular responses to pathogens and in viral pathogenesis. However, little is known about the roles of autophagy in DTMUV replication and viral pathogenesis, especially in neuropathogenesis. In this study, mouse neuroblastoma cells (Neuro-2a) were used to establish a cell model of DTMUV infection. Our experiments indicated that DTMUV infection induced incomplete autophagy in Neuro-2a cells. Then, we used different autophagy regulators to alter the autophagy induced by DTMUV and found that incomplete autophagy promoted DTMUV replication. Furthermore, we showed that DTMUV infection activated the ERK and AMPK pathways, resulting in decreased phosphorylation of the autophagy repressor mTOR, subsequently leading to autophagic induction. In addition, we utilized ICR mice in an animal model of DTMUV infection to evaluate the autophagic responses in brain tissues and investigate the effects of autophagy on viral replication and tissue lesions. Our results confirmed that DTMUV induced incomplete autophagy in mouse brain tissues and that autophagy inducer treatment promoted DTMUV replication and aggravated DTMUV-induced lesions, whereas autophagy inhibitor treatment had the opposite effects. In summary, DTMUV infection induced incomplete autophagy through the ERK/mTOR and AMPK/mTOR signalling pathways to promote viral replication in mouse neuronal cells, and DTMUV-induced incomplete autophagy contributed to the neuropathogenesis of DTMUV.

Keywords:  Duck Tembusu virus; incomplete autophagy; neuropathogenesis; signalling pathways; viral replication

DOI:  https://doi.org/10.1186/s13567-023-01235-0
Mol Neurobiol. 2023 Nov 09.

Molecular Mechanisms Associated with Neurodegeneration of Neurotropic Viral Infection.

Prapimpun Wongchitrat, Theerawut Chanmee, Piyarat Govitrapong.

  Viral infections of the central nervous system (CNS) cause variable outcomes from acute to severe neurological sequelae with increased morbidity and mortality. Viral neuroinvasion directly or indirectly induces encephalitis via dysregulation of the immune response and contributes to the alteration of neuronal function and the degeneration of neuronal cells. This review provides an overview of the cellular and molecular mechanisms of virus-induced neurodegeneration. Neurotropic viral infections influence many aspects of neuronal dysfunction, including promoting chronic inflammation, inducing cellular oxidative stress, impairing mitophagy, encountering mitochondrial dynamics, enhancing metabolic rewiring, altering neurotransmitter systems, and inducing misfolded and aggregated pathological proteins associated with neurodegenerative diseases. These pathogenetic mechanisms create a multidimensional injury of the brain that leads to specific neuronal and brain dysfunction. The understanding of the molecular mechanisms underlying the neurophathogenesis associated with neurodegeneration of viral infection may emphasize the strategies for prevention, protection, and treatment of virus infection of the CNS.

Keywords:  Alzheimer’s disease; Apoptosis; Autophagy; CNS infection; Mitophagy; Neurodegeneration; Neuroinflammation; Neuronal metabolism; Neurotransmission system; Neurotropic virus; Oxidative stress; Viral infection

DOI:  https://doi.org/10.1007/s12035-023-03761-6
Sci Rep. 2023 11 03. 13(1): 18973

Plasma essential fatty acid on hospital admission is a marker of COVID-19 disease severity.

Vera C Mazurak, Irma Magaly Rivas-Serna, Sarah R Parsons, Md Monirujjaman, Krista E Maybank, Stanley K Woo, Oleksa G Rewa, Andrew J Cave, Caroline Richard, M Thomas Clandinin.

It is important for allocation of resources to predict those COVID patients at high risk of dying or organ failure. Early signals to initiate cellular events of host immunity can be derived from essential fatty acid metabolites preceding the cascade of proinflammatory signals. Much research has focused on understanding later proinflammatory responses. We assessed if remodelling of plasma phospholipid content of essential fatty acids by the COVID-19 virus provides early markers for potential death and disease severity. Here we show that, at hospital admission, COVID-19 infected subjects who survive exhibit higher proportions of C20:4n-6 in plasma phospholipids concurrent with marked proinflammatory cytokine elevation in plasma compared to healthy subjects. In contrast, more than half of subjects who die of this virus exhibit very low C18:2n-6 and C20:4n-6 content in plasma phospholipids on hospital admission compared with healthy control subjects. Moreover, in these subjects who die, the low level of primary inflammatory signals indicates limited or aberrant stimulation of host immunity. We conclude that COVID-19 infection results in early fundamental remodelling of essential fatty acid metabolism. In subjects with high mortality, it appears that plasma n-6 fatty acid content is too low to stimulate cellular events of host immunity.

