Targeting ACLY efficiently inhibits SARS-CoV-2 replication

The Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the biggest public health challenge the world has witnessed in the past decades. SARS-CoV-2 undergoes constant mutations and new variants of concerns (VOCs) with altered transmissibility, virulence, and/or susceptibility to vaccines and therapeutics continue to emerge. Detailed analysis of host factors involved in virus replication may help to identify novel treatment targets. In this study, we dissected the metabolome derived from COVID-19 patients to identify key host factors that are required for efficient SARS-CoV-2 replication. Through a series of metabolomic analyses, in vitro, and in vivo investigations, we identified ATP citrate lyase (ACLY) as a novel host factor required for efficient replication of SARS-CoV-2 wild-type and variants, including Omicron. ACLY should be further explored as a novel intervention target for COVID-19.

[1]  K. Yuen,et al.  Pathogenicity of SARS‐CoV‐2 Omicron , 2022, Clinical and translational medicine.

[2]  Jian-Piao Cai,et al.  Bacillus Calmette-Guérin–induced trained immunity protects against SARS-CoV-2 challenge in K18-hACE2 mice , 2022, JCI insight.

[3]  J. Chan,et al.  Animal models in SARS-CoV-2 research , 2022, Nature Methods.

[4]  Liyuan Liu,et al.  Antibody evasion properties of SARS-CoV-2 Omicron sublineages , 2022, Nature.

[5]  A. Cifuentes,et al.  Metabolomics study of COVID-19 patients in four different clinical stages , 2022, Scientific Reports.

[6]  X. Fu,et al.  The mTOR/PGC-1α/SIRT3 Pathway Drives Reductive Glutamine Metabolism to Reduce Oxidative Stress Caused by ISKNV in CPB Cells , 2022, Microbiology spectrum.

[7]  K. To,et al.  Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron , 2021, Nature.

[8]  P. Maes,et al.  Considerable escape of SARS-CoV-2 Omicron to antibody neutralization , 2021, Nature.

[9]  Fei Shao,et al.  Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies , 2021, bioRxiv.

[10]  Liyuan Liu,et al.  Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2 , 2021, Nature.

[11]  A. Telenti,et al.  Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift , 2021, Nature.

[12]  S. Sarin,et al.  Global metabolome profiling of COVID-19 respiratory specimen using high-resolution mass spectrometry (HRMS) , 2021, STAR Protocols.

[13]  K. To,et al.  SARS-CoV-2 exploits host DGAT and ADRP for efficient replication , 2021, Cell discovery.

[14]  K. To,et al.  Emerging SARS-CoV-2 variants expand species tropism to murines , 2021, EBioMedicine.

[15]  Oihane E. Albóniga,et al.  Metabolic snapshot of plasma samples reveals new pathways implicated in SARS-CoV-2 pathogenesis , 2021, bioRxiv.

[16]  Jian-Piao Cai,et al.  Low Environmental Temperature Exacerbates Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Golden Syrian Hamsters. , 2021, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[17]  Jian-Piao Cai,et al.  Targeting highly pathogenic coronavirus-induced apoptosis reduces viral pathogenesis and disease severity , 2021, Science Advances.

[18]  Jian-Piao Cai,et al.  In silico structure-based discovery of a SARS-CoV-2 main protease inhibitor , 2021, International journal of biological sciences.

[19]  K. Plath,et al.  SARS-CoV-2 infection rewires host cell metabolism and is potentially susceptible to mTORC1 inhibition , 2021, Nature Communications.

[20]  Ronald A. Li,et al.  Clofazimine broadly inhibits coronaviruses including SARS-CoV-2 , 2021, Nature.

[21]  K. To,et al.  Coinfection by Severe Acute Respiratory Syndrome Coronavirus 2 and Influenza A(H1N1)pdm09 Virus Enhances the Severity of Pneumonia in Golden Syrian Hamsters , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[22]  G. Cappellano,et al.  Large-Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS-CoV-2 , 2020, International journal of molecular sciences.

[23]  K. To,et al.  SARS-CoV-2 Induces a More Robust Innate Immune Response and Replicates Less Efficiently Than SARS-CoV in the Human Intestines: An Ex Vivo Study With Implications on Pathogenesis of COVID-19 , 2020, Cellular and Molecular Gastroenterology and Hepatology.

[24]  K. To,et al.  Oral SARS-CoV-2 Inoculation Establishes Subclinical Respiratory Infection with Virus Shedding in Golden Syrian Hamsters , 2020, Cell Reports Medicine.

[25]  Dong Yang,et al.  Host and viral determinants for efficient SARS-CoV-2 infection of the human lung , 2020, Nature Communications.

[26]  K. To,et al.  Broad-Spectrum Host-Based Antivirals Targeting the Interferon and Lipogenesis Pathways as Potential Treatment Options for the Pandemic Coronavirus Disease 2019 (COVID-19) , 2020, Viruses.

[27]  Kwok-Hung Chan,et al.  Long SARS-CoV-2 nucleocapsid sequences in blood monocytes collected soon after hospital admission , 2020, bioRxiv.

[28]  J. Chan,et al.  Targeting the inositol-requiring enzyme-1 pathway efficiently reverts Zika virus-induced neurogenesis and spermatogenesis marker perturbations. , 2020, ACS infectious diseases.

[29]  O. Tsang,et al.  Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study , 2020, The Lancet Microbe.

[30]  Dong Yang,et al.  Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study with implications for the pathogenesis of COVID-19 , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[31]  K. To,et al.  Simulation of the clinical and pathological manifestations of Coronavirus Disease 2019 (COVID-19) in golden Syrian hamster model: implications for disease pathogenesis and transmissibility , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[32]  Kwok-Hung Chan,et al.  Improved Molecular Diagnosis of COVID-19 by the Novel, Highly Sensitive and Specific COVID-19-RdRp/Hel Real-Time Reverse Transcription-PCR Assay Validated In Vitro and with Clinical Specimens , 2020, Journal of Clinical Microbiology.

