Viruses and Metabolism: The Effects of Viral Infections and Viral Insulins on Host Metabolism

Khyati Girdhar, Amaya Powis, Amol Raisingani, Martina Chrudinová, Ruixu Huang, Tu Tran, Kaan Sevgi, Yusuf Dogus Dogru, Emrah Altindis, Khyati Girdhar, Amaya Powis, Amol Raisingani, Martina Chrudinová, Ruixu Huang, Tu Tran, Kaan Sevgi, Yusuf Dogus Dogru, Emrah Altindis

Abstract

Over the past decades, there have been tremendous efforts to understand the cross-talk between viruses and host metabolism. Several studies have elucidated the mechanisms through which viral infections manipulate metabolic pathways including glucose, fatty acid, protein, and nucleotide metabolism. These pathways are evolutionarily conserved across the tree of life and extremely important for the host's nutrient utilization and energy production. In this review, we focus on host glucose, glutamine, and fatty acid metabolism and highlight the pathways manipulated by the different classes of viruses to increase their replication. We also explore a new system of viral hormones in which viruses mimic host hormones to manipulate the host endocrine system. We discuss viral insulin/IGF-1-like peptides and their potential effects on host metabolism. Together, these pathogenesis mechanisms targeting cellular signaling pathways create a multidimensional network of interactions between host and viral proteins. Defining and better understanding these mechanisms will help us to develop new therapeutic tools to prevent and treat viral infections.

Keywords: glutaminolysis; glycolysis; lipid metabolism; metabolism; viral insulins; viruses.

Figures

Figure 1
Figure 1
Glucose metabolism and related signaling pathways are altered by viruses. Upon infection, there is an increase in the rate of glycolysis that is mainly accomplished by an increase in GLUT activity, rate-limiting glycolytic enzyme activity, and several signaling proteins and transcription factors. Abbreviations: 4E-BP1, 4E-binding protein 1; 6-PG, 6-phosphogluconate; AdV, adenovirus; AMPK, AMP-activated protein kinase; ARV, avian reovirus; EBV, Epstein-Barr virus; EGFR, epidermal growth factor receptor; eIF4E, eukaryotic translation initiation factor 4E; F1,6BP, fructose-1,6-bisphosphate; G6PDH, glucose-6-phosphate dehydrogenase; GLUT, glucose transporter; HBV, hepatitis B virus; HCMV, human cytomegalovirus; HIF, hypoxia-inducible factor; HIV, human immunodeficiency virus; HK, hexokinase; ISKNV, infectious spleen and kidney necrosis virus; KSHV, Kaposi’s sarcoma herpesvirus; LDH, lactate dehydrogenase; MNV, murine norovirus; mTOR, mechanistic target of rapamycin; Myc, proto-oncogene, basic helix-loop-helix transcription factor; P, phosphate group; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PFK-1, phosphofructokinase 1; PI3K, phosphoinositide 3-kinase; PKM2, pyruvate kinase M2; Ras, rat sarcoma; RTK, receptor tyrosine kinase; RV, rhinovirus; TCA, tricarboxylic acid; TGEV, transmissible gastroenteritis virus; ZIKV, Zika virus. Created with BioRender.com.
Figure 2
Figure 2
Glutaminolysis signaling and related pathways are altered by viruses. Viruses increase glutaminolysis by targeting the glutamine transporter (SLC1A5/SLC7A5) and the activity and expression of the main enzymes GLS, GDH1, and ASAT to establish infection. Red type indicates main glutamine metabolism. Abbreviations: α-KG, α-ketoglutarate; AdV, adenovirus; ASAT, aspartate aminotransferase; GDH1, glutamate dehydrogenase 1; GLNA, glutamine synthetase; GLS, glutaminase; GLUT, glucose transporter; HSV-1, herpes simplex virus 1; KSHV, Kaposi’s sarcoma herpesvirus; Myc, proto-oncogene, basic helix-loop-helix transcription factor; OAA, oxaloacetate; Ras, rat sarcoma; SucCoA, succinyl-CoA; TCA, tricarboxylic acid; WSSV, white spot syndrome virus. Created with BioRender.com.
Figure 3
Figure 3
Lipid metabolism and related pathways are altered by viruses. Upon infection, there is an increase in lipid synthesis, which is mediated by increasing the activity of main fatty acid synthesis enzymes such as ACC and FASN and transcription factors such as SREBP. Moreover, this figure also represents virus modulation of beta-oxidation and lipid droplet formation. Abbreviations: ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; COPII, coat protein complex II; COVID-19, coronavirus disease 2019; CPT, carnitine palmitoyltransferase; CVB3, coxsackievirus B3; DGAT, diacylglycerol O-acyltransferase; FACS, fatty acyl-CoA synthetase; FASN, fatty acid synthase; FATP, fatty acid transport protein; FFA, free fatty acid; HCMV, human cytomegalovirus; HCV, hepatitis C virus; JEV, Japanese encephalitis virus; LXR, liver X receptor; MERS, Middle East respiratory syndrome; mTOR, mechanistic target of rapamycin; MTP, mitochondrial trifunctional protein; OAA, oxaloacetate; P, phosphate group; PLIN, perlipin; PPARγ, peroxisome proliferator-activated receptor γ; Rheb, Ras homolog enriched in brain; RSV, respiratory syncytial virus; RTK, receptor tyrosine kinase; RV, rhinovirus; S6K1, S6 kinase beta-1; SCAP, SREBP cleavage-activating protein; SRE, sterol regulatory element; SREBP, sterol regulatory element-binding protein; TG, triacylglycerol; TIP47, tail-interacting protein-47; TSC, tuberous sclerosis complex; WNV, West Nile virus. Created with BioRender.com.
Figure 4
Figure 4
Potential effects of VILPs on the host cell metabolism. We hypothesize that upon infection, VILPs will be translated and secreted by the host cells and act on a target cell in an autocrine (a), paracrine (b), or endocrine (c) manner. In the target cells, VILP may activate several aspects of insulin/IGF signaling and alter several pathways regulating carbohydrate metabolism, cell growth, proliferation, and apoptosis. Abbreviations: IGF, insulin-like growth factor; IGF1R, insulin-like growth factor 1 receptor; IR, insulin receptor; MAPK, mitogen-activated protein kinase; P, phosphate group; PI3K, phosphoinositide 3-kinase; Ras, rat sarcoma; T1D/T2D, type 1 diabetes/type 2 diabetes; VILP, viral insulin/IGF-like peptide. Created with BioRender.com.

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