bims-mevinf 2023-03-12 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023–03–12
seven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Viruses and phospholipids: Friends and foes during infection.
Metabolic reprogramming and lipid droplets are involved in Zika virus replication in neural cells.
G6PD deficiency-does it alter the course of COVID-19 infections?
Autophagy is induced by swine acute diarrhea syndrome coronavirus through the cellular IRE1-JNK-Beclin 1 signaling pathway after an interaction of viral membrane-associated papain-like protease and GRP78.
Deregulated intracellular pathways define novel molecular targets for HBV-specific CD8 T cell reconstitution in chronic hepatitis B.
Characterization of Dendritic Cell Metabolism by Flow Cytometry.
Altered lipid metabolites accelerate early dysfunction of T cells in HIV-infected rapid progressors by impairing mitochondrial function.

J Med Virol. 2023 Mar 11.

Viruses and phospholipids: Friends and foes during infection.

Stephanie Rattay, Martin Hufbauer, Peter Hoboth, Martin Sztacho, Baki Akgül.

  Viruses have evolved complex and dynamic interactions with their host cells to enable viral replication. In recent years, insights have been gained into the increasingly important role of the host cell lipidome in the life cycle of several viruses. In particular, viruses target phospholipid signaling, synthesis, and metabolism to remodel their host cells into an optimal environment for their replication cycle. Conversely, phospholipids and their associated regulatory enzymes can interfere with viral infection or replication. This review highlights examples of different viruses that illustrate the importance of these diverse virus-phospholipid interactions in different cellular compartments, particularly the role of nuclear phospholipids and their association with human papillomavirus (HPV)-mediated cancer development. This article is protected by copyright. All rights reserved.

Keywords:  phospholipids; virus host interactions; virus lipid interactions

DOI:  https://doi.org/10.1002/jmv.28658
J Neuroinflammation. 2023 Mar 08. 20(1): 61

Metabolic reprogramming and lipid droplets are involved in Zika virus replication in neural cells.

Suelen Silva Gomes Dias, Tamires Cunha-Fernandes, Luciana Souza-Moreira, Vinicius Cardoso Soares, Giselle Barbosa Lima, Isaclaudia G Azevedo-Quintanilha, Julia Santos, Filipe Pereira-Dutra, Caroline Freitas, Patricia A Reis, Stevens Kastrup Rehen, Fernando A Bozza, Thiago M Lopes Souza, Cecilia J G de Almeida, Patricia T Bozza.

  Zika virus (ZIKV) infection is a global public health concern linked to adult neurological disorders and congenital diseases in newborns. Host lipid metabolism, including lipid droplet (LD) biogenesis, has been associated with viral replication and pathogenesis of different viruses. However, the mechanisms of LD formation and their roles in ZIKV infection in neural cells are still unclear. Here, we demonstrate that ZIKV regulates the expression of pathways associated with lipid metabolism, including the upregulation and activation of lipogenesis-associated transcription factors and decreased expression of lipolysis-associated proteins, leading to significant LD accumulation in human neuroblastoma SH-SY5Y cells and in neural stem cells (NSCs). Pharmacological inhibition of DGAT-1 decreased LD accumulation and ZIKV replication in vitro in human cells and in an in vivo mouse model of infection. In accordance with the role of LDs in the regulation of inflammation and innate immunity, we show that blocking LD formation has major roles in inflammatory cytokine production in the brain. Moreover, we observed that inhibition of DGAT-1 inhibited the weight loss and mortality induced by ZIKV infection in vivo. Our results reveal that LD biogenesis triggered by ZIKV infection is a crucial step for ZIKV replication and pathogenesis in neural cells. Therefore, targeting lipid metabolism and LD biogenesis may represent potential strategies for anti-ZIKV treatment development.

Keywords:  Immunometabolism; Inflammation; Lipid droplets; Lipid metabolism; Neuroinfection; Zika virus

DOI:  https://doi.org/10.1186/s12974-023-02736-7
Ann Hematol. 2023 Mar 11.

G6PD deficiency-does it alter the course of COVID-19 infections?

Tsz Yuen Au, Oskar Wojciech Wiśniewski, Shamiram Benjamin, Tadeusz Kubicki, Dominik Dytfeld, Lidia Gil.

