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1
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Cruz-Pulido YE, LoMascolo NJ, May D, Hatahet J, Thomas CE, Chu AKW, Stacey SP, Villanueva Guzman MDM, Aubert G, Mounce BC. Polyamines mediate cellular energetics and lipid metabolism through mitochondrial respiration to facilitate virus replication. PLoS Pathog 2024; 20:e1012711. [PMID: 39556649 DOI: 10.1371/journal.ppat.1012711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 10/30/2024] [Indexed: 11/20/2024] Open
Abstract
Polyamines are critical cellular components that regulate a variety of processes, including translation, cell cycling, and nucleic acid metabolism. The polyamines, putrescine, spermidine, and spermine, are found abundantly within cells and are positively-charged at physiological pH. Polyamine metabolism is connected to distinct other metabolic pathways, including nucleotide and amino acid metabolism. However, the breadth of the effect of polyamines on cellular metabolism remains to be fully understood. We recently demonstrated a role for polyamines in cholesterol metabolism, and following these studies, we measured the impact of polyamines on global lipid metabolism. We find that lipid droplets increase in number and size with polyamine depletion. We further demonstrate that lipid anabolism is markedly decreased, and lipid accumulation is due to reduced mitochondrial fatty acid oxidation. In fact, mitochondrial structure and function are largely ablated with polyamine depletion. To compensate, cells depleted of polyamines switch from aerobic respiration to glycolysis in a polyamine depletion-mediated Warburg-like effect. Finally, we show that inhibitors of lipid metabolism are broadly antiviral, suggesting that polyamines and lipids are promising antiviral targets. Together, these data demonstrate a novel role for polyamines in mitochondrial function, lipid metabolism, and cellular energetics.
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Affiliation(s)
- Yazmin E Cruz-Pulido
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Natalie J LoMascolo
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Delaina May
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Jomana Hatahet
- Department of Cellular and Molecular Physiology, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Caroline E Thomas
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Andrea K W Chu
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Samantha P Stacey
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Maria Del Mar Villanueva Guzman
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, Illinois, United States of America
- Infectious Disease and Immunology Research Institute, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Gregory Aubert
- Division of Cardiology, Department of Internal Medicine, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Bryan C Mounce
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, Illinois, United States of America
- Infectious Disease and Immunology Research Institute, Loyola University Chicago, Maywood, Illinois, United States of America
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2
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Jo A, Kim KS, Won J, Shin H, Kim S, Kim B, Kim DJ, Cho JY, Kim HJ. Nasal symbiont Staphylococcus epidermidis restricts influenza A virus replication via the creation of a polyamine-deficient cellular environment. Commun Biol 2024; 7:1031. [PMID: 39174732 PMCID: PMC11341892 DOI: 10.1038/s42003-024-06706-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 08/08/2024] [Indexed: 08/24/2024] Open
Abstract
Studies on the immune-regulatory roles played by the commensal microbes residing in the nasal mucosa consider the contribution of antiviral immune responses. Here, we sought to identify the nasal microbiome, Staphylococcus epidermidis-regulated antiviral immune responses and the alteration of polyamine metabolites in nasal epithelium. We found that polyamines were required for the life cycle of influenza A virus (IAV) and depletion of polyamines disturbed IAV replication in normal human nasal epithelial (NHNE) cells. Inoculation of S. epidermidis also suppressed IAV infection and the concentration of polyamines including putrescine, spermidine, and spermine was completely attenuated in S. epidermidis-inoculated NHNE cells. S. epidermidis activated the enzyme involved in the production of ornithine from arginine and downregulated the activity of the enzyme involved in the production of putrescine from ornithine in nasal epithelium. S. epidermidis also induced the activation of enzymes that promote the extracellular export of spermine and spermidine in NHNE cells. Our findings demonstrate that S. epidermidis is shown to be able of creating an intracellular environment lacking polyamines in the nasal epithelium and promote the balance of cellular polyamines in favor of the host to restrict influenza virus replication.
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Affiliation(s)
- Ara Jo
- Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kyeong-Seog Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jina Won
- Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Haeun Shin
- Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sujin Kim
- Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Bora Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Da Jung Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
- Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Joo-Youn Cho
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Hyun Jik Kim
- Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Republic of Korea.
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
- Seoul National University Hospital, Seoul, Republic of Korea.
- Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul, Republic of Korea.
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3
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Zakirova NF, Khomich OA, Smirnova OA, Molle J, Duponchel S, Yanvarev DV, Valuev-Elliston VT, Monnier L, Grigorov B, Ivanova ON, Karpenko IL, Golikov MV, Bovet C, Rindlisbacher B, Khomutov AR, Kochetkov SN, Bartosch B, Ivanov AV. Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle. Cells 2024; 13:1036. [PMID: 38920664 PMCID: PMC11201506 DOI: 10.3390/cells13121036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/05/2024] [Accepted: 06/11/2024] [Indexed: 06/27/2024] Open
Abstract
Hepatitis C virus (HCV) is an oncogenic virus that causes chronic liver disease in more than 80% of patients. During the last decade, efficient direct-acting antivirals were introduced into clinical practice. However, clearance of the virus does not reduce the risk of end-stage liver diseases to the level observed in patients who have never been infected. So, investigation of HCV pathogenesis is still warranted. Virus-induced changes in cell metabolism contribute to the development of HCV-associated liver pathologies. Here, we studied the impact of the virus on the metabolism of polyamines and proline as well as on the urea cycle, which plays a crucial role in liver function. It was found that HCV strongly suppresses the expression of arginase, a key enzyme of the urea cycle, leading to the accumulation of arginine, and up-regulates proline oxidase with a concomitant decrease in proline concentrations. The addition of exogenous proline moderately suppressed viral replication. HCV up-regulated transcription but suppressed protein levels of polyamine-metabolizing enzymes. This resulted in a decrease in polyamine content in infected cells. Finally, compounds targeting polyamine metabolism demonstrated pronounced antiviral activity, pointing to spermine and spermidine as compounds affecting HCV replication. These data expand our understanding of HCV's imprint on cell metabolism.
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Affiliation(s)
- Natalia F. Zakirova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (N.F.Z.); (O.A.K.); (O.A.S.); (D.V.Y.); (V.T.V.-E.); (O.N.I.); (I.L.K.); (M.V.G.); (A.R.K.); (S.N.K.)
| | - Olga A. Khomich
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (N.F.Z.); (O.A.K.); (O.A.S.); (D.V.Y.); (V.T.V.-E.); (O.N.I.); (I.L.K.); (M.V.G.); (A.R.K.); (S.N.K.)
- INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, 69434 Lyon, France; (J.M.); (L.M.); (B.G.); (B.B.)
| | - Olga A. Smirnova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (N.F.Z.); (O.A.K.); (O.A.S.); (D.V.Y.); (V.T.V.-E.); (O.N.I.); (I.L.K.); (M.V.G.); (A.R.K.); (S.N.K.)
| | - Jennifer Molle
- INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, 69434 Lyon, France; (J.M.); (L.M.); (B.G.); (B.B.)
| | - Sarah Duponchel
- INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, 69434 Lyon, France; (J.M.); (L.M.); (B.G.); (B.B.)
| | - Dmitry V. Yanvarev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (N.F.Z.); (O.A.K.); (O.A.S.); (D.V.Y.); (V.T.V.-E.); (O.N.I.); (I.L.K.); (M.V.G.); (A.R.K.); (S.N.K.)
| | - Vladimir T. Valuev-Elliston
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (N.F.Z.); (O.A.K.); (O.A.S.); (D.V.Y.); (V.T.V.-E.); (O.N.I.); (I.L.K.); (M.V.G.); (A.R.K.); (S.N.K.)
| | - Lea Monnier
- INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, 69434 Lyon, France; (J.M.); (L.M.); (B.G.); (B.B.)
| | - Boyan Grigorov
- INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, 69434 Lyon, France; (J.M.); (L.M.); (B.G.); (B.B.)
| | - Olga N. Ivanova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (N.F.Z.); (O.A.K.); (O.A.S.); (D.V.Y.); (V.T.V.-E.); (O.N.I.); (I.L.K.); (M.V.G.); (A.R.K.); (S.N.K.)
| | - Inna L. Karpenko
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (N.F.Z.); (O.A.K.); (O.A.S.); (D.V.Y.); (V.T.V.-E.); (O.N.I.); (I.L.K.); (M.V.G.); (A.R.K.); (S.N.K.)
| | - Mikhail V. Golikov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (N.F.Z.); (O.A.K.); (O.A.S.); (D.V.Y.); (V.T.V.-E.); (O.N.I.); (I.L.K.); (M.V.G.); (A.R.K.); (S.N.K.)
| | - Cedric Bovet
- University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (C.B.); (B.R.)
| | - Barbara Rindlisbacher
- University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (C.B.); (B.R.)
| | - Alex R. Khomutov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (N.F.Z.); (O.A.K.); (O.A.S.); (D.V.Y.); (V.T.V.-E.); (O.N.I.); (I.L.K.); (M.V.G.); (A.R.K.); (S.N.K.)
| | - Sergey N. Kochetkov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (N.F.Z.); (O.A.K.); (O.A.S.); (D.V.Y.); (V.T.V.-E.); (O.N.I.); (I.L.K.); (M.V.G.); (A.R.K.); (S.N.K.)
| | - Birke Bartosch
- INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, 69434 Lyon, France; (J.M.); (L.M.); (B.G.); (B.B.)
| | - Alexander V. Ivanov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (N.F.Z.); (O.A.K.); (O.A.S.); (D.V.Y.); (V.T.V.-E.); (O.N.I.); (I.L.K.); (M.V.G.); (A.R.K.); (S.N.K.)
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4
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Xie G, Zhu L, Liu S, Li C, Diao X, Zhang Y, Su X, Song Y, Cao G, Zhong L, Wang P, Liu X, Mok BWY, Zhang S, Jin DY, Zhou J, Chen H, Cai Z. Multi-omics analysis of attenuated variant reveals potential evaluation marker of host damaging for SARS-CoV-2 variants. SCIENCE CHINA. LIFE SCIENCES 2024; 67:83-95. [PMID: 37721637 DOI: 10.1007/s11427-022-2379-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 05/30/2023] [Indexed: 09/19/2023]
Abstract
SARS-CoV-2 continues to threaten human society by generating novel variants via mutation and recombination. The high number of mutations that appeared in emerging variants not only enhanced their immune-escaping ability but also made it difficult to predict the pathogenicity and virulence based on viral nucleotide sequences. Molecular markers for evaluating the pathogenicity of new variants are therefore needed. By comparing host responses to wild-type and variants with attenuated pathogenicity at proteome and metabolome levels, six key molecules on the polyamine biosynthesis pathway including putrescine, SAM, dc-SAM, ODC1, SAMS, and SAMDC were found to be differentially upregulated and associated with pathogenicity of variants. To validate our discovery, human airway organoids were subsequently used which recapitulates SARS-CoV-2 replication in the airway epithelial cells of COVID-19 patients. Using ODC1 as a proof-of-concept, differential activation of polyamine biosynthesis was found to be modulated by the renin-angiotensin system (RAS) and positively associated with ACE2 activity. Further experiments demonstrated that ODC1 expression could be differentially activated upon a panel of SARS-CoV-2 variants of concern (VOCs) and was found to be correlated with each VOCs' pathogenic properties. Particularly, the presented study revealed the discriminative ability of key molecules on polyamine biosynthesis as a predictive marker for virulence evaluation and assessment of SARS-CoV-2 variants in cell or organoid models. Our work, therefore, presented a practical strategy that could be potentially applied as an evaluation tool for the pathogenicity of current and emerging SARS-CoV-2 variants.
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Affiliation(s)
- Guangshan Xie
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR, China
| | - Lin Zhu
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR, China.
- HKBU Shenzhen Institute of Research and Continuing Education, Shenzhen, 518000, China.
| | - Siwen Liu
- State Key Laboratory for Emerging Infectious Diseases, and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Cun Li
- State Key Laboratory for Emerging Infectious Diseases, and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Xin Diao
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR, China
| | - Yanhao Zhang
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR, China
| | - Xiuli Su
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR, China
| | - Yuanyuan Song
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR, China
| | - Guodong Cao
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR, China
| | - Li Zhong
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR, China
| | - Pui Wang
- State Key Laboratory for Emerging Infectious Diseases, and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Xiaojuan Liu
- State Key Laboratory for Emerging Infectious Diseases, and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Bobo Wing-Yee Mok
- State Key Laboratory for Emerging Infectious Diseases, and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Shusheng Zhang
- College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China
| | - Dong-Yan Jin
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China
| | - Jie Zhou
- State Key Laboratory for Emerging Infectious Diseases, and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Honglin Chen
- State Key Laboratory for Emerging Infectious Diseases, and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Zongwei Cai
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR, China.
- HKBU Shenzhen Institute of Research and Continuing Education, Shenzhen, 518000, China.
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5
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Hu Y, Bao F, Fu S, Feng S, Miao J, Miao P, Xu Y. A facile electrochemical biosensor for coronavirus RNA assay with silver deposition. Talanta 2024; 266:125013. [PMID: 37536110 DOI: 10.1016/j.talanta.2023.125013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 07/23/2023] [Accepted: 07/28/2023] [Indexed: 08/05/2023]
Abstract
Coronaviruses are highly infectious and pose a serious threat to human and animal healths. In this work, a facile electrochemical method based on Exonuclease III (Exo III) catalyzed digestion and silver deposition is developed for coronavirus RNA analysis. A magnetic separation procedure is performed to specifically identify target sequence and release single-stranded DNA modified gold nanoparticles (AuNPs). The nanoparticles can thus be immobilized at a screen-printed electrode and catalyze silver deposition for signal readout. This method allows sensitive analysis of PEDV and SARS-CoV-2 RNAs in the concentration range from 1 to 1000 nM with the limits of detection as low as 0.47 nM and 0.17 nM, respectively. Good specificities are demonstrated. Thus, the proposed method may have great potential use in the applications of coronaviruses analysis.
