bims-mevinf 2023-03-19 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023–03–19
seven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Ectopic expression of SARS-CoV-2 S and ORF-9B proteins alters metabolic profiles and impairs contractile function in cardiomyocytes.
KSHV Hijacks FoxO1 to Promote Cell Proliferation and Cellular Transformation by Antagonizing Oxidative Stress.
Hepatitis C virus nonstructural protein 4B induces lipogenesis via the Hippo pathway.
Canine distemper virus N protein induces autophagy to facilitate viral replication.
Orf virus induces complete autophagy to promote viral replication via inhibition of AKT/mTOR and activation of the ERK1/2/mTOR signalling pathway in OFTu cells.
Phenolic compound SG-1 from Balanophora harlandii and its derivatives exert anti-influenza A virus activity via activation of the Nrf2/HO-1 pathway.
Implications of metabolic dysfunction associated fatty liver disease in COVID-19.

Front Cell Dev Biol. 2023 ;11 1110271

Ectopic expression of SARS-CoV-2 S and ORF-9B proteins alters metabolic profiles and impairs contractile function in cardiomyocytes.

Peng Zhang, Yu Liu, Chunfeng Li, Lindsay D Stine, Pei-Hui Wang, Matthew W Turnbull, Haodi Wu, Qing Liu.

  Coronavirus disease 2019 (COVID-19) is associated with adverse impacts in the cardiovascular system, but the mechanisms driving this response remain unclear. In this study, we conducted "pseudoviral infection" of SARS-CoV-2 subunits to evaluate their toxic effects in cardiomyocytes (CMs), that were derived from human induced pluripotent stem cells (hiPSCs). We found that the ectopic expression of S and ORF-9B subunits significantly impaired the contractile function and altered the metabolic profiles in human cardiomyocytes. Further mechanistic study has shown that the mitochondrial oxidative phosphorylation (OXPHOS), membrane potential, and ATP production were significantly decreased two days after the overexpression of S and ORF-9B subunits, while S subunits induced higher level of reactive oxygen species (ROS). Two weeks after overexpression, glycolysis was elevated in the ORF-9B group. Based on the transcriptomic analysis, both S and ORF-9B subunits dysregulated signaling pathways associated with metabolism and cardiomyopathy, including upregulated genes involved in HIF-signaling and downregulated genes involved in cholesterol biosynthetic processes. The ORF-9B subunit also enhanced glycolysis in the CMs. Our results collectively provide an insight into the molecular mechanisms underlying SARS-CoV-2 subunits-induced metabolic alterations and cardiac dysfunctions in the hearts of COVID-19 patients.

Keywords:  9b; S; SARS-CoV-2; cardiomyocyte; metabolism

DOI:  https://doi.org/10.3389/fcell.2023.1110271
J Med Virol. 2023 Mar 17.

KSHV Hijacks FoxO1 to Promote Cell Proliferation and Cellular Transformation by Antagonizing Oxidative Stress.

Tingting Li, Shou-Jiang Gao.

  Reactive oxygen species (ROS) are a group of a highly short-lived molecules that control diverse behaviors of cells. Normal cells maintain ROS balance to ensure their functions. Because of oncogenic stress, cancer cells often have excessive ROS, also known as oxidative stress, which are often counteracted by enhanced antioxidant systems in order to maintain redox homeostasis. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus associated with Kaposi's sarcoma (KS), which manifests hyper inflammation and oxidative stress as the hallmarks. We have previously shown that excessive ROS can disrupt KSHV latency by inducing viral lytic replication, leading to cell death. Paradoxically, most KS tumor cells are latently infected by KSHV in a highly inflammatory and oxidative stress tumor microenvironment, which is in part due to the activation of alternative complement and TLR4 pathways, indicating the existence of an enhanced antioxidant defense system in KS tumor cells. In this study, we show that KSHV upregulates antioxidant genes, including SOD2 and CAT by hijacking the forkhead box protein O1 (FoxO1), to maintain intracellular ROS level. Moreover, the fine-tuned balance of ROS level in KSHV-transformed cells is essential for cell survival. Consequently, KSHV-transformed cells are extremely sensitive to exogenous ROS insult such as treatment with a low level of hydrogen peroxide (H2 O2 ). Either chemical inhibition or knockdown of FoxO1 by siRNAs decreases the expression of antioxidant genes and subsequently increases the intracellular ROS level in KSHV-transformed cells, resulting in the inhibition of cell proliferation and colony formation in soft agar. Mechanistically, KSHV-encoded microRNAs and vFLIP upregulate FoxO1 by activating the NF-κB pathway. These results reveal a novel mechanism by which an oncogenic virus counteracts oxidative stress by upregulating FoxO1, which is essential for KSHV-induced cell proliferation and cellular transformation. Therefore, FoxO1 might be a potential therapeutic target for KSHV-related malignancies. This article is protected by copyright. All rights reserved.

