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Hammad N, Ransy C, Pinson B, Talmasson J, Bréchot C, Rossignol JF, Bouillaud F. Nitazoxanide controls virus viability through its impact on membrane bioenergetics. Sci Rep 2024; 14:30679. [PMID: 39730386 DOI: 10.1038/s41598-024-78694-8] [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: 01/30/2024] [Accepted: 11/04/2024] [Indexed: 12/29/2024] Open
Abstract
Viruses are dependent on cellular energy metabolism for their replication, and the drug nitazoxanide (Alinia) was shown to interfere with both processes. Nitazoxanide is an uncoupler of mitochondrial oxidative phosphorylation (OXPHOS). Our hypothesis was that mitochondrial uncoupling underlies the antiviral effects of nitazoxanide. Tizoxanide (the active metabolite of nitazoxanide), its derivative RM4848 and the uncoupler CCCP were applied to a virus-releasing cell line to obtain the same increasing levels of mitochondrial uncoupling, hence identical impact on OXPHOS. A decrease in infectious viral particle release was observed and reflected the intensity of impact on OXPHOS, irrespective of the nature of the drug. The antiviral effect was significant although the impact on OXPHOS was modest (≤ 25%), and disappeared when a high concentration (25 mM) of glucose was used to enhance glycolytic generation of ATP. Accordingly, the most likely explanation is that moderate interference with mitochondrial OXPHOS induced rearrangement of ATP use and acquisition of infective properties of the viral particles be highly sensitive to this rearrangement. The antiviral effect of nitazoxanide has been supported by clinical trials, and nitazoxanide is considered a safe drug. However, serious adverse effects of the uncoupler dinitrophenol occurred when used to increase significantly metabolic rate with the purpose of weight loss. Taken together, while impairment of mitochondrial bioenergetics is an unwanted drug effect, moderate interference should be considered as a basis for therapeutic efficacy.
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Affiliation(s)
- Noureddine Hammad
- Institut Cochin, INSERM, CNRS, Université de Paris, 75014, Paris, France
| | - Céline Ransy
- Institut Cochin, INSERM, CNRS, Université de Paris, 75014, Paris, France
| | - Benoit Pinson
- Service Analyses Métaboliques-TBMcore, Université Bordeaux - CNRS UAR 3427 - INSERM US005, Bordeaux, France
| | - Jeremy Talmasson
- Institut Cochin, INSERM, CNRS, Université de Paris, 75014, Paris, France
| | - Christian Bréchot
- Romark Institute of Medical Research, Tampa, FL, USA
- College of Medicine, University of South Florida, Tampa, FL, USA
- Global Virus Network, Tampa, FL, USA
| | | | - Frédéric Bouillaud
- Institut Cochin, INSERM, CNRS, Université de Paris, 75014, Paris, France.
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2
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Zhang Y, Chang L, Xin X, Qiao Y, Qiao W, Ping J, Xia J, Su J. Influenza A virus-induced glycolysis facilitates virus replication by activating ROS/HIF-1α pathway. Free Radic Biol Med 2024; 225:910-924. [PMID: 39491735 DOI: 10.1016/j.freeradbiomed.2024.10.304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 10/22/2024] [Accepted: 10/28/2024] [Indexed: 11/05/2024]
Abstract
As a highly contagious acute respiratory disease, influenza A virus (A/WSN/1933) poses a huge threat to human health and public health. influenza A virus proliferation relies on glucose metabolism in host cells, yet the effects of influenza A virus on glucose metabolism and the underlying molecular mechanisms remain unclear. Here, we created models of WSN virus-infected mice and A549 cells, along with analyzing metabolomics and transcriptomics data, to investigate how WSN virus infection affects host cell glucose metabolism and specific mechanisms. Analysis of metabolites and gene expression showed that WSN virus infection triggers glycolysis in A549 cells, with notable upregulation of hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), hypoxia-inducible factor-1 alpha (HIF-1α), and elevated lactate levels. Additionally, it leads to mitochondrial impairment and heightened reactive oxygen species (ROS) generation. Elevated levels of glucose may enhance the replication of WSN virus, whereas inhibitors of glycolysis can reduce it. Enhancement of HIF-1α activation facilitated replication of WSN virus through stimulation of lactate synthesis, with the primary influence of glycolysis on WSN virus replication being mediated by ROS/HIF-1α signaling. Mice given HIF-1α inhibitor PTX-478 or glycolysis inhibitor 2-Deoxyglucose (2-DG) exhibited reduced lactate levels and decreased WSN virus replication, along with mitigated weight loss and lung damage. In summary, WSN virus-induced glycolysis has been demonstrated to enhance virus replication through the activation of the ROS/HIF-1α pathway, suggesting potential new targets for combating the virus.
