bims-mevinf 2025-01-12 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–01–12
nine papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Pseudorabies virus inhibits the unfolded protein response for viral replication during the late stages of infection.
HCMV infection downregulates GPX4 and stimulates lipid peroxidation but does not induce ferroptosis.
Reactive oxygen species favors Varicellovirus bovinealpha 5 (BoAHV-5) replication in neural cells.
Mpox-Induced Metabolic Alterations.
Metformin in Antiviral Therapy: Evidence and Perspectives.
Long-term mitochondrial and metabolic impairment in lymphocytes of subjects who recovered after severe COVID-19.
Decanoylcarnitine improves liver mitochondrial dysfunction in hepatitis B virus infection by enhancing fatty acid β-oxidation.
Infection-induced lysine lactylation enables herpesvirus immune evasion.
Metabolomic and microbiota profiles in cervicovaginal lavage fluid of women with high-risk human papillomavirus infection.

Vet Microbiol. 2024 Dec 28. pii: S0378-1135(24)00382-1. [Epub ahead of print]301 110360

Pseudorabies virus inhibits the unfolded protein response for viral replication during the late stages of infection.

Peng Gao, Jianle Ren, Qiongqiong Zhou, Peng Chen, Ailin Zhang, Yongning Zhang, Lei Zhou, Xinna Ge, Xin Guo, Jun Han, Hanchun Yang.

  Pseudorabies virus (PRV) poses a significant threat to the global swine breeding industry and public health, but how the virus transverses the host defense systems for efficient viral replication and pathogenesis remains unclear. Here, we report that PRV could inhibit the unfolded protein response (UPR), a critical component of host innate immunity against viral infection, to promote virus replication during the late infection stages. PERK was shown phosphorylated and active in PRV-infected cells, but the subsequent events were suppressed post virus infection, such as eIF2α phosphorylation, ATF4 expression, and the formation of stress granules (SGs). In the meantime, although IRE1α was also active, its activated effector XBP1s was suppressed through downregulation of XBP1 mRNA levels and cleavage of XBP1s protein. Our findings also indicate that the Golgi apparatus, where ATF6 activation occur, was severely damaged in PRV-infected cells. Meanwhile, the downstream regulatory genes associated with the three UPR sensors, such as ERp60, CHOP, and EDEM1, remained silent in PRV-infected cells. Enhanced viral replication was observed post knockdown of UPR effectors ATF4 or XBP1, while stimulation with UPR activators inhibits virus replication. In conclusion, our findings address the critical question of how PRV regulates cellular UPR in favor of viral replication, and expand understanding of viruses mediated UPR suppression in general.

Keywords:  ATF4; Pseudorabies virus (PRV); Unfolded protein response (UPR); XBP1

DOI:  https://doi.org/10.1016/j.vetmic.2024.110360
J Virol. 2025 Jan 07. e0185124

HCMV infection downregulates GPX4 and stimulates lipid peroxidation but does not induce ferroptosis.

Madison Martin, Rinki Kumar, Nicholas J Buchkovich, Christopher C Norbury.

  Human cytomegalovirus (HCMV) modulates numerous cellular pathways to facilitate infection, including key components in cellular iron homeostasis. Iron is essential to many cellular processes but, if present in excess, drives cell death through ferroptosis. Ferroptosis is a process that is dependent upon the accumulation of oxidatively damaged phospholipids (lipid peroxides); when these lipid peroxides accumulate in membranes, this culminates in plasma membrane rupture and eventual cell lysis. Here, we demonstrate that HCMV infection downregulates the expression of a key modulator of lipid peroxidation, glutathione peroxidase 4 (GPX4). HCMV infection also markedly increased levels of lipid peroxides within infected cells. Despite the marked downregulation of GPX4 by HCMV, further inhibition of GPX4 impaired virus replication. Interestingly, overexpression of GPX4 did not reduce the production of lipid peroxides within infected cells. In contrast, lipid peroxide levels were reduced by treatment with ferrostatin-1, a ferrous iron-dependent scavenger of alkoxyl radicals, indicating a role for iron in the production of lipid peroxides. HCMV-infected cells became less sensitive to GPX4 inhibition as infection progressed, requiring substantially higher levels of GPX4 inhibitors to induce ferroptosis compared to uninfected cells. This observed difference in sensitivity to ferroptosis upon infection correlated with a large increase in lipid production by infected cells. Therefore, the marked stimulation of lipid peroxidation by HCMV likely proceeds through a pathway that is independent of GPX4 regulation, but the ability of lipid peroxides to stimulate ferroptosis by modulating plasma membrane rupture is likely blunted by the massive increase in lipid production during HCMV infection.
IMPORTANCE: Human cytomegalovirus (HCMV) infection is intimately linked with countless host cell pathways that are modulated in a coordinated fashion to facilitate infection. Here, we describe HCMV-induced regulation of lipid peroxidation, a precursor of the iron-regulated cell death pathway known as ferroptosis, during human cytomegalovirus infection. These studies reveal hitherto unidentified changes in metabolism mediated by HCMV that decrease sensitivity to ferroptosis, despite increases in lipid peroxidation and transient increases in intracellular iron levels in infected cells.