DOI: https://doi.org/10.1038/s41598-023-46247-0
Virus Res. 2023 Nov 01. pii: S0168-1702(23)00223-X. [Epub ahead of print] 199261

Rotavirus-induced lncRNA SLC7A11-AS1 promotes ferroptosis by targeting cystine/glutamate antiporter xCT (SLC7A11) to facilitate virus infection.

Shreya Banerjee, Rakesh Sarkar, Arpita Mukherjee, Suvrotoa Mitra, Animesh Gope, Mamta Chawla-Sarkar.

  Rotavirus (RV) is the primary etiological agent of virus-associated gastroenteritis in infants, causing 200,000 childhood death annually. Despite the availability of vaccines, rotaviral diarrhea continues to be a severe issue in underdeveloped nations in Asia and Africa. The situation demands continual studies on host-rotavirus interactions to understand disease pathogenesis and develop effective antiviral therapeutics. Long non-coding RNAs (lncRNAs), which are a subset of non-coding RNAs of more than 200 nucleotides in length, are reported to play a regulatory function in numerous viral infections. Virus infection often alters the host transcriptome including lncRNA that are differentially expressed either to play an antiviral role or to be advantageous towards virus propagation. In the current study, qPCR array-based expression profiling of host lncRNAs was performed in rotavirus-infected HT-29 cells that identified the lncRNA SLC7A11-AS1 to be upregulated during RV infection. Knockdown of SLC7A11-AS1 conspicuously reduced RV titers implying its pro-viral significance. RV-induced SLC7A11-AS1 downregulates the gene SLC7A11/xCT that encodes the light chain subunit of the system XC- cystine-glutamate exchange transporter, leading to decrease in intracellular glutathione level and increase in lipid peroxidation, which are signature features of ferroptotic pathway. Ectopic expression of xCT also abrogated RV infection by reversing the virus optimized levels of intracellular GSH and lipid ROS levels. Cumulatively, the study reveals that RV infection triggers ferroptotic cell death via SLC7A11-AS1/xCT axis to facilitate its own propagation.

Keywords:  Glutathione; Lipid peroxidation; ROS; Rotavirus; SLC7A11-AS1; lncRNA; xCT

DOI:  https://doi.org/10.1016/j.virusres.2023.199261
Toxicol Sci. 2023 Nov 06. pii: kfad112. [Epub ahead of print]

Metabolic reprograming and increased inflammation by cadmium exposure following early-life respiratory syncytial virus infection-the involvement of protein S-palmitoylation.

Zachery R Jarrell, Choon-Myung Lee, Ki-Hye Kim, Xiaojia He, Matthew R Smith, Jannatul R Raha, Noopur Bhatnagasr, Michael Orr, Sang-Moo Kang, Yan Chen, Dean P Jones, Young-Mi Go.

  Early-life respiratory syncytial virus (RSV) infection (eRSV) is one of the leading causes of serious pulmonary disease in children. eRSV is associated with higher risk of developing asthma and compromised lung function later in life. Cadmium (Cd) is a toxic metal, widely present in the environment and in food. We recently showed that eRSV re-programs metabolism and potentiates Cd toxicity in the lung, and our transcriptome-metabolome-wide study showed strong associations between S-palmitoyl transferase expression and Cd-stimulated lung inflammation and fibrosis signaling. Limited information is available on the mechanism by which eRSV re-programs metabolism and potentiates Cd toxicity in the lung. In the current study, we used a mouse model to examine the role of protein S-palmitoylation (Pr-S-Pal) in low dose Cd-elevated lung metabolic disruption and inflammation following eRSV. Mice exposed to eRSV were later treated with Cd (3.3 mg CdCl2/L) in drinking water for 6 weeks (RSV+Cd). The role of Pr-S-Pal was studied using a palmitoyl transferase inhibitor, 2-bromopalmitate (BP, 10 µM). Inflammatory marker analysis showed that cytokines, chemokines and inflammatory cells were highest in the RSV+Cd group, and BP decreased inflammatory markers. Lung metabolomics analysis showed that pathways including phenylalanine, tyrosine and tryptophan, phosphatidylinositol and sphingolipid were altered across treatments. BP antagonized metabolic disruption of sphingolipid and glycosaminoglycan metabolism by RSV+Cd, consistent with BP effect on inflammatory markers. This study shows that Cd exposure following eRSV has a significant impact on subsequent inflammatory response and lung metabolism, which is mediated by Pr-S-Pal, and warrants future research for a therapeutic target.

Keywords:  dietary metal; early life exposure; environmental exposure; lung pathology; metabolic disruption; post-translational protein modification

DOI:  https://doi.org/10.1093/toxsci/kfad112