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Affiliation(s)
- Yijia Zhang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Lifeng Chang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Xin Xin
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Yixuan Qiao
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Wenna Qiao
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Jihui Ping
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Jun Xia
- Institute of Veterinary Medicine, Xinjiang Academy of Animal Science, Key Laboratory for Prevention and Control of Herbivorous Animal Diseases of the Ministry of Agriculture and Rural Affairs & Xinjiang Animal Disease Research Key Laboratory, 830000, China.
| | - Juan Su
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China.
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3
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Hofstadter WA, Cook KC, Tsopurashvili E, Gebauer R, Pražák V, Machala EA, Park JW, Grünewald K, Quemin ERJ, Cristea IM. Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics. Nat Commun 2024; 15:7352. [PMID: 39187492 PMCID: PMC11347691 DOI: 10.1038/s41467-024-51680-4] [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: 02/06/2024] [Accepted: 08/12/2024] [Indexed: 08/28/2024] Open
Abstract
The dynamic regulation of mitochondria shape via fission and fusion is critical for cellular responses to stimuli. In homeostatic cells, two modes of mitochondrial fission, midzone and peripheral, provide a decision fork between either proliferation or clearance of mitochondria. However, the relationship between specific mitochondria shapes and functions remains unclear in many biological contexts. While commonly associated with decreased bioenergetics, fragmented mitochondria paradoxically exhibit elevated respiration in several disease states, including infection with the prevalent pathogen human cytomegalovirus (HCMV) and metastatic melanoma. Here, incorporating super-resolution microscopy with mass spectrometry and metabolic assays, we use HCMV infection to establish a molecular mechanism for maintaining respiration within a fragmented mitochondria population. We establish that HCMV induces fragmentation through peripheral mitochondrial fission coupled with suppression of mitochondria fusion. Unlike uninfected cells, the progeny of peripheral fission enter mitochondria-ER encapsulations (MENCs) where they are protected from degradation and bioenergetically stabilized during infection. MENCs also stabilize pro-viral inter-mitochondria contacts (IMCs), which electrochemically link mitochondria and promote respiration. Demonstrating a broader relevance, we show that the fragmented mitochondria within metastatic melanoma cells also form MENCs. Our findings establish a mechanism where mitochondria fragmentation can promote increased respiration, a feature relevant in the context of human diseases.