  Despite the existence of well-founded data around the relationship between reactive oxygen species (ROS) and glucose-6-phosphate dehydrogenase (G6PD), current research around G6PD-deficient patients with viral infections, and limitations as a result of their condition, are inadequate. Here, we analyze existing data around immunological risks, complications, and consequences of this disease, particularly in relation to COVID-19 infections and treatment. The relationship between G6PD deficiency and elevated ROS leading to increased viral load suggests that these patients may confer heightened infectivity. Additionally, worsened prognoses and more severe complications of infection may be realized in class I G6PD-deficient individuals. Though more research is demanded on the topic, preliminary studies suggest that antioxidative therapy which reduces ROS levels in these patients could prove beneficial in the treatment of viral infections in G6PD-deficient individuals.

Keywords:  Antioxidative therapy; COVID-19; G6PD deficiency; Oxidative stress; Viral load

DOI:  https://doi.org/10.1007/s00277-023-05164-y
PLoS Pathog. 2023 Mar;19(3): e1011201

Autophagy is induced by swine acute diarrhea syndrome coronavirus through the cellular IRE1-JNK-Beclin 1 signaling pathway after an interaction of viral membrane-associated papain-like protease and GRP78.

Da Shi, Ling Zhou, Hongyan Shi, Jiyu Zhang, Jialin Zhang, Liaoyuan Zhang, Dakai Liu, Tingshuai Feng, Miaomiao Zeng, Jianfei Chen, Xin Zhang, Mei Xue, Zhaoyang Jing, Jianbo Liu, Zhaoyang Ji, Haojie He, Longjun Guo, Yang Wu, Jingyun Ma, Li Feng.

Autophagy plays an important role in the infectious processes of diverse pathogens. For instance, cellular autophagy could be harnessed by viruses to facilitate replication. However, it is still uncertain about the interplay of autophagy and swine acute diarrhea syndrome coronavirus (SADS-CoV) in cells. In this study, we reported that SADS-CoV infection could induce a complete autophagy process both in vitro and in vivo, and an inhibition of autophagy significantly decreased SADS-CoV production, thus suggesting that autophagy facilitated the replication of SADS-CoV. We found that ER stress and its downstream IRE1 pathway were indispensable in the processes of SADS-CoV-induced autophagy. We also demonstrated that IRE1-JNK-Beclin 1 signaling pathway, neither PERK-EIF2S1 nor ATF6 pathways, was essential during SADS-CoV-induced autophagy. Importantly, our work provided the first evidence that expression of SADS-CoV PLP2-TM protein induced autophagy through the IRE1-JNK-Beclin 1 signaling pathway. Furthermore, the interaction of viral PLP2-TMF451-L490 domain and substrate-binding domain of GRP78 was identified to activate the IRE1-JNK-Beclin 1 signaling pathway, and thus resulting in autophagy, and in turn, enhancing SADS-CoV replication. Collectively, these results not only showed that autophagy promoted SADS-CoV replication in cultured cells, but also revealed that the molecular mechanism underlying SADS-CoV-induced autophagy in cells.

DOI: https://doi.org/10.1371/journal.ppat.1011201
J Hepatol. 2023 Mar 07. pii: S0168-8278(23)00167-8. [Epub ahead of print]

Deregulated intracellular pathways define novel molecular targets for HBV-specific CD8 T cell reconstitution in chronic hepatitis B.

Ilaria Montali, Camilla Ceccatelli Berti, Marco Morselli, Greta Acerbi, Valeria Barili, Giuseppe Pedrazzi, Barbara Montanini, Carolina Boni, Arianna Alfieri, Marco Pesci, Alessandro Loglio, Elisabetta Degasperi, Marta Borghi, Riccardo Perbellini, Amalia Penna, Diletta Laccabue, Marzia Rossi, Andrea Vecchi, Camilla Tiezzi, Valentina Reverberi, Chiara Boarini, Gianluca Abbati, Marco Massari, Pietro Lampertico, Gabriele Missale, Carlo Ferrari, Paola Fisicaro.