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Affiliation(s)
- Yaqi Hu
- Sanya Institute of Nanjing Agricultural University, MOE Joint International Research Laboratory of Animal Health and Food Safety, Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China
| | - Fang Bao
- Sanya Institute of Nanjing Agricultural University, MOE Joint International Research Laboratory of Animal Health and Food Safety, Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China
| | - Siyuan Fu
- Sanya Institute of Nanjing Agricultural University, MOE Joint International Research Laboratory of Animal Health and Food Safety, Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China
| | - Shiyuan Feng
- Sanya Institute of Nanjing Agricultural University, MOE Joint International Research Laboratory of Animal Health and Food Safety, Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China
| | - Jinfeng Miao
- Sanya Institute of Nanjing Agricultural University, MOE Joint International Research Laboratory of Animal Health and Food Safety, Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China
| | - Peng Miao
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, 215163, PR China.
| | - Yuanyuan Xu
- Sanya Institute of Nanjing Agricultural University, MOE Joint International Research Laboratory of Animal Health and Food Safety, Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China.
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6
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Peñas-Sanjuán A, Chica-Armenteros JJ, Cruz-Sánchez R, García-Gallarín C, Melguizo M. Sequential Nitrile Amidination-Reduction as a Straightforward Procedure to Selective Linear Polyamine Preparation. J Org Chem 2023; 88:17274-17283. [PMID: 38006401 PMCID: PMC10729039 DOI: 10.1021/acs.joc.3c02128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/10/2023] [Accepted: 11/15/2023] [Indexed: 11/27/2023]
Abstract
A straightforward strategy toward the efficient synthesis of linear saturated polyamines containing 1,2-diaminoethane and/or 1,3-diaminopropane fragments has been developed. The procedure is based on the chemistry of 5- and 6-membered cyclic amidines, including their efficient synthesis from nitrile precursors and subsequent chemoselective reductive-opening by a borane-dimethyl sulfide complex. This two-step procedure provides a robust methodology for the synthesis of linear polyamine skeletons under nonharsh conditions and free of using selective protective groups or tedious workups.
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Affiliation(s)
- Antonio Peñas-Sanjuán
- Departamento de Química Inorgánica
y Orgánica. Facultad de Ciencias Experimentales, Universidad de Jaén, 23071 Jaén, Spain
| | - Jose J. Chica-Armenteros
- Departamento de Química Inorgánica
y Orgánica. Facultad de Ciencias Experimentales, Universidad de Jaén, 23071 Jaén, Spain
| | - Rubén Cruz-Sánchez
- Departamento de Química Inorgánica
y Orgánica. Facultad de Ciencias Experimentales, Universidad de Jaén, 23071 Jaén, Spain
| | - Celeste García-Gallarín
- Departamento de Química Inorgánica
y Orgánica. Facultad de Ciencias Experimentales, Universidad de Jaén, 23071 Jaén, Spain
| | - Manuel Melguizo
- Departamento de Química Inorgánica
y Orgánica. Facultad de Ciencias Experimentales, Universidad de Jaén, 23071 Jaén, Spain
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7
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Cruz-Pulido YE, Mounce BC. Good cop, bad cop: Polyamines play both sides in host immunity and viral replication. Semin Cell Dev Biol 2023; 146:70-79. [PMID: 36604249 PMCID: PMC10101871 DOI: 10.1016/j.semcdb.2022.12.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 01/05/2023]
Abstract
Viruses rely on host cells for energy and synthesis machinery required for genome replication and particle assembly. Due to the dependence of viruses on host cells, viruses have evolved multiple mechanisms by which they can induce metabolic changes in the host cell to suit their specific requirements. The host immune response also involves metabolic changes to be able to react to viral insult. Polyamines are small ubiquitously expressed polycations, and their metabolism is critical for viral replication and an adequate host immune response. This is due to the variety of functions that polyamines have, ranging from condensing DNA to enhancing the translation of polyproline-containing proteins through the hypusination of eIF5A. Here, we review the diverse mechanisms by which viruses exploit polyamines, as well as the mechanisms by which immune cells utilize polyamines for their functions. Furthermore, we highlight potential avenues for further study of the host-virus interface.
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Affiliation(s)
- Yazmin E Cruz-Pulido
- Department of Microbiology and Immunology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Bryan C Mounce
- Department of Microbiology and Immunology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA; Infectious Disease and Immunology Research Institute, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA.
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8
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López-Hernández Y, Monárrez-Espino J, López DAG, Zheng J, Borrego JC, Torres-Calzada C, Elizalde-Díaz JP, Mandal R, Berjanskii M, Martínez-Martínez E, López JA, Wishart DS. The plasma metabolome of long COVID patients two years after infection. Sci Rep 2023; 13:12420. [PMID: 37528111 PMCID: PMC10394026 DOI: 10.1038/s41598-023-39049-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 07/19/2023] [Indexed: 08/03/2023] Open
Abstract
One of the major challenges currently faced by global health systems is the prolonged COVID-19 syndrome (also known as "long COVID") which has emerged as a consequence of the SARS-CoV-2 epidemic. It is estimated that at least 30% of patients who have had COVID-19 will develop long COVID. In this study, our goal was to assess the plasma metabolome in a total of 100 samples collected from healthy controls, COVID-19 patients, and long COVID patients recruited in Mexico between 2020 and 2022. A targeted metabolomics approach using a combination of LC-MS/MS and FIA MS/MS was performed to quantify 108 metabolites. IL-17 and leptin were measured in long COVID patients by immunoenzymatic assay. The comparison of paired COVID-19/long COVID-19 samples revealed 53 metabolites that were statistically different. Compared to controls, 27 metabolites remained dysregulated even after two years. Post-COVID-19 patients displayed a heterogeneous metabolic profile. Lactic acid, lactate/pyruvate ratio, ornithine/citrulline ratio, and arginine were identified as the most relevant metabolites for distinguishing patients with more complicated long COVID evolution. Additionally, IL-17 levels were significantly increased in these patients. Mitochondrial dysfunction, redox state imbalance, impaired energy metabolism, and chronic immune dysregulation are likely to be the main hallmarks of long COVID even two years after acute COVID-19 infection.