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Affiliation(s)
| | - Katelyn C Cook
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | | | - Robert Gebauer
- Department of Chemistry, MIN Faculty, Universität Hamburg, Hamburg, Germany
- Department of Structural Cell Biology of Viruses, Centre for Structural Systems Biology, Leibniz Institute of Virology, Hamburg, Germany
| | - Vojtěch Pražák
- Department of Chemistry, MIN Faculty, Universität Hamburg, Hamburg, Germany
- Department of Structural Cell Biology of Viruses, Centre for Structural Systems Biology, Leibniz Institute of Virology, Hamburg, Germany
| | - Emily A Machala
- Department of Chemistry, MIN Faculty, Universität Hamburg, Hamburg, Germany
- Department of Structural Cell Biology of Viruses, Centre for Structural Systems Biology, Leibniz Institute of Virology, Hamburg, Germany
| | - Ji Woo Park
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | - Kay Grünewald
- Department of Chemistry, MIN Faculty, Universität Hamburg, Hamburg, Germany
- Department of Structural Cell Biology of Viruses, Centre for Structural Systems Biology, Leibniz Institute of Virology, Hamburg, Germany
| | - Emmanuelle R J Quemin
- Department of Chemistry, MIN Faculty, Universität Hamburg, Hamburg, Germany
- Department of Structural Cell Biology of Viruses, Centre for Structural Systems Biology, Leibniz Institute of Virology, Hamburg, Germany
- Department of Virology, Institute for Integrative Biology of the Cell, CNRS UMR9198, Gif-sur-Yvette, France
| | - Ileana M Cristea
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
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4
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Martineau CA, Rivard N, Bisaillon M. From viruses to cancer: exploring the role of the hepatitis C virus NS3 protein in carcinogenesis. Infect Agent Cancer 2024; 19:40. [PMID: 39192306 DOI: 10.1186/s13027-024-00606-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 08/21/2024] [Indexed: 08/29/2024] Open
Abstract
Hepatitis C virus (HCV) chronically infects approximately 170 million people worldwide and is a known etiological agent of hepatocellular carcinoma (HCC). The molecular mechanisms of HCV-mediated carcinogenesis are not fully understood. This review article focuses on the oncogenic potential of NS3, a viral protein with transformative effects on cells, although the precise mechanisms remain elusive. Unlike the more extensively studied Core and NS5A proteins, NS3's roles in cancer development are less defined but critical. Research indicates that NS3 is implicated in several carcinogenic processes such as proliferative signaling, cell death resistance, genomic instability and mutations, invasion and metastasis, tumor-related inflammation, immune evasion, and replicative immortality. Understanding the direct impact of viral proteins such as NS3 on cellular transformation is crucial for elucidating HCV's role in HCC development. Overall, this review sheds light on the molecular mechanisms used by NS3 to contribute to hepatocarcinogenesis, and highlights its significance in the context of HCV-associated HCC, underscoring the need for further investigation into its specific molecular and cellular actions.
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Affiliation(s)
- Carole-Anne Martineau
- Département de Biochimie et de Génomique Fonctionnelle, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3201 Rue Jean-Mignault, Sherbrooke, QC, J1E 4K8, Canada
| | - Nathalie Rivard
- Département d'Immunologie et Biologie Cellulaire, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3201 Rue Jean-Mignault, Sherbrooke, QC, J1E 4K8, Canada
| | - Martin Bisaillon
- Département de Biochimie et de Génomique Fonctionnelle, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3201 Rue Jean-Mignault, Sherbrooke, QC, J1E 4K8, Canada.
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5
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Hafner A, Meurs N, Garner A, Azar E, Kannan A, Passalacqua KD, Nagrath D, Wobus CE. Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication. PLoS Pathog 2024; 20:e1011909. [PMID: 38976719 PMCID: PMC11257395 DOI: 10.1371/journal.ppat.1011909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 07/18/2024] [Accepted: 06/24/2024] [Indexed: 07/10/2024] Open
Abstract
Viruses are obligate intracellular parasites that rely on host cell metabolism for successful replication. Thus, viruses rewire host cell pathways involved in central carbon metabolism to increase the availability of building blocks for successful propagation. However, the underlying mechanisms of virus-induced alterations to host metabolism are largely unknown. Noroviruses (NoVs) are highly prevalent pathogens that cause sporadic and epidemic viral gastroenteritis. In the present study, we uncovered several strain-specific and shared host cell metabolic requirements of three murine norovirus (MNV) strains, MNV-1, CR3, and CR6. While all three strains required glycolysis, glutaminolysis, and the pentose phosphate pathway for optimal infection of macrophages, only MNV-1 relied on host oxidative phosphorylation. Furthermore, the first metabolic flux analysis of NoV-infected cells revealed that both glycolysis and glutaminolysis are upregulated during MNV-1 infection of macrophages. Glutamine deprivation affected the viral lifecycle at the stage of genome replication, resulting in decreased non-structural and structural protein synthesis, viral assembly, and egress. Mechanistic studies further showed that MNV infection and overexpression of the non-structural protein NS1/2 increased the enzymatic activity of the rate-limiting enzyme glutaminase. In conclusion, the inaugural investigation of NoV-induced alterations to host glutaminolysis identified NS1/2 as the first viral molecule for RNA viruses that regulates glutaminolysis either directly or indirectly. This increases our fundamental understanding of virus-induced metabolic alterations and may lead to improvements in the cultivation of human NoVs.