[33]  Kai Zhao,et al.  A pneumonia outbreak associated with a new coronavirus of probable bat origin , 2020, Nature.

[34]  S. Lo,et al.  A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster , 2020, The Lancet.

[35]  K. To,et al.  Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan , 2020, Emerging microbes & infections.

[36]  C. Yip,et al.  Lipidomic Profiling Reveals Significant Perturbations of Intracellular Lipid Homeostasis in Enterovirus-Infected Cells , 2019, International journal of molecular sciences.

[37]  R. Sun,et al.  Differential Metabolic Reprogramming by Zika Virus Promotes Cell Death in Human versus Mosquito Cells. , 2019, Cell metabolism.

[38]  O. Fiehn,et al.  Systematic Error Removal Using Random Forest for Normalizing Large-Scale Untargeted Lipidomics Data. , 2019, Analytical chemistry.

[39]  Dong Yang,et al.  SREBP-dependent lipidomic reprogramming as a broad-spectrum antiviral target , 2019, Nature Communications.

[40]  Karin H. Frühwirth,et al.  Rhinovirus induces an anabolic reprogramming in host cell metabolism essential for viral replication , 2018, Proceedings of the National Academy of Sciences.

[41]  J. Chan,et al.  Middle East respiratory syndrome coronavirus and bat coronavirus HKU9 both can utilize GRP78 for attachment onto host cells , 2018, The Journal of Biological Chemistry.

[42]  Kristin E. Burnum-Johnson,et al.  MPLEx: a method for simultaneous pathogen inactivation and extraction of samples for multi-omics profiling. , 2017, The Analyst.

[43]  J. Chan,et al.  Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 Is an Important Surface Attachment Factor That Facilitates Entry of Middle East Respiratory Syndrome Coronavirus , 2016, Journal of Virology.

[44]  Minoru Kanehisa,et al.  KEGG as a reference resource for gene and protein annotation , 2015, Nucleic Acids Res..

[45]  Chuan Qin,et al.  Middle East Respiratory Syndrome Coronavirus Efficiently Infects Human Primary T Lymphocytes and Activates the Extrinsic and Intrinsic Apoptosis Pathways , 2015, The Journal of infectious diseases.

[46]  Masanori Arita,et al.  MS-DIAL: Data Independent MS/MS Deconvolution for Comprehensive Metabolome Analysis , 2015, Nature Methods.

[47]  Wan-ying Wu,et al.  UHPLC-LTQ-Orbitrap MS combined with spike-in method for plasma metabonomics analysis of acute myocardial ischemia rats and pretreatment effect of Danqi Tongmai tablet. , 2015, Molecular bioSystems.

[48]  Roman Camarda,et al.  Dengue Virus Induces and Requires Glycolysis for Optimal Replication , 2014, Journal of Virology.

[49]  K. Konan,et al.  Lipids and RNA virus replication. , 2014, Current opinion in virology.

[50]  I. Su,et al.  Activation of ATP Citrate Lyase by mTOR Signal Induces Disturbed Lipid Metabolism in Hepatitis B Virus Pre-S2 Mutant Tumorigenesis , 2014, Journal of Virology.

[51]  Johan Trygg,et al.  Variable influence on projection (VIP) for orthogonal projections to latent structures (OPLS) , 2014 .

[52]  M. Akram.  Citric Acid Cycle and Role of its Intermediates in Metabolism , 2014, Cell Biochemistry and Biophysics.

[53]  K. To,et al.  Productive replication of Middle East respiratory syndrome coronavirus in monocyte-derived dendritic cells modulates innate immune response , 2014, Virology.

[54]  Roman Camarda,et al.  Vaccinia Virus Requires Glutamine but Not Glucose for Efficient Replication , 2014, Journal of Virology.

[55]  Oliver Fiehn,et al.  LipidBlast - in-silico tandem mass spectrometry database for lipid identification , 2013, Nature Methods.

[56]  A. Al-Ahmad,et al.  A comprehensive method for determination of fatty acids in the initial oral biofilm (pellicle) , 2012, Journal of Lipid Research.

[57]  G. Siuzdak,et al.  Innovation: Metabolomics: the apogee of the omics trilogy , 2012, Nature Reviews Molecular Cell Biology.

[58]  Baek Kim,et al.  Metabolite profiles of human immunodeficiency virus infected CD4+ T cells and macrophages using LC-MS/MS analysis. , 2011, Virology.

[59]  Joshua D. Knowles,et al.  Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry , 2011, Nature Protocols.

[60]  Qibin Zhang,et al.  Temporal Proteome and Lipidome Profiles Reveal Hepatitis C Virus-Associated Reprogramming of Hepatocellular Metabolism and Bioenergetics , 2010, PLoS pathogens.

[61]  J. Pawlotsky,et al.  Hepatitis C Virus Proteins Induce Lipogenesis and Defective Triglyceride Secretion in Transgenic Mice* , 2009, The Journal of Biological Chemistry.

[62]  Ute Roessner,et al.  An Investigation of Boron Toxicity in Barley Using Metabolomics1[W] , 2006, Plant Physiology.

[63]  S. Kersten.  Mechanisms of nutritional and hormonal regulation of lipogenesis , 2001, EMBO reports.

[64]  C. Grunfeld,et al.  Increased de novo hepatic lipogenesis in human immunodeficiency virus infection. , 1993, The Journal of clinical endocrinology and metabolism.