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Affiliation(s)
- Yamilé López-Hernández
- CONAHCyT-Metabolomics and Proteomics Laboratory, Academic Unit of Biological Sciences, Autonomous University of Zacatecas, 98000, Zacatecas, Mexico.
| | - Joel Monárrez-Espino
- Department of Health Research, Christus Muguerza del Parque Hospital - University of Monterrey, 31125, Chihuahua, Mexico
| | | | - Jiamin Zheng
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB, T6G 1C9, Canada
| | - Juan Carlos Borrego
- Departamento de Epidemiología, Hospital General de Zona #1 "Emilio Varela Luján", Instituto Mexicano del Seguro Social, Zacatecas, 98000, México
| | | | - José Pedro Elizalde-Díaz
- Laboratory of Cell Communication & Extracellular Vesicles, Division of Basic Science, Instituto Nacional de Medicina Genómica, 14610, Ciudad de México, Mexico
| | - Rupasri Mandal
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB, T6G 1C9, Canada
| | - Mark Berjanskii
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB, T6G 1C9, Canada
| | - Eduardo Martínez-Martínez
- Laboratory of Cell Communication & Extracellular Vesicles, Division of Basic Science, Instituto Nacional de Medicina Genómica, 14610, Ciudad de México, Mexico
| | - Jesús Adrián López
- MicroRNAs and Cancer Laboratory, Academic Unit of Biological Sciences, Autonomous University of Zacatecas, 98000, Zacatecas, Mexico
| | - David S Wishart
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB, T6G 1C9, Canada.
- Department of Biological Sciences, University of Alberta, Edmonton, AB, T6G 1C9, Canada.
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9
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Mastrodomenico V, LoMascolo NJ, Firpo MR, Villanueva Guzman MDM, Zaporowski A, Mounce BC. Persistent Coxsackievirus B3 Infection in Pancreatic Ductal Cells In Vitro Downregulates Cellular Polyamine Metabolism. mSphere 2023:e0003623. [PMID: 37097178 DOI: 10.1128/msphere.00036-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023] Open
Abstract
Picornaviruses infect a wide variety of cell types in vitro, with rapid replication kinetics and pronounced cytopathic effect. Coxsackievirus B3 (CVB3) can also establish a persistent infection in vivo that can lead to pathology, including dilated cardiomyopathy and myocarditis. One model system to study persistent infection is the pancreatic ductal cell line PANC-1, which CVB3 infects and is maintained indefinitely. We have characterized this model for CVB3 infection to study persistent infection for over 6 months. We find that CVB3 rapidly replicates within PANC-1 cells without robust cytopathic effect, and after 1 month in culture, titers stabilize. We find that infection does not significantly affect cellular viability. Persistent virus reverts to lytic infection when transferred to Huh7 or Vero cells. We find that persistent CVB3 adapts to PANC-1 cells via mutation of its capsid proteins and, curiously, the viral polymerase (3Dpol) to generate a high-fidelity polymerase. Persistent infection is associated with reduced cleavage of eIF4G, reduced plaque size, and decreasing particle infectivity. We further find that polyamine metabolism is altered in persistently infected cells, with the rate-limiting enzyme ornithine decarboxylase (ODC1) reduced in translation. We further find that targeting polyamine synthesis reduces persistent infection without affecting the viability of the PANC-1 cells. Finally, we find that viral fidelity is essential to maintaining CVB3 infection, and targeting viral fidelity reduces persistent virus infection. Together, these data highlight a novel role for polyamines and fidelity in persistent CVB3 infection and suggest avenues for therapeutic development to target persistent infection. IMPORTANCE Enteroviruses are significant human pathogens that can cause severe disease, including cardiomyopathies. Viruses like coxsackievirus B3 (CVB3) can cause tissue damage by lytically infecting cells; however, CVB3 can also persistently infect, which has been associated with several pathologies. Studying persistent infection in vitro is challenging, as CVB3 lytically infects most cellular model systems. Here, we show that CVB3 establishes persistent infection in pancreatic ductal cells in vitro, similar to prior studies on other coxsackieviruses. We also show that this infection results in adaptation of the virus to these cells, as well as changes to cellular metabolism of polyamines.
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Affiliation(s)
- Vincent Mastrodomenico
- Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA
| | - Natalie J LoMascolo
- Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA
| | - Mason R Firpo
- Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA
| | - Maria Del Mar Villanueva Guzman
- Infectious Disease and Immunology Research Institute, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA
| | - Adam Zaporowski
- Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA
| | - Bryan C Mounce
- Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA
- Infectious Disease and Immunology Research Institute, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA
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10
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Bourgin M, Durand S, Kroemer G. Diagnostic, Prognostic and Mechanistic Biomarkers of COVID-19 Identified by Mass Spectrometric Metabolomics. Metabolites 2023; 13:metabo13030342. [PMID: 36984782 PMCID: PMC10056171 DOI: 10.3390/metabo13030342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/14/2023] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
A number of studies have assessed the impact of SARS-CoV-2 infection and COVID-19 severity on the metabolome of exhaled air, saliva, plasma, and urine to identify diagnostic and prognostic biomarkers. In spite of the richness of the literature, there is no consensus about the utility of metabolomic analyses for the management of COVID-19, calling for a critical assessment of the literature. We identified mass spectrometric metabolomic studies on specimens from SARS-CoV2-infected patients and subjected them to a cross-study comparison. We compared the clinical design, technical aspects, and statistical analyses of published studies with the purpose to identify the most relevant biomarkers. Several among the metabolites that are under- or overrepresented in the plasma from patients with COVID-19 may directly contribute to excessive inflammatory reactions and deficient immune control of SARS-CoV2, hence unraveling important mechanistic connections between whole-body metabolism and the course of the disease. Altogether, it appears that mass spectrometric approaches have a high potential for biomarker discovery, especially if they are subjected to methodological standardization.
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Affiliation(s)
- Mélanie Bourgin
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, 75005 Paris, France
- Correspondence:
| | - Sylvère Durand
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, 75005 Paris, France
| | - Guido Kroemer
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, 75005 Paris, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, 75610 Paris, France
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11
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Rojas-Luna L, Posadas-Modragón A, Avila-Trejo AM, Alcántara-Farfán V, Rodríguez-Páez LI, Santiago-Cruz JA, Pastor-Alonso MO, Aguilar-Faisal JL. Inhibition of chikungunya virus replication by N-ω-Chloroacetyl-L-Ornithine in C6/36, Vero cells and human fibroblast BJ. Antivir Ther 2023; 28:13596535231155263. [PMID: 36724136 DOI: 10.1177/13596535231155263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Polyamines are involved in several cellular processes and inhibiting their synthesis affects chikungunya virus (CHIKV) replication and translation, and, therefore, reduces the quantity of infectious viral particles produced. In this study, we evaluated the inhibition of CHIKV replication by N-ω-chloroacetyl-L-ornithine (NCAO), a competitive inhibitor of ornithine decarboxylase, an enzyme which is key in the biosynthesis of polyamines (PAs). METHODS The cytotoxicity of NCAO was evaluated by MTT in cell culture. The inhibitory effect of CHIKV replication by NCAO was evaluated in Vero and C6/36 cells. The intracellular polyamines were quantified by HPLC in CHIKV-infected cells. We evaluated the yield of CHIKV in titres via the addition of PAs in Vero, C6/36 cells and human fibroblast BJ treated with NCAO. RESULTS We found that NCAO inhibits the replication of CHIKV in Vero and C6/36 cells in a dose-dependent manner, causing a decrease in the PFU/mL of at least 4 logarithms (p < 0.01) in both cell lines. Viral yields were restored by the addition of exogenous polyamines, mainly putrescine. The HPLC analyses showed that NCAO decreases the content of intracellular PAs, even though it is predominantly spermidines and spermines which are present in infected cells. Inhibition of CHIKV replication was observed in human fibroblast BJ treated with 100 μM NCAO 24 h before and 48 h after the infection at a MOI 1. CONCLUSIONS NCAO inhibits CHIKV replication by depleting the intracellular polyamines in Vero, C6/36 cells and human fibroblast BJ, suggesting that this compound is a possible antiviral agent for CHIKV.