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Affiliation(s)
- Adam Hafner
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Noah Meurs
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Ari Garner
- Department of Microbiology, Immunology, and Inflammation, University of Illinois, Chicago, Illinois, United States of America
| | - Elaine Azar
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Aditya Kannan
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Karla D. Passalacqua
- Graduate Medical Education, Henry Ford Health, Detroit, Michigan, United States of America
| | - Deepak Nagrath
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Christiane E. Wobus
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, United States of America
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6
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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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7
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Naidu AS, Wang CK, Rao P, Mancini F, Clemens RA, Wirakartakusumah A, Chiu HF, Yen CH, Porretta S, Mathai I, Naidu SAG. Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID. NPJ Sci Food 2024; 8:19. [PMID: 38555403 PMCID: PMC10981760 DOI: 10.1038/s41538-024-00261-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 03/15/2024] [Indexed: 04/02/2024] Open
Abstract
SARS-CoV-2, the etiological agent of COVID-19, is devoid of any metabolic capacity; therefore, it is critical for the viral pathogen to hijack host cellular metabolic machinery for its replication and propagation. This single-stranded RNA virus with a 29.9 kb genome encodes 14 open reading frames (ORFs) and initiates a plethora of virus-host protein-protein interactions in the human body. These extensive viral protein interactions with host-specific cellular targets could trigger severe human metabolic reprogramming/dysregulation (HMRD), a rewiring of sugar-, amino acid-, lipid-, and nucleotide-metabolism(s), as well as altered or impaired bioenergetics, immune dysfunction, and redox imbalance in the body. In the infectious process, the viral pathogen hijacks two major human receptors, angiotensin-converting enzyme (ACE)-2 and/or neuropilin (NRP)-1, for initial adhesion to cell surface; then utilizes two major host proteases, TMPRSS2 and/or furin, to gain cellular entry; and finally employs an endosomal enzyme, cathepsin L (CTSL) for fusogenic release of its viral genome. The virus-induced HMRD results in 5 possible infectious outcomes: asymptomatic, mild, moderate, severe to fatal episodes; while the symptomatic acute COVID-19 condition could manifest into 3 clinical phases: (i) hypoxia and hypoxemia (Warburg effect), (ii) hyperferritinemia ('cytokine storm'), and (iii) thrombocytosis (coagulopathy). The mean incubation period for COVID-19 onset was estimated to be 5.1 days, and most cases develop symptoms after 14 days. The mean viral clearance times were 24, 30, and 39 days for acute, severe, and ICU-admitted COVID-19 patients, respectively. However, about 25-70% of virus-free COVID-19 survivors continue to sustain virus-induced HMRD and exhibit a wide range of symptoms that are persistent, exacerbated, or new 'onset' clinical incidents, collectively termed as post-acute sequelae of COVID-19 (PASC) or long COVID. PASC patients experience several debilitating clinical condition(s) with >200 different and overlapping symptoms that may last for weeks to months. Chronic PASC is a cumulative outcome of at least 10 different HMRD-related pathophysiological mechanisms involving both virus-derived virulence factors and a multitude of innate host responses. Based on HMRD and virus-free clinical impairments of different human organs/systems, PASC patients can be categorized into 4 different clusters or sub-phenotypes: sub-phenotype-1 (33.8%) with cardiac and renal manifestations; sub-phenotype-2 (32.8%) with respiratory, sleep and anxiety disorders; sub-phenotype-3 (23.4%) with skeleto-muscular and nervous disorders; and sub-phenotype-4 (10.1%) with digestive and pulmonary dysfunctions. This narrative review elucidates the effects of viral hijack on host cellular machinery during SARS-CoV-2 infection, ensuing detrimental effect(s) of virus-induced HMRD on human metabolism, consequential symptomatic clinical implications, and damage to multiple organ systems; as well as chronic pathophysiological sequelae in virus-free PASC patients. We have also provided a few evidence-based, human randomized controlled trial (RCT)-tested, precision nutrients to reset HMRD for health recovery of PASC patients.