   BACKGROUND AND AIMS: In chronic HBV infection elevated ROS levels derived from dysfunctional mitochondria can cause increased protein oxidation and DNA damage in exhausted virus-specific CD8 T cells. Aim of this study was to understand how these defects are mechanistically interconnected in order to further elucidate T cell exhaustion pathogenesis and, doing so, to devise novel T cell-based therapies.
METHODS: DNA damage and repair mechanisms, including parylation, CD38 expression and telomere length were studied in HBV-specific CD8 T cells from chronic HBV patients. Correction of intracellular signaling alterations and improvement of anti-viral T cell functions by the NAD precursor NMN and by CD38 inhibition was assessed.
RESULTS: Elevated DNA damage was associated with defective DNA repair processes, including NAD-dependent parylation, in HBV-specific CD8 cells of chronic HBV patients. NAD depletion was indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, mitochondrial and proteostasis functions by NAD supplementation, which could also improve the HBV-specific antiviral CD8 T cell function.
CONCLUSIONS: Our study delineates a model of CD8 T cell exhaustion whereby multiple interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion suggesting similarities between T cell exhaustion and cell senescence. Correction of these deregulated intracellular functions by NAD supplementation can also restore anti-viral CD8 T cell activity and thus represents a promising potential therapeutic strategy for chronic HBV infection.

Keywords:  DNA repair; NAD; immune-modulation; senescence

DOI:  https://doi.org/10.1016/j.jhep.2023.02.035
Methods Mol Biol. 2023 ;2618 219-237

Characterization of Dendritic Cell Metabolism by Flow Cytometry.

Eline C Brombacher, Thiago A Patente, Marjolein Quik, Bart Everts.

  In response to different stimuli, dendritic cells (DCs) undergo metabolic reprogramming to support their function. Here we describe how fluorescent dyes and antibody-based approaches can be used to assess various metabolic parameters of DCs including glycolysis, lipid metabolism, mitochondrial activity, and the activity of important sensors and regulators of cellular metabolism, mTOR and AMPK. These assays can be performed using standard flow cytometry and will allow for the determination of metabolic properties of DC populations at single-cell level and to characterize metabolic heterogeneity within them.

Keywords:  Dendritic cells; Flow cytometry; Glucose; Lipids; Metabolism; Mitochondria; ROS

DOI:  https://doi.org/10.1007/978-1-0716-2938-3_16
Front Immunol. 2023 ;14 1106881

Altered lipid metabolites accelerate early dysfunction of T cells in HIV-infected rapid progressors by impairing mitochondrial function.

Si-Yao Li, Lin-Bo Yin, Hai-Bo Ding, Mei Liu, Jun-Nan Lv, Jia-Qi Li, Jing Wang, Tian Tang, Ya-Jing Fu, Yong-Jun Jiang, Zi-Ning Zhang, Hong Shang.

  The complex mechanism of immune-system damage in HIV infection is incompletely understood. HIV-infected "rapid progressors" (RPs) have severe damage to the immune system early in HIV infection, which provides a "magnified" opportunity to study the interaction between HIV and the immune system. In this study, forty-four early HIV-infected patients (documented HIV acquisition within the previous 6 months) were enrolled. By study the plasma of 23 RPs (CD4+ T-cell count < 350 cells/µl within 1 year of infection) and 21 "normal progressors" (NPs; CD4+ T-cell count > 500 cells/μl after 1 year of infection), eleven lipid metabolites were identified that could distinguish most of the RPs from NPs using an unsupervised clustering method. Among them, the long chain fatty acid eicosenoate significantly inhibited the proliferation and secretion of cytokines and induced TIM-3 expression in CD4+ and CD8+ T cells. Eicosenoate also increased levels of reactive oxygen species (ROS) and decreased oxygen consumption rate (OCR) and mitochondrial mass in T cells, indicating impairment in mitochondrial function. In addition, we found that eicosenoate induced p53 expression in T cells, and inhibition of p53 effectively decreased mitochondrial ROS in T cells. More importantly, treatment of T cells with the mitochondrial-targeting antioxidant mito-TEMPO restored eicosenoate-induced T-cell functional impairment. These data suggest that the lipid metabolite eicosenoate inhibits immune T-cell function by increasing mitochondrial ROS by inducing p53 transcription. Our results provide a new mechanism of metabolite regulation of effector T-cell function and provides a potential therapeutic target for restoring T-cell function during HIV infection.

Keywords:  HIV rapid progression; T-cell dysfunction; immunometabolism; lipid metabolites; metabolomics; mitochondrial ROS

DOI:  https://doi.org/10.3389/fimmu.2023.1106881