Keywords:  HCMV; ferroptosis; iron; lipid peroxides

DOI:  https://doi.org/10.1128/jvi.01851-24
Mitochondrion. 2025 Jan 06. pii: S1567-7249(25)00002-9. [Epub ahead of print]81 102005

Reactive oxygen species favors Varicellovirus bovinealpha 5 (BoAHV-5) replication in neural cells.

Juan José Rosales, María Belén Brunner, Marcelo Rodríguez, Maia Marin, Eduardo Néstor Maldonado, Sandra Pérez.

  Varicellovirus bovinealpha (BoAHV) 1 and 5 are closely related neurotropic alphaherpesviruses with distinct neuropathogenic potential. BoAHV-5 causes meningoencephalitis in calves whereas encephalitis by BoAHV-1 infection is sporadic. the mechanisms underlying the differences in tropism and clinical outcomes of the infections are not yet completely understood. Here, we used neuroblastoma SH-SY5Y cells as non-differentiated in comparison with the SH-SY5Y neuronal-like cells obtained after exposing SH-SY5Y undifferentiated cells to trans-retinoic acid. We aimed to establish whether there was a relationship between the production of reactive oxygen species (ROS) and the kinetics of virus replication. We demonstrated that ROS production after BoAHV infection was higher in differentiated cells. Generation of ROS was also dependent on the infecting BoAHV strain. Higher ROS levels were produced during BoAHV-5 infection concomitantly with enhanced viral replication. We propose that increased ROS production mechanistically contributes to the tissue damage and neuroinflammation induced by BoAHV-5 infection. Future studies will determine specific targets of ROS that mediate the effects on viral replication.

Keywords:  Bovine alphaherpesviruses; Neural cells; Reactive oxygen species; Replication kinetics

DOI:  https://doi.org/10.1016/j.mito.2025.102005
J Cell Mol Med. 2025 Jan;29(1): e70341

Mpox-Induced Metabolic Alterations.

Milad Zandi, Fatemeh Sadat Mousavi, Seyyed Mohammed Reza Hashemnia.

The resurgence of mpox as a global health threat highlights the need to understand its interaction with host cell metabolism. Unlike other well-studied viruses, research on mpox is limited, particularly regarding its impact on cellular processes. In this article, we explore how mpox might manipulate metabolic pathways-such as glycolysis, lipid synthesis and mitochondrial dynamics-to enhance its replication and evade immune responses. By drawing parallels with related poxviruses, we underscore the potential for targeting these metabolic shifts as novel therapeutic strategies. Understanding these interactions is crucial for developing effective treatments against mpox.

DOI: https://doi.org/10.1111/jcmm.70341
Viruses. 2024 Dec 18. pii: 1938. [Epub ahead of print]16(12):

Metformin in Antiviral Therapy: Evidence and Perspectives.

Iryna Halabitska, Pavlo Petakh, Oleh Lushchak, Iryna Kamyshna, Valentyn Oksenych, Oleksandr Kamyshnyi.