Keywords:  FoxO1; KS; KSHV; Kaposi's sarcoma; Kaposi's sarcoma-associated herpesvirus; NF-κB; ROS; Reactive oxygen species; Viral miRNAs; vFLIP

DOI:  https://doi.org/10.1002/jmv.28676
Arch Virol. 2023 Mar 15. 168(4): 113

Hepatitis C virus nonstructural protein 4B induces lipogenesis via the Hippo pathway.

Chen Zou, Hongxi Tan, Jun Zeng, Minqi Liu, Guangping Zhang, Yi Zheng, Zhanfeng Zhang.

Hepatitis C virus (HCV) infection causes abnormal lipid metabolism in hepatocytes, which leads to hepatic steatosis and even hepatocellular carcinoma. HCV nonstructural protein 4B (NS4B) has been reported to induce lipogenesis, but the underlying mechanism is unclear. In this study, western blots were performed to investigate the effect of NS4B protein levels on key effectors of the Hippo and AKT signaling pathways. Yes-associated protein (YAP) and moesin-ezrin-radixin-like protein (Merlin) are effectors of the Hippo pathway. NS4B downregulated Merlin and phosphorylated YAP (p-YAP) protein expression while increasing the expression of the key AKT pathway proteins p-AKT and NF-κB. By observing the levels of AKT pathway proteins when Merlin was overexpressed or silenced, it was determined that Merlin mediates the AKT pathway. We suggest that HCV NS4B may mediate the AKT signaling pathway by inhibiting the Hippo pathway. Lipid droplets were observed in Huh7.5 cells overexpressing NS4B, and they increased significantly in number when Merlin was silenced. Overexpression of NS4B and Merlin silencing enhanced the expression of sterol regulatory element binding proteins (SREBPs), which have been demonstrated to be key regulatory factors controlling fatty acid synthesis. NS4B and Merlin silencing also enhanced the in vitro proliferative capacity of hepatocellular carcinoma cells. In conclusion, NS4B induces lipogenesis via the effect of the Hippo-YAP pathway on the AKT signaling pathway and thereby plays a significant role in the pathogenesis of HCV-associated diseases.

DOI: https://doi.org/10.1007/s00705-023-05743-4
BMC Vet Res. 2023 Mar 15. 19(1): 60

Canine distemper virus N protein induces autophagy to facilitate viral replication.

Fei Chen, Zijing Guo, Rui Zhang, Zhixiong Zhang, Bo Hu, Ling Bai, Shuaiyang Zhao, Yongshu Wu, Zhidong Zhang, Yanmin Li.

   BACKGROUND: Canine distemper virus (CDV) is one of the most contagious and lethal viruses known to the Canidae, with a very broad and expanding host range. Autophagy serves as a fundamental stabilizing response against pathogens, but some viruses have been able to evade or exploit it for their replication. However, the effect of autophagy mechanisms on CDV infection is still unclear.
RESULTS: In the present study, autophagy was induced in CDV-infected Vero cells as demonstrated by elevated LC3-II levels and aggregation of green fluorescent protein (GFP)-LC3 spots. Furthermore, CDV promoted the complete autophagic process, which could be determined by the degradation of p62, co-localization of LC3 with lysosomes, GFP degradation, and accumulation of LC3-II and p62 due to the lysosomal protease inhibitor E64d. In addition, the use of Rapamycin to promote autophagy promoted CDV replication, and the inhibition of autophagy by Wortmannin, Chloroquine and siRNA-ATG5 inhibited CDV replication, revealing that CDV-induced autophagy facilitated virus replication. We also found that UV-inactivated CDV still induced autophagy, and that nucleocapsid (N) protein was able to induce complete autophagy in an mTOR-dependent manner.
CONCLUSIONS: This study for the first time revealed that CDV N protein induced complete autophagy to facilitate viral replication.

Keywords:  Autophagy; Canine distemper virus; Nucleocapsid protein; Replication

DOI:  https://doi.org/10.1186/s12917-023-03575-7
Vet Res. 2023 Mar 14. 54(1): 22

Orf virus induces complete autophagy to promote viral replication via inhibition of AKT/mTOR and activation of the ERK1/2/mTOR signalling pathway in OFTu cells.

Lijun Lv, Jiyu Guan, Ruixue Zhen, Pin Lv, Mengshi Xu, Xingyuan Liu, Shishi He, Ziyu Fang, Zi Li, Yungang Lan, Huijun Lu, Wenqi He, Feng Gao, Kui Zhao.