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Affiliation(s)
- A Satyanarayan Naidu
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA.
- N-terminus Research Laboratory, 232659 Via del Rio, Yorba Linda, CA, 92887, USA.
| | - Chin-Kun Wang
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- School of Nutrition, Chung Shan Medical University, 110, Section 1, Jianguo North Road, Taichung, 40201, Taiwan
| | - Pingfan Rao
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- College of Food and Bioengineering, Fujian Polytechnic Normal University, No.1, Campus New Village, Longjiang Street, Fuqing City, Fujian, China
| | - Fabrizio Mancini
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- President-Emeritus, Parker University, 2540 Walnut Hill Lane, Dallas, TX, 75229, USA
| | - Roger A Clemens
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- University of Southern California, Alfred E. Mann School of Pharmacy/D. K. Kim International Center for Regulatory & Quality Sciences, 1540 Alcazar St., CHP 140, Los Angeles, CA, 90089, USA
| | - Aman Wirakartakusumah
- International Union of Food Science and Technology (IUFoST), Guelph, ON, Canada
- IPMI International Business School Jakarta; South East Asian Food and Agriculture Science and Technology, IPB University, Bogor, Indonesia
| | - Hui-Fang Chiu
- Department of Chinese Medicine, Taichung Hospital, Ministry of Health & Well-being, Taichung, Taiwan
| | - Chi-Hua Yen
- Department of Family and Community Medicine, Chung Shan Medical University Hospital; School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Sebastiano Porretta
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- President, Italian Association of Food Technology (AITA), Milan, Italy
- Experimental Station for the Food Preserving Industry, Department of Consumer Science, Viale Tanara 31/a, I-43121, Parma, Italy
| | - Issac Mathai
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- Soukya International Holistic Health Center, Whitefield, Bengaluru, India
| | - Sreus A G Naidu
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- N-terminus Research Laboratory, 232659 Via del Rio, Yorba Linda, CA, 92887, USA
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8
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Peng C, Xiao P, Li N. Does oncolytic viruses-mediated metabolic reprogramming benefit or harm the immune microenvironment? FASEB J 2024; 38:e23450. [PMID: 38294796 DOI: 10.1096/fj.202301947rr] [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: 09/22/2023] [Revised: 12/11/2023] [Accepted: 01/11/2024] [Indexed: 02/01/2024]
Abstract
Oncolytic virus immunotherapy as a new tumor therapy has made remarkable achievements in clinical practice. And metabolic reprogramming mediated by oncolytic virus has a significant impact on the immune microenvironment. This review summarized the reprogramming of host cell glucose metabolism, lipid metabolism, oxidative phosphorylation, and glutamine metabolism by oncolytic virus and illustrated the effects of metabolic reprogramming on the immune microenvironment. It was found that oncolytic virus-induced reprogramming of glucose metabolism in tumor cells has both beneficial and detrimental effects on the immune microenvironment. In addition, oncolytic virus can promote fatty acid synthesis in tumor cells, inhibit oxidative phosphorylation, and promote glutamine catabolism, which facilitates the anti-tumor immune function of immune cells. Therefore, targeted metabolic reprogramming is a new direction to improve the efficacy of oncolytic virus immunotherapy.