  Metformin, a widely used antidiabetic medication, has emerged as a promising broad-spectrum antiviral agent due to its ability to modulate cellular pathways essential for viral replication. By activating AMPK, metformin depletes cellular energy reserves that viruses rely on, effectively limiting the replication of pathogens such as influenza, HIV, SARS-CoV-2, HBV, and HCV. Its role in inhibiting the mTOR pathway, crucial for viral protein synthesis and reactivation, is particularly significant in managing infections caused by HIV, CMV, and EBV. Furthermore, metformin reduces oxidative stress and reactive oxygen species (ROS), which are critical for replicating arboviruses such as Zika and dengue. The drug also regulates immune responses, cellular differentiation, and inflammation, disrupting the life cycle of HPV and potentially other viruses. These diverse mechanisms suppress viral replication, enhance immune system functionality, and contribute to better clinical outcomes. This multifaceted approach highlights metformin's potential as an adjunctive therapy in treating a wide range of viral infections.

Keywords:  AMPK activation; broad-spectrum antiviral; inflammation; mTOR inhibition; metformin; oxidative stress; viral replication

DOI:  https://doi.org/10.3390/v16121938
Cell Biol Toxicol. 2025 Jan 10. 41(1): 27

Long-term mitochondrial and metabolic impairment in lymphocytes of subjects who recovered after severe COVID-19.

Irene Gómez-Delgado, Andrea R López-Pastor, Adela González-Jiménez, Carlos Ramos-Acosta, Yenitzeh Hernández-Garate, Neus Martínez-Micaelo, Núria Amigó, Laura Espino-Paisán, Eduardo Anguita, Elena Urcelay.

  The underlying mechanisms explaining the differential course of SARS-CoV-2 infection and the potential clinical consequences after COVID-19 resolution have not been fully elucidated. As a dysregulated mitochondrial activity could impair the immune response, we explored long-lasting changes in mitochondrial functionality, circulating cytokine levels, and metabolomic profiles of infected individuals after symptoms resolution, to evaluate whether a complete recovery could be achieved. Results of this pilot study evidenced that different parameters of aerobic respiration in lymphocytes of individuals recuperated from a severe course lagged behind those shown upon mild COVID-19 recovery, in basal conditions and after simulated reinfection, and they also showed altered glycolytic capacity. The severe groups showed trends to enhanced superoxide production in parallel to lower OPA1-S levels. Unbalance of pivotal mitochondrial fusion (MFN2, OPA1) and fission (DRP1, FIS1) proteins was detected, suggesting a disruption in mitochondrial dynamics, as well as a lack of structural integrity in the electron transport chain. In serum, altered cytokine levels of IL-1β, IFN-α2, and IL-27 persisted long after clinical recovery, and growing amounts of the latter after severe infection correlated with lower basal and maximal respiration, ATP production, and glycolytic capacity. Finally, a trend for higher circulating levels of 3-hydroxybutyrate was found in individuals recovered after severe compared to mild course. In summary, long after acute infection, mitochondrial and metabolic changes seem to differ in a situation of full recovery after mild infection versus the one evolving from severe infection.

Keywords:  COVID-19; Cytokines; Disease severity; Immune system; Metabolomics; Mitochondria; SARS-CoV-2

DOI:  https://doi.org/10.1007/s10565-024-09976-0
J Infect Dis. 2025 Jan 08. pii: jiaf014. [Epub ahead of print]

Decanoylcarnitine improves liver mitochondrial dysfunction in hepatitis B virus infection by enhancing fatty acid β-oxidation.

Ye Sun, Qingling Chen, Yuxiao Liu, Mengfan Jiao, Zixing Dai, Xiaoxue Hou, Rui Liu, Yuwen Li, Chuanlong Zhu.