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Affiliation(s)
- Lucero Rojas-Luna
- Laboratorio de Medicina de Conservación, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, 27740Instituto Politécnico Nacional, Mexico City, Mexico
| | - Araceli Posadas-Modragón
- Laboratorio de Medicina de Conservación, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, 27740Instituto Politécnico Nacional, Mexico City, Mexico
| | - Amanda M Avila-Trejo
- Laboratorio de Medicina de Conservación, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, 27740Instituto Politécnico Nacional, Mexico City, Mexico.,Laboratorio de Bioquímica Farmacológica, 61735Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Verónica Alcántara-Farfán
- Laboratorio de Bioquímica Farmacológica, 61735Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Lorena I Rodríguez-Páez
- Laboratorio de Bioquímica Farmacológica, 61735Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - José Angel Santiago-Cruz
- Laboratorio de Medicina de Conservación, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, 27740Instituto Politécnico Nacional, Mexico City, Mexico
| | - Marvin O Pastor-Alonso
- Laboratorio de Medicina de Conservación, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, 27740Instituto Politécnico Nacional, Mexico City, Mexico
| | - J Leopoldo Aguilar-Faisal
- Laboratorio de Medicina de Conservación, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, 27740Instituto Politécnico Nacional, Mexico City, Mexico
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12
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Yoon JH, Do JS, Velankanni P, Lee CG, Kwon HK. Gut Microbial Metabolites on Host Immune Responses in Health and Disease. Immune Netw 2023; 23:e6. [PMID: 36911800 PMCID: PMC9995988 DOI: 10.4110/in.2023.23.e6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/12/2023] [Accepted: 02/13/2023] [Indexed: 03/07/2023] Open
Abstract
Intestinal microorganisms interact with various immune cells and are involved in gut homeostasis and immune regulation. Although many studies have discussed the roles of the microorganisms themselves, interest in the effector function of their metabolites is increasing. The metabolic processes of these molecules provide important clues to the existence and function of gut microbes. The interrelationship between metabolites and T lymphocytes in particular plays a significant role in adaptive immune functions. Our current review focuses on 3 groups of metabolites: short-chain fatty acids, bile acids metabolites, and polyamines. We collated the findings of several studies on the transformation and production of these metabolites by gut microbes and explained their immunological roles. Specifically, we summarized the reports on changes in mucosal immune homeostasis represented by the Tregs and Th17 cells balance. The relationship between specific metabolites and diseases was also analyzed through latest studies. Thus, this review highlights microbial metabolites as the hidden treasure having potential diagnostic markers and therapeutic targets through a comprehensive understanding of the gut-immune interaction.
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Affiliation(s)
- Jong-Hwi Yoon
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jun-Soo Do
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul 03722, Korea
- Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Priyanka Velankanni
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Korea
| | - Choong-Gu Lee
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Korea
- Division of Bio-Medical Science and Technology, Korea Institute of Science and Technology (KIST) School, University of Science and Technology, Seoul 02792, Korea
| | - Ho-Keun Kwon
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul 03722, Korea
- Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Korea
- Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 03722, Korea
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13
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Kumar R, Kumar V, Arya R, Anand U, Priyadarshi RN. Association of COVID-19 with hepatic metabolic dysfunction. World J Virol 2022; 11:237-251. [PMID: 36188741 PMCID: PMC9523326 DOI: 10.5501/wjv.v11.i5.237] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/25/2022] [Accepted: 06/20/2022] [Indexed: 02/05/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic continues to be a global problem with over 438 million cases reported so far. Although it mostly affects the respiratory system, the involvement of extrapulmonary organs, including the liver, is not uncommon. Since the beginning of the pandemic, metabolic com-orbidities, such as obesity, diabetes, hypertension, and dyslipidemia, have been identified as poor prognostic indicators. Subsequent metabolic and lipidomic studies have identified several metabolic dysfunctions in patients with COVID-19. The metabolic alterations appear to be linked to the course of the disease and inflammatory reaction in the body. The liver is an important organ with high metabolic activity, and a significant proportion of COVID-19 patients have metabolic comorbidities; thus, this factor could play a key role in orchestrating systemic metabolic changes during infection. Evidence suggests that metabolic dysregulation in COVID-19 has both short- and long-term metabolic implications. Furthermore, COVID-19 has adverse associations with metabolic-associated fatty liver disease. Due to the ensuing effects on the renin-angiotensin-aldosterone system and ammonia metabolism, COVID-19 can have significant implications in patients with advanced chronic liver disease. A thorough understanding of COVID-19-associated metabolic dysfunction could lead to the identification of important plasma biomarkers and novel treatment targets. In this review, we discuss the current understanding of metabolic dysfunction in COVID-19, focusing on the liver and exploring the underlying mechanistic pathogenesis and clinical implications.
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Affiliation(s)
- Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Vijay Kumar
- Department of Medicine, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Rahul Arya
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Utpal Anand
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Rajeev Nayan Priyadarshi
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
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14
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Sfera A, Hazan S, Anton JJ, Sfera DO, Andronescu CV, Sasannia S, Rahman L, Kozlakidis Z. Psychotropic drugs interaction with the lipid nanoparticle of COVID-19 mRNA therapeutics. Front Pharmacol 2022; 13:995481. [PMID: 36160443 PMCID: PMC9503827 DOI: 10.3389/fphar.2022.995481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 08/09/2022] [Indexed: 11/18/2022] Open
Abstract
The messenger RNA (mRNA) vaccines for COVID-19, Pfizer-BioNTech and Moderna, were authorized in the US on an emergency basis in December of 2020. The rapid distribution of these therapeutics around the country and the world led to millions of people being vaccinated in a short time span, an action that decreased hospitalization and death but also heightened the concerns about adverse effects and drug-vaccine interactions. The COVID-19 mRNA vaccines are of particular interest as they form the vanguard of a range of other mRNA therapeutics that are currently in the development pipeline, focusing both on infectious diseases as well as oncological applications. The Vaccine Adverse Event Reporting System (VAERS) has gained additional attention during the COVID-19 pandemic, specifically regarding the rollout of mRNA therapeutics. However, for VAERS, absence of a reporting platform for drug-vaccine interactions left these events poorly defined. For example, chemotherapy, anticonvulsants, and antimalarials were documented to interfere with the mRNA vaccines, but much less is known about the other drugs that could interact with these therapeutics, causing adverse events or decreased efficacy. In addition, SARS-CoV-2 exploitation of host cytochrome P450 enzymes, reported in COVID-19 critical illness, highlights viral interference with drug metabolism. For example, patients with severe psychiatric illness (SPI) in treatment with clozapine often displayed elevated drug levels, emphasizing drug-vaccine interaction.