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Affiliation(s)
- Chengcheng Peng
- Institute of Virology, Wenzhou University, Wenzhou, China
- Key Laboratory of Virology and Immunology of Wenzhou, Wenzhou University, Wenzhou, China
| | - Pengpeng Xiao
- Institute of Virology, Wenzhou University, Wenzhou, China
- Key Laboratory of Virology and Immunology of Wenzhou, Wenzhou University, Wenzhou, China
| | - Nan Li
- Institute of Virology, Wenzhou University, Wenzhou, China
- Key Laboratory of Virology and Immunology of Wenzhou, Wenzhou University, Wenzhou, China
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9
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Hafner A, Meurs N, Garner A, Azar E, Passalacqua KD, Nagrath D, Wobus CE. Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.19.572316. [PMID: 38187600 PMCID: PMC10769279 DOI: 10.1101/2023.12.19.572316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Viruses are obligate intracellular parasites that rely on host cell metabolism for successful replication. Thus, viruses rewire host cell pathways involved in central carbon metabolism to increase the availability of building blocks for replication. However, the underlying mechanisms of virus-induced alterations to host metabolism are largely unknown. Noroviruses (NoVs) are highly prevalent pathogens that cause sporadic and epidemic viral gastroenteritis. In the present study, we uncovered several strain-specific and shared host cell metabolic requirements of three murine norovirus (MNV) strains, the acute MNV-1 strain and the persistent CR3 and CR6 strains. While all three strains required glycolysis, glutaminolysis, and the pentose phosphate pathway for optimal infection of macrophages, only MNV-1 relied on host oxidative phosphorylation. Furthermore, the first metabolic flux analysis of NoV-infected cells revealed that both glycolysis and glutaminolysis are upregulated during MNV-1 infection of macrophages. Glutamine deprivation affected the MNV lifecycle at the stage of genome replication, resulting in decreased non-structural and structural protein synthesis, viral assembly, and egress. Mechanistic studies further showed that MNV infection and overexpression of the MNV non-structural protein NS1/2 increased the enzymatic activity of the rate-limiting enzyme glutaminase. In conclusion, the inaugural investigation of NoV-induced alterations to host glutaminolysis identified the first viral regulator of glutaminolysis for RNA viruses, which increases our fundamental understanding of virus-induced metabolic alterations.
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Affiliation(s)
- Adam Hafner
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA
| | - Noah Meurs
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Ari Garner
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA
| | - Elaine Azar
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Deepak Nagrath
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Christiane E Wobus
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA
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10
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Prabhu SS, Nair AS, Nirmala SV. Multifaceted roles of mitochondrial dysfunction in diseases: from powerhouses to saboteurs. Arch Pharm Res 2023; 46:723-743. [PMID: 37751031 DOI: 10.1007/s12272-023-01465-y] [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: 02/05/2023] [Accepted: 09/19/2023] [Indexed: 09/27/2023]
Abstract
The fact that mitochondria play a crucial part in energy generation has led to the nickname "powerhouses" of the cell being applied to them. They also play a significant role in many other cellular functions, including calcium signalling, apoptosis, and the creation of vital biomolecules. As a result, cellular function and health as a whole can be significantly impacted by mitochondrial malfunction. Indeed, malignancies frequently have increased levels of mitochondrial biogenesis and quality control. Adverse selection exists for harmful mitochondrial genome mutations, even though certain malignancies include modifications in the nuclear-encoded tricarboxylic acid cycle enzymes that generate carcinogenic metabolites. Since rare human cancers with mutated mitochondrial genomes are often benign, removing mitochondrial DNA reduces carcinogenesis. Therefore, targeting mitochondria offers therapeutic options since they serve several functions and are crucial to developing malignant tumors. Here, we discuss the various steps involved in the mechanism of cancer for which mitochondria plays a significant role, as well as the role of mitochondria in diseases other than cancer. It is crucial to understand mitochondrial malfunction to target these organelles for therapeutic reasons. This highlights the significance of investigating mitochondrial dysfunction in cancer and other disease research.
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Affiliation(s)
- Surapriya Surendranath Prabhu
- Department of Pharmaceutical Chemistry and Analysis, Amrita School of Pharmacy, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - Aathira Sujathan Nair
- Department of Pharmaceutical Chemistry and Analysis, Amrita School of Pharmacy, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - Saiprabha Vijayakumar Nirmala
- Department of Pharmaceutical Chemistry and Analysis, Amrita School of Pharmacy, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India.