   BACKGROUND: The incidence of metabolic-associated steatotic liver disease in patients with chronic hepatitis B is increasing annually; however, the interaction between hepatitis B virus (HBV) infection and lipid metabolism remains unclear. This study attempted to clarify whether fatty acid metabolism regulation could alleviate mitochondrial dysfunction caused by HBV infection.
METHODS: Public gene set of human livers was analyzed, and a proteomic analysis on mouse livers was conducted to explore metabolic disorders and affected organelles associated with HBV infection. The effect of decanoylcarnitine on fatty acid β-oxidation and mitochondria was investigated in vivo and in vitro. The pathways involved were shown by proteomic analysis and confirmed by Western blot.
RESULTS: HBV infection could cause fatty acid β-oxidation disorder and mitochondrial dysfunction in vivo and in vitro. CPT1A overexpression could improve mitochondrial function in hepatocytes. Furthermore, decanoylcarnitine supplementation could activate CPT1A expression, thus improving fatty acid metabolism and repairing mitochondrial dysfunction. Proteomic analysis of mouse livers suggests that decanoylcarnitine stimulates the peroxisome proliferator-activated receptor (PPAR) signaling pathway, and the PPARα was the most important among PPARs.
CONCLUSIONS: Impaired fatty acid metabolism and mitochondrial dysfunction in hepatocytes caused by HBV infection could be partially restored by exogenous supplementation of decanoylcarnitine. It elucidated the therapeutic potential of decanoylcarnitine in HBV infection and provided a new approach for diseases related to mitochondrial dysfunction.

Keywords:  Decanoylcarnitine; Fatty acid β-oxidation; Hepatitis B; Mitochondrial dysfunction; PPARα

DOI:  https://doi.org/10.1093/infdis/jiaf014
Sci Adv. 2025 Jan 10. 11(2): eads6215

Infection-induced lysine lactylation enables herpesvirus immune evasion.

Matthew D Tyl, Victoria U Merengwa, Ileana M Cristea.

Aerobic glycolysis is a hallmark of many viral infections, leading to substantial accumulation of lactate. However, the regulatory roles of lactate during viral infections remain poorly understood. Here, we report that human cytomegalovirus (HCMV) infection leverages lactate to induce widespread protein lactylation and promote viral spread. We establish that lactyllysine is enriched in intrinsically disordered regions, regulating viral protein condensates and immune signaling transduction. Dynamic lactylation of immune factors suppresses immunity, a feature we show to be shared for HCMV and herpes simplex virus 1 infections, through regulation of RNA binding protein 14 and interferon-γ-inducible protein 16 (IFI16). K90 lactylation of the viral DNA sensor IFI16 inhibits recruitment of the DNA damage response kinase DNA-PK, preventing IFI16-driven virus gene repression and cytokine induction. Together, we characterize global protein lactylation dynamics during virus infection, finding that virus-induced lactate contributes to its immune evasion through direct inhibition of immune signaling pathways.

DOI: https://doi.org/10.1126/sciadv.ads6215
Sci Rep. 2025 Jan 04. 15(1): 796

Metabolomic and microbiota profiles in cervicovaginal lavage fluid of women with high-risk human papillomavirus infection.

Su Shen, Shixian Zhao, Jinjun Shan, Qingling Ren.

  The presence of high-risk human papillomavirus (HR-HPV) contributes to the development of cervical lesions and cervical cancer. Recent studies suggest that an imbalance in the cervicovaginal microbiota might be a factor in the persistence of HR-HPV infections. In this study, we collected 156 cervicovaginal fluid (CVF) of women with HR-HPV infection, which were divided into three groups (negative for intraepithelial lesions = 78, low/high-grade squamous intraepithelial lesions = 52/26). We performed metabolomics and 16 S rRNA sequencing to identify changes in metabolites and cervicovaginal microbiota among patients with HR-HPV infection and varying grades of cervical lesions. We detected 164 metabolites and 389 flora types in the three groups. Ten CVF metabolites-N-methylalanine, phenylacetaldehyde, succinic acid, 2-3-dihydroxypyridine, DL-p-hydroxylphenyllactic acid, gluconic acid lactone, guanine, glucose-6-phosphate, erythrose, and sucrose showed significant associations with disease severity and distinct separation patterns in HR-HPV-infected patients with LSIL and HSIL, with an area under the curve of 0.928. The most abundant microbial communities in the CVF were Gardnerella. Gardnerella was found to be associated with increased levels of succinic acid, thereby highlighting distinct metabolic profiles. These findings suggest that the development of cervical lesions resulting from persistent HR-HPV infection is associated with significant alterations in systemic metabolism and shifts in the cervicovaginal microbiota, providing valuable insights into the metabolic and microbiota changes linked to disease severity.

Keywords:  16S rRNA sequencing; Cervicovaginal fluid; Human papillomavirus; Metabolomics

DOI:  https://doi.org/10.1038/s41598-024-84796-0