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Affiliation(s)
- Adonis Sfera
- Patton State Hospital, San Bernardino, CA, United States
- Department of Psychiatry, University of California, Riverside, Riverside, CA, United States
| | - Sabine Hazan
- Department of Psychiatry, University of California, Riverside, Riverside, CA, United States
| | - Jonathan J. Anton
- Patton State Hospital, San Bernardino, CA, United States
- Department of Biology, California Baptist University, Riverside, CA, United States
| | - Dan O. Sfera
- Patton State Hospital, San Bernardino, CA, United States
| | | | | | - Leah Rahman
- Department of Medicine, University of Oregon, Eugene, OR, United States
| | - Zisis Kozlakidis
- International Agency For Research On Cancer (IARC), Lyon, France
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15
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Byeon SK, Madugundu AK, Garapati K, Ramarajan MG, Saraswat M, Kumar-M P, Hughes T, Shah R, Patnaik MM, Chia N, Ashrafzadeh-Kian S, Yao JD, Pritt BS, Cattaneo R, Salama ME, Zenka RM, Kipp BR, Grebe SKG, Singh RJ, Sadighi Akha AA, Algeciras-Schimnich A, Dasari S, Olson JE, Walsh JR, Venkatakrishnan AJ, Jenkinson G, O'Horo JC, Badley AD, Pandey A. Development of a multiomics model for identification of predictive biomarkers for COVID-19 severity: a retrospective cohort study. Lancet Digit Health 2022; 4:e632-e645. [PMID: 35835712 PMCID: PMC9273185 DOI: 10.1016/s2589-7500(22)00112-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 04/26/2022] [Accepted: 05/27/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND COVID-19 is a multi-system disorder with high variability in clinical outcomes among patients who are admitted to hospital. Although some cytokines such as interleukin (IL)-6 are believed to be associated with severity, there are no early biomarkers that can reliably predict patients who are more likely to have adverse outcomes. Thus, it is crucial to discover predictive markers of serious complications. METHODS In this retrospective cohort study, we analysed samples from 455 participants with COVID-19 who had had a positive SARS-CoV-2 RT-PCR result between April 14, 2020, and Dec 1, 2020 and who had visited one of three Mayo Clinic sites in the USA (Minnesota, Arizona, or Florida) in the same period. These participants were assigned to three subgroups depending on disease severity as defined by the WHO ordinal scale of clinical improvement (outpatient, severe, or critical). Our control cohort comprised of 182 anonymised age-matched and sex-matched plasma samples that were available from the Mayo Clinic Biorepository and banked before the COVID-19 pandemic. We did a deep profiling of circulatory cytokines and other proteins, lipids, and metabolites from both cohorts. Most patient samples were collected before, or around the time of, hospital admission, representing ideal samples for predictive biomarker discovery. We used proximity extension assays to quantify cytokines and circulatory proteins and tandem mass spectrometry to measure lipids and metabolites. Biomarker discovery was done by applying an AutoGluon-tabular classifier to a multiomics dataset, producing a stacked ensemble of cutting-edge machine learning algorithms. Global proteomics and glycoproteomics on a subset of patient samples with matched pre-COVID-19 plasma samples was also done. FINDINGS We quantified 1463 cytokines and circulatory proteins, along with 902 lipids and 1018 metabolites. By developing a machine-learning-based prediction model, a set of 102 biomarkers, which predicted severe and clinical COVID-19 outcomes better than the traditional set of cytokines, were discovered. These predictive biomarkers included several novel cytokines and other proteins, lipids, and metabolites. For example, altered amounts of C-type lectin domain family 6 member A (CLEC6A), ether phosphatidylethanolamine (P-18:1/18:1), and 2-hydroxydecanoate, as reported here, have not previously been associated with severity in COVID-19. Patient samples with matched pre-COVID-19 plasma samples showed similar trends in muti-omics signatures along with differences in glycoproteomics profile. INTERPRETATION A multiomic molecular signature in the plasma of patients with COVID-19 before being admitted to hospital can be exploited to predict a more severe course of disease. Machine learning approaches can be applied to highly complex and multidimensional profiling data to reveal novel signatures of clinical use. The absence of validation in an independent cohort remains a major limitation of the study. FUNDING Eric and Wendy Schmidt.
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Affiliation(s)
- Seul Kee Byeon
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Anil K Madugundu
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka, India; Center for Molecular Medicine, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India; Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Kishore Garapati
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka, India; Center for Molecular Medicine, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India; Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Madan Gopal Ramarajan
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka, India; Center for Molecular Medicine, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India; Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Mayank Saraswat
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Manipal Academy of Higher Education, Manipal, Karnataka, India
| | | | | | - Rameen Shah
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Mrinal M Patnaik
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Nicholas Chia
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | | | - Joseph D Yao
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Bobbi S Pritt
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Roberto Cattaneo
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Mohamed E Salama
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | | | - Benjamin R Kipp
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Stefan K G Grebe
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Ravinder J Singh
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Amir A Sadighi Akha
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | | | - Surendra Dasari
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Janet E Olson
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Jesse R Walsh
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | | | - Garrett Jenkinson
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - John C O'Horo
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Andrew D Badley
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Akhilesh Pandey
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
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16
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Singh K, Martinez MG, Lin J, Gregory J, Nguyen TU, Abdelaal R, Kang K, Brennand K, Grünweller A, Ouyang Z, Phatnani H, Kielian M, Wendel HG. Transcriptional and Translational Dynamics of Zika and Dengue Virus Infection. Viruses 2022; 14:1418. [PMID: 35891396 PMCID: PMC9316442 DOI: 10.3390/v14071418] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/18/2022] [Indexed: 11/16/2022] Open
Abstract
Zika virus (ZIKV) and dengue virus (DENV) are members of the Flaviviridae family of RNA viruses and cause severe disease in humans. ZIKV and DENV share over 90% of their genome sequences, however, the clinical features of Zika and dengue infections are very different reflecting tropism and cellular effects. Here, we used simultaneous RNA sequencing and ribosome footprinting to define the transcriptional and translational dynamics of ZIKV and DENV infection in human neuronal progenitor cells (hNPCs). The gene expression data showed induction of aminoacyl tRNA synthetases (ARS) and the translation activating PIM1 kinase, indicating an increase in RNA translation capacity. The data also reveal activation of different cell stress responses, with ZIKV triggering a BACH1/2 redox program, and DENV activating the ATF/CHOP endoplasmic reticulum (ER) stress program. The RNA translation data highlight activation of polyamine metabolism through changes in key enzymes and their regulators. This pathway is needed for eIF5A hypusination and has been implicated in viral translation and replication. Concerning the viral RNA genomes, ribosome occupancy readily identified highly translated open reading frames and a novel upstream ORF (uORF) in the DENV genome. Together, our data highlight both the cellular stress response and the activation of RNA translation and polyamine metabolism during DENV and ZIKV infection.