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11
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Gvozdjáková A, Sumbalová Z, Kucharská J, Rausová Z, Kovalčíková E, Takácsová T, Navas P, López-Lluch G, Mojto V, Palacka P. Mountain spa rehabilitation improved health of patients with post-COVID-19 syndrome: pilot study. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:14200-14211. [PMID: 36151435 PMCID: PMC9510276 DOI: 10.1007/s11356-022-22949-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 09/05/2022] [Indexed: 04/15/2023]
Abstract
European Association of Spa Rehabilitation (ESPA) recommends spa rehabilitation for patients with post-COVID-19 syndrome. We tested the hypothesis that a high-altitude environment with clean air and targeted spa rehabilitation (MR - mountain spa rehabilitation) can contribute to the improving platelet mitochondrial bioenergetics, to accelerating patient health and to the reducing socioeconomic problems. Fifteen healthy volunteers and fourteen patients with post-COVID-19 syndrome were included in the study. All parameters were determined before MR (MR1) and 16-18 days after MR (MR2). Platelet mitochondrial respiration and OXPHOS were evaluated using high resolution respirometry method, coenzyme Q10 level was determined by HPLC, and concentration of thiobarbituric acid reactive substances (TBARS) as a parameter of lipid peroxidation was determined spectrophotometrically. This pilot study showed significant improvement of clinical symptoms, lungs function, and regeneration of reduced CI-linked platelet mitochondrial respiration after MR in patients with post-COVID-19 syndrome. High-altitude environment with spa rehabilitation can be recommended for the acceleration of recovery of patients with post-COVID-19 syndrome.
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Affiliation(s)
- Anna Gvozdjáková
- Faculty of Medicine, Pharmacobiochemical Laboratory of 3rd Department of Internal Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia
| | - Zuzana Sumbalová
- Faculty of Medicine, Pharmacobiochemical Laboratory of 3rd Department of Internal Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia
| | - Jarmila Kucharská
- Faculty of Medicine, Pharmacobiochemical Laboratory of 3rd Department of Internal Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia
| | - Zuzana Rausová
- Faculty of Medicine, Pharmacobiochemical Laboratory of 3rd Department of Internal Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia
| | | | - Timea Takácsová
- Sanatorium of Dr. Guhr, 059 81 High Tatras, Tatranská, Polianka, Slovakia
| | - Plácido Navas
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, and CIBERER, Instituto de Salud Carlos III, Sevilla, Spain
| | - Guillermo López-Lluch
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, and CIBERER, Instituto de Salud Carlos III, Sevilla, Spain
| | - Viliam Mojto
- Faculty of Medicine and UNB, 3rd Department of Internal Medicine, Derer’s Hospital in Bratislava, Comenius University in Bratislava, Limbová 5, 833 05 Bratislava, Slovakia
| | - Patrik Palacka
- Faculty of Medicine, 2nd Department of Oncology, Comenius University in Bratislava, Klenová 1, 833 10 Bratislava, Slovakia
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12
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Ahmed D, Al-Daraawi M, Cassol E. Innate sensing and cellular metabolism: role in fine tuning antiviral immune responses. J Leukoc Biol 2023; 113:164-190. [PMID: 36822175 DOI: 10.1093/jleuko/qiac011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Indexed: 01/19/2023] Open
Abstract
Several studies over the last decade have identified intimate links between cellular metabolism and macrophage function. Metabolism has been shown to both drive and regulate macrophage function by producing bioenergetic and biosynthetic precursors as well as metabolites (and other bioactive molecules) that regulate gene expression and signal transduction. Many studies have focused on lipopolysaccharide-induced reprogramming, assuming that it is representative of most inflammatory responses. However, emerging evidence suggests that diverse pathogen-associated molecular patterns (PAMPs) are associated with unique metabolic profiles, which may drive pathogen specific immune responses. Further, these metabolic pathways and processes may act as a rheostat to regulate the magnitude of an inflammatory response based on the biochemical features of the local microenvironment. In this review, we will discuss recent work examining the relationship between cellular metabolism and macrophage responses to viral PAMPs and describe how these processes differ from lipopolysaccharide-associated responses. We will also discuss how an improved understanding of the specificity of these processes may offer new insights to fine-tune macrophage function during viral infections or when using viral PAMPs as therapeutics.