  Orf virus (ORFV) is the causative agent of contagious ecthyma, which is an important zoonotic pathogen with a widespread distribution affecting sheep, goats and humans. Our previous research showed that autophagy can be induced in host cells by ORFV infection. However, the exact mechanism of ORFV-induced autophagy remains unknown. In this study, we investigated the underlying mechanisms of autophagy induced by ORFV in OFTu cells and the impact of autophagy on ORFV replication. By using specific autophagy inhibitors and activators, Western blotting, immunofluorescence and transmission electron microscopy imaging, we confirmed that ORFV infection triggered intracellular autophagosome accumulation and the activation of autophagic flux. Moreover, ORFV-induced autophagic activity was found to rely on an increase in the phosphorylation of tuberous sclerosis complex 2 (TSC2) and a decrease in the phosphorylation of mammalian target of rapamycin (mTOR), which is mediated by the suppression of the PI3K/AKT/mTOR signalling pathway and activation of the ERK1/2/mTOR signalling pathway. Furthermore, we investigated the role of mTOR-mediated autophagy during ORFV replication using pharmacological agents and demonstrated that ORFV-induced autophagy correlated positively with viral replication. Taken together, our data reveal the pathways of ORFV-induced autophagy and the impact of autophagy on ORFV replication, providing new insights into ORFV pathogenesis.

Keywords:  ERK1/2/mTOR; ORFV; PI3K/AKT/mTOR; autophagy; replication

DOI:  https://doi.org/10.1186/s13567-023-01153-1
Biochem Pharmacol. 2023 Mar 12. pii: S0006-2952(23)00086-2. [Epub ahead of print]210 115495

Phenolic compound SG-1 from Balanophora harlandii and its derivatives exert anti-influenza A virus activity via activation of the Nrf2/HO-1 pathway.

Runhong Zhou, Jianan Hu, Jingnan Qiu, Shengsheng Lu, Haixing Lin, Ruifeng Huang, Shaofen Zhou, Guoqing Huang, Jian He.

  Influenza A virus (IAV) is one of the leading causes of respiratory illness and continues to cause pandemics around the world. Against this backdrop, drug resistance poses a challenge to existing antiviral drugs, and hence, there is an urgent need for developing new antiviral drugs. In this study, we obtained a phenolic compound SG-7, a derivative of natural compound 2-hydroxymethyl-1,4-hydroquinone, which exhibits inhibitory activity toward a panel of influenza viruses and has low cellular toxicity. Mechanistic studies have shown that SG-7 exerts its anti-IAV properties by acting on the virus itself and modulating host signaling pathways. Namely, SG-7 targets the HA2 subunit of hemagglutinin (HA) to block the fusion of viral-cellular membranes and inhibits IAV-induced oxidative stress and overexpression of pro-inflammatory factors by activating the Nrf2/HO-1 pathway and reducing NF-κB activation. In addition, SG-7 can enhance type I IFN antiviral response by inducing Nrf2 expression. Importantly, SG-7 showed the ability to inhibit viral replication in the lungs of IAV-infected mice and reduce their mortality. Therefore, SG-7 may be a promising lead compound for anti-influenza drug development.

Keywords:  Hemagglutinin; Influenza A viruses; Nrf2; Oxidative stress

DOI:  https://doi.org/10.1016/j.bcp.2023.115495
World J Clin Cases. 2023 Feb 26. 11(6): 1275-1286

Implications of metabolic dysfunction associated fatty liver disease in COVID-19.

Raja Chakraborty, Deepak Sharma, Devesh U Kapoor, Akanksha Dwivedi, Rakhi Khabiya, Saikat Sen.

  Metabolic associated fatty liver disorder (MAFLD) characterizes the contributing etiologies (i.e., type 2 diabetes mellitus, metabolic syndrome, overweight) of individuals with fatty liver disease that affects 1/3rd of the world population. In 2020, the coronavirus disease 2019 (COVID-19) crisis was unprecedented, and people with different comorbidities became more susceptible to the infection caused by severe acute respiratory syndrome coronavirus 2. MAFLD patients are frequently obese with added metabolic menace like diabetes, hypertension, and dyslipidemia leading to greater jeopardy of COVID-19. MAFLD patients are 4 to 6-fold more prone towards infections. COVID-19 induces liver injury with elevated levels of aspartate aminotransferase and alanine aminotransferase and insignificantly elevated bilirubin. Hence, MAFLD in COVID-19 patients worsens the condition significantly. The evidence highlighting the interaction between MAFLD and altered liver functioning in COVID-19 suggested that COVID-19 patients with pre-existing MAFLD are at greater risk of morbidity or intensive care unit admission. Direct hepatic injury, enhanced levels of inflammatory cytokines, declined hepatic mitochondrial activity, and compromised immunity are considered as some underlying mechanisms. The main focus of this review is to discuss the implications of metabolic dysfunction associated with fatty liver disease in COVID-19 patients. The review systematically analyzes the effect of striking two worldwide pandemics (MAFLD and COVID-19) together in the present era.

Keywords:  COVID-19; Cytokine storm; Hepatic damage; Metabolic associated fatty liver disorder; Metabolic dysfunction

DOI:  https://doi.org/10.12998/wjcc.v11.i6.1275