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Affiliation(s)
- Kamini Singh
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA;
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Albert Einstein Cancer, Center, Bronx, NY 10461, USA;
| | - Maria Guadalupe Martinez
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (M.G.M.); (R.A.); (M.K.)
- Global Innovation, Boehringer Ingelheim Animal Health, 69800 Saint-Priest, France
| | - Jianan Lin
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 and Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269, USA;
| | - James Gregory
- Department of Neurology, Vagelos College of Physicians & Surgeons of Columbia University, New York, NY 10032, USA; (J.G.); (K.K.); (H.P.)
- Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY 10013, USA
| | - Trang Uyen Nguyen
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Albert Einstein Cancer, Center, Bronx, NY 10461, USA;
| | - Rawan Abdelaal
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (M.G.M.); (R.A.); (M.K.)
| | - Kristy Kang
- Department of Neurology, Vagelos College of Physicians & Surgeons of Columbia University, New York, NY 10032, USA; (J.G.); (K.K.); (H.P.)
- Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY 10013, USA
| | - Kristen Brennand
- Division of Molecular Psychiatry, Departments of Psychiatry and Genetics, Yale School of Medicine, New Haven, CT 06510, USA;
| | - Arnold Grünweller
- Institute of Pharmaceutical Chemistry, Philipps University Marburg, 35032 Marburg, Germany;
| | - Zhengqing Ouyang
- Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003, USA;
| | - Hemali Phatnani
- Department of Neurology, Vagelos College of Physicians & Surgeons of Columbia University, New York, NY 10032, USA; (J.G.); (K.K.); (H.P.)
- Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY 10013, USA
| | - Margaret Kielian
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (M.G.M.); (R.A.); (M.K.)
| | - Hans-Guido Wendel
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA;
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17
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Xie H, Ai Q, Tong T, Liao M, Fan H. PEDV infection affects the expression of polyamine-related genes inhibiting viral proliferation. Virus Res 2022; 312:198708. [PMID: 35151773 PMCID: PMC8830936 DOI: 10.1016/j.virusres.2022.198708] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 12/26/2022]
Abstract
Porcine epidemic diarrhea virus (PEDV) is an alpha-coronavirus that causes epidemic diarrhea in swines. The mortality of PEDV infection in one-week-old piglets is extremely high, which causes a huge significant economic loss to the global pig husbandry and blocks its healthy development. There was a lack of adequate studies to elucidate pathogenic mechanism associated with PEDV infection. In the present study, we detected the expression profiles of polyamine metabolism associated genes in Vero cells infected with PEDV by RT-qPCR. It is shown that PAOX(acetylpolyamine oxidase), SMOX(spermine oxidase), SAT1(spermidine-spermine acetyltransferase 1), ODC1(ornithine decarboxylase 1), DHPS(deoxyhypusine synthase) and EIF5A( eukaryotic initiation factor 5A) were significantly upregulated. Through intervening SAT1 level in PEDV-infected Vero cells, it is identified that overexpression of SAT1 inhibited PEDV replication by reducing polyamine levels. Furthermore, polyamine depletion and upregulation were found to regulate the proliferation of PEDV. PEDV infection in Vero cells did not result in a significant change in the protein level of eIF5A, and in addition, the activated eIF5A did not affect the proliferation of PEDV. Our results provided new insights into the influence of polyamine metabolism on the proliferation of PEDV.
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Affiliation(s)
- Hangao Xie
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, China; Key Laboratory of Animal Vaccine Development, Ministry of Agriculture, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, China
| | - Qiangyun Ai
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, China; Key Laboratory of Animal Vaccine Development, Ministry of Agriculture, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, China
| | | | - Ming Liao
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, China; Key Laboratory of Animal Vaccine Development, Ministry of Agriculture, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, China.
| | - Huiying Fan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, China; Key Laboratory of Animal Vaccine Development, Ministry of Agriculture, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, China.
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18
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Pozzi C, Levi R, Braga D, Carli F, Darwich A, Spadoni I, Oresta B, Dioguardi CC, Peano C, Ubaldi L, Angelotti G, Bottazzi B, Garlanda C, Desai A, Voza A, Azzolini E, Cecconi M, Mantovani A, Penna G, Barbieri R, Politi LS, Rescigno M. A 'Multiomic' Approach of Saliva Metabolomics, Microbiota, and Serum Biomarkers to Assess the Need of Hospitalization in Coronavirus Disease 2019. GASTRO HEP ADVANCES 2022; 1:194-209. [PMID: 35174369 PMCID: PMC8818445 DOI: 10.1016/j.gastha.2021.12.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 12/06/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS The SARS-CoV-2 pandemic has overwhelmed the treatment capacity of the health care systems during the highest viral diffusion rate. Patients reaching the emergency department had to be either hospitalized (inpatients) or discharged (outpatients). Still, the decision was taken based on the individual assessment of the actual clinical condition, without specific biomarkers to predict future improvement or deterioration, and discharged patients often returned to the hospital for aggravation of their condition. Here, we have developed a new combined approach of omics to identify factors that could distinguish coronavirus disease 19 (COVID-19) inpatients from outpatients. METHODS Saliva and blood samples were collected over the course of two observational cohort studies. By using machine learning approaches, we compared salivary metabolome of 50 COVID-19 patients with that of 270 healthy individuals having previously been exposed or not to SARS-CoV-2. We then correlated the salivary metabolites that allowed separating COVID-19 inpatients from outpatients with serum biomarkers and salivary microbiota taxa differentially represented in the two groups of patients. RESULTS We identified nine salivary metabolites that allowed assessing the need of hospitalization. When combined with serum biomarkers, just two salivary metabolites (myo-inositol and 2-pyrrolidineacetic acid) and one serum protein, chitinase 3-like-1 (CHI3L1), were sufficient to separate inpatients from outpatients completely and correlated with modulated microbiota taxa. In particular, we found Corynebacterium 1 to be overrepresented in inpatients, whereas Actinomycetaceae F0332, Candidatus Saccharimonas, and Haemophilus were all underrepresented in the hospitalized population. CONCLUSION This is a proof of concept that a combined omic analysis can be used to stratify patients independently from COVID-19.