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Affiliation(s)
- Duale Ahmed
- Department of Health Sciences, Carleton University, Ottawa, Ontario, Canada.,Department of Biology, Carleton University, Ottawa, Ontario, Canada
| | - Malak Al-Daraawi
- Department of Health Sciences, Carleton University, Ottawa, Ontario, Canada
| | - Edana Cassol
- Department of Health Sciences, Carleton University, Ottawa, Ontario, Canada.,Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Ontario, Canada
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13
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An Update on the Metabolic Landscape of Oncogenic Viruses. Cancers (Basel) 2022; 14:cancers14235742. [PMID: 36497226 PMCID: PMC9738352 DOI: 10.3390/cancers14235742] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/10/2022] [Accepted: 11/17/2022] [Indexed: 11/24/2022] Open
Abstract
Viruses play an important role in cancer development as about 12% of cancer types are linked to viral infections. Viruses that induce cellular transformation are known as oncoviruses. Although the mechanisms of viral oncogenesis differ between viruses, all oncogenic viruses share the ability to establish persistent chronic infections with no obvious symptoms for years. During these prolonged infections, oncogenic viruses manipulate cell signaling pathways that control cell cycle progression, apoptosis, inflammation, and metabolism. Importantly, it seems that most oncoviruses depend on these changes for their persistence and amplification. Metabolic changes induced by oncoviruses share many common features with cancer metabolism. Indeed, viruses, like proliferating cancer cells, require increased biosynthetic precursors for virion production, need to balance cellular redox homeostasis, and need to ensure host cell survival in a given tissue microenvironment. Thus, like for cancer cells, viral replication and persistence of infected cells frequently depend on metabolic changes. Here, we draw parallels between metabolic changes observed in cancers or induced by oncoviruses, with a focus on pathways involved in the regulation of glucose, lipid, and amino acids. We describe whether and how oncoviruses depend on metabolic changes, with the perspective of targeting them for antiviral and onco-therapeutic approaches in the context of viral infections.
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14
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Zou X, Yang Y, Lin F, Chen J, Zhang H, Li L, Ouyang H, Pang D, Ren L, Tang X. Lactate facilitates classical swine fever virus replication by enhancing cholesterol biosynthesis. iScience 2022; 25:105353. [PMID: 36339254 PMCID: PMC9626675 DOI: 10.1016/j.isci.2022.105353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 09/14/2022] [Accepted: 10/11/2022] [Indexed: 11/29/2022] Open
Abstract
An emerging topic in virology is that viral replication is closely linked with the metabolic reprogramming of host cells. Understanding the effects of reprogramming host cell metabolism due to classical swine fever virus (CSFV) infection and the underling mechanisms would facilitate controlling the spread of classical swine fever (CSF). In the current study, we found that CSFV infection enhanced aerobic glycolysis in PK-15 cells. Blocking glycolysis with 2-deoxy-d-glycose or disrupting the enzymes PFKL and LDHA decreased CSFV replication. Lactate was identified as an important molecule in CSFV replication, independent of the pentose phosphate pathway and tricarboxylic acid cycle. Further analysis demonstrated that the accumulated lactate in cells promoted cholesterol biosynthesis, which facilitated CSFV replication and disrupted the type I interferon response during CSFV replication, and the disruption of cholesterol synthesis abolished the lactate effects on CSFV replication. The results provided more insights into the complex pathological mechanisms of CSFV.
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Affiliation(s)
- Xiaodong Zou
- College of Animal Sciences, Jilin University, Changchun, China
| | - Yang Yang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Feng Lin
- College of Animal Sciences, