HMR/D
Metabolic Reprogram
Integration of Viral RNA with Human Genome (DNA) leads to HMR/D
SARS-CoV-2 is an enveloped, +ve sense, singled-stranded RNA virus - the causative agent of COVID-19. SARS‐CoV‐2 is totally devoid of any metabolic capacity; therefore, it is critical for the virus to hijack host cell metabolic machinery for its own replication and propagation. The 29.9-kb genome of this RNA virus encodes 14 open reading frames (ORFs), which initiate a plethora of virus-host protein-protein interactions in the human body. Such extensive viral protein interactions with specific host cellular targets could trigger severe human metabolic reprogramming/ dysregulation (HMR/D), an alteration of sugar, amino acid, lipid, and nucleotide metabolism; as well as impair bioenergetics, immune defense, and redox balance in the body.
Based on the structural map of SARS-CoV-2, about 6% of the viral proteome mimics human proteins, while nearly 7% is implicated in host cell hijacking mechanisms, and about 29% proteome self-assembles into heteromeric components to support viral replication. A ribo-nucleoprotein (RNP) capture has identified a direct interaction of SARS-CoV-2 RNA with 109 human host factors. Besides hijack of specific host cellular factors (i.e., ACE2, NRP1, Furin, TMPRSS2, CTSL), this ‘novel’ coronavirus RNA encodes 14 open reading frames (ORFs) that could partake in ~4,781 unique high-confidence virus-host protein-protein interactions in the human body. Such extensive viral ORF/protein interactions with host specific cellular targets could trigger HMR/D including: hypoxia (’Warburg’ effect) with mitochondrial dysregulation (m-Dys, altered ATP synthesis), oxidative stress (OxS), immune impairment, and iron (Fe) redox dysregulation (FeRD) in an infected individual. Accordingly, SARS‐CoV‐2 genome and its products could potentially modulate human metabolism at transcription, translation, and post-translational modification (PTM) levels and induce HMR/D. A plethora of clinical symptoms and related metabolic impairments indicate an involvement of different pathophysiological mechanisms originating from virus induced HMR/D – a ‘new onset’ metabolic syndrome.
SARS-CoV-2 Reprograms Human Genome (DNA)
SARS-CoV-2 protein, nsp-1, binds to human ribosomes and inhibits host cellular translation. SARS-CoV-2 protein ORF3a interacts with host transcription factor ZNF579 and directly affects human gene transcription. Viral ORF8 acts as a histone mimic and disrupts host cell epigenetic regulation. Viral protein nsp-12 (RNA-dependent RNA polymerase) could sense host nucleotide availability and modulate replication efficacy of the viral genome. SARS-CoV-2 infection reprograms host folate and one-carbon metabolism at the PTM level to support de novo purine synthesis for replication of viral genome, via bypassing the viral shutoff of host translation.
SARS-CoV-2 Reprograms Human Bioenergetic Machinery
Interaction of viral gene nsp-6 with mitochondrial proteins (i.e., ATP synthase) alters cellular ATP synthesis. Thus, SARS-CoV-2 infection dysregulates mitochondrial metabolism and forces the host cell to generate energy (ATP) and other metabolites to support viral life cycle. Viral nsp-12 could alter amino acid metabolism (especially of the branched‐chain amino acids, BCAA), while nsp-12, nsp-7, and nsp-8 interactions with electron transport chain (ETC) and ribosomal proteins could potentially dysregulate mitochondrial respiration.
SARS-CoV-2 Reprograms Human Lipid Metabolism
Lipids play a major role in viral life cycle, accordingly the SARS-CoV-2 infection affects host lipidome by reprogramming cellular fatty acid metabolism and nucleotide biosynthesis. Viral protein nsp-7 could potentially alter host lipid metabolism, through its avid interaction with host enzymes involved in fatty acid-β‐oxidation and lipogenesis. SARS‐CoV‐2 up-regulates lipid biosynthesis to support the assembly of lipid bilayer‐envelope of the virion particle.
SARS-CoV-2-induced HMR/D Impairs Innate Host Defense
Viral ORF3a interacts with heme oxygenase-1 (HO-1) and reprograms heme metabolism leading to iron (Fe)-redox dysregulation (FeRD) during SARS‐CoV‐2 infection. HO-1 is a stress-induced, anti-inflammatory, immune- modulatory, and cyto-protective enzyme that degrades heme into carbon monoxide, free iron, and biliverdin, consequently the viral-induced HMR/D could compromise host innate and adaptive immune responses. Redox imbalance, FeRD in particular, results from viral-induced HMR/D and represents a critical state both in the pathogenesis of SARS‐CoV‐2 infection and host inflammatory response. Antioxidant enzymes such as superoxide dismutase 1 (SOD1), and glucose‐6‐phosphate dehydrogenase (G6PD) decrease from HMR/D-induced OxS and protein degradation. Furthermore, viral protein nsp-5 and nsp-14 interact with host redox-enzymes: glutathione peroxidase (GPx) and peroxiredoxin (Prx), in both cytoplasm and mitochondria to dysregulate redox balance in different cellular compartments and enhance SARS-CoV-2 infection. Viral protein encoded by ORF6 potently inhibits nuclear trafficking and helps viral evasion of IFN-mediated host defenses. Viral protein, nsp-14, interacts with the catalytic domain of Sirt1, dysregulates Nrf2/ HO1 axis, and impairs host antioxidant defense.