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Key Words
- AUC, area under the curve
- CHI3L1
- CHI3L1, chitinase 3-like-1
- CI, confidence interval
- COVID-19
- COVID-19, coronavirus disease 19
- DT, decision tree
- ELISA, enzyme-linked immunosorbent assay
- ESI, electrospray ionization
- FDR, false discovery rate
- IgG, immunoglobulin G
- LR, logistic regression
- Metabolome
- Microbiota
- PCA, principal component analysis
- PTX3, pentraxin 3
- RFE, recursive feature elimination
- SVM, support vector machine
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Affiliation(s)
- Chiara Pozzi
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Riccardo Levi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Daniele Braga
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Francesco Carli
- Department of Informatics, Università degli Studi di Torino, Torino, Piemonte, Italy
| | - Abbass Darwich
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Ilaria Spadoni
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Bianca Oresta
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Carola Conca Dioguardi
- Institute of Genetic and Biomedical Research, UoS of Milan, National Research Council, Rozzano, Milan, Italy
| | - Clelia Peano
- Institute of Genetic and Biomedical Research, UoS of Milan, National Research Council, Rozzano, Milan, Italy
| | - Leonardo Ubaldi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | | | | | - Cecilia Garlanda
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Antonio Desai
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Antonio Voza
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Elena Azzolini
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Maurizio Cecconi
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | | | - Alberto Mantovani
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy,The William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Giuseppe Penna
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Riccardo Barbieri
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milano, Italy
| | - Letterio S. Politi
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Maria Rescigno
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy,Correspondence: Address correspondence to: Prof. Maria Rescigno, PhD, Humanitas University Pieve Emanuele, Milan, Italy
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19
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Biogenic Polyamines and Related Metabolites. Biomolecules 2021; 12:biom12010014. [PMID: 35053162 PMCID: PMC8773558 DOI: 10.3390/biom12010014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 12/20/2021] [Indexed: 11/16/2022] Open
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20
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Biomedical Text Link Prediction for Drug Discovery: A Case Study with COVID-19. Pharmaceutics 2021; 13:pharmaceutics13060794. [PMID: 34073456 PMCID: PMC8230210 DOI: 10.3390/pharmaceutics13060794] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/05/2021] [Accepted: 05/19/2021] [Indexed: 01/03/2023] Open
Abstract
Link prediction in artificial intelligence is used to identify missing links or derive future relationships that can occur in complex networks. A link prediction model was developed using the complex heterogeneous biomedical knowledge graph, SemNet, to predict missing links in biomedical literature for drug discovery. A web application visualized knowledge graph embeddings and link prediction results using TransE, CompleX, and RotatE based methods. The link prediction model achieved up to 0.44 hits@10 on the entity prediction tasks. The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19, served as a case study to demonstrate the efficacy of link prediction modeling for drug discovery. The link prediction algorithm guided identification and ranking of repurposed drug candidates for SARS-CoV-2 primarily by text mining biomedical literature from previous coronaviruses, including SARS and middle east respiratory syndrome (MERS). Repurposed drugs included potential primary SARS-CoV-2 treatment, adjunctive therapies, or therapeutics to treat side effects. The link prediction accuracy for nodes ranked highly for SARS coronavirus was 0.875 as calculated by human in the loop validation on existing COVID-19 specific data sets. Drug classes predicted as highly ranked include anti-inflammatory, nucleoside analogs, protease inhibitors, antimalarials, envelope proteins, and glycoproteins. Examples of highly ranked predicted links to SARS-CoV-2: human leukocyte interferon, recombinant interferon-gamma, cyclosporine, antiviral therapy, zidovudine, chloroquine, vaccination, methotrexate, artemisinin, alkaloids, glycyrrhizic acid, quinine, flavonoids, amprenavir, suramin, complement system proteins, fluoroquinolones, bone marrow transplantation, albuterol, ciprofloxacin, quinolone antibacterial agents, and hydroxymethylglutaryl-CoA reductase inhibitors. Approximately 40% of identified drugs were not previously connected to SARS, such as edetic acid or biotin. In summary, link prediction can effectively suggest repurposed drugs for emergent diseases.
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21
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Hulsebosch BM, Mounce BC. Polyamine Analog Diethylnorspermidine Restricts Coxsackievirus B3 and Is Overcome by 2A Protease Mutation In Vitro. Viruses 2021; 13:310. [PMID: 33669273 PMCID: PMC7920041 DOI: 10.3390/v13020310] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/10/2021] [Accepted: 02/12/2021] [Indexed: 12/27/2022] Open
Abstract
Enteroviruses, including Coxsackievirus B3 (CVB3), are pervasive pathogens that cause significant disease, including cardiomyopathies. Unfortunately, no treatments or vaccines are available for infected individuals. We identified the host polyamine pathway as a potential drug target, as inhibiting polyamine biosynthesis significantly reduces enterovirus replication in vitro and in vivo. Here, we show that CVB3 is sensitive to polyamine depletion through the polyamine analog diethylnorspermidine (DENSpm), which enhances polyamine catabolism through induction of polyamine acetylation. We demonstrate that CVB3 acquires resistance to DENSpm via mutation of the 2A protease, which enhances proteolytic activity in the presence of DENSpm. Resistance to DENSpm occurred via mutation of a non-catalytic site mutation and results in decreased fitness. These data demonstrate that potential for targeting polyamine catabolism as an antiviral target as well as highlight a potential mechanism of resistance.
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Affiliation(s)
- Bridget M. Hulsebosch
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA;
- Infectious Disease and Immunology Research Institute, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
| | - Bryan C. Mounce
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA;
- Infectious Disease and Immunology Research Institute, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
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22
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Groaz E, De Clercq E, Herdewijn P. Anno 2021: Which antivirals for the coming decade? ANNUAL REPORTS IN MEDICINAL CHEMISTRY 2021; 57:49-107. [PMID: 34744210 PMCID: PMC8563371 DOI: 10.1016/bs.armc.2021.09.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Despite considerable progress in the development of antiviral drugs, among which anti-immunodeficiency virus (HIV) and anti-hepatitis C virus (HCV) medications can be considered real success stories, many viral infections remain without an effective treatment. This not only applies to infectious outbreaks caused by zoonotic viruses that have recently spilled over into humans such as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), but also ancient viral diseases that have been brought under control by vaccination such as variola (smallpox), poliomyelitis, measles, and rabies. A largely unsolved problem are endemic respiratory infections due to influenza, respiratory syncytial virus (RSV), and rhinoviruses, whose associated morbidity will likely worsen with increasing air pollution. Furthermore, climate changes will expose industrialized countries to a dangerous resurgence of viral hemorrhagic fevers, which might also become global infections. Herein, we summarize the recent progress that has been made in the search for new antivirals against these different threats that the world population will need to confront with increasing frequency in the next decade.
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Affiliation(s)
- Elisabetta Groaz
- Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium,Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy,Corresponding author:
| | - Erik De Clercq
- Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Piet Herdewijn
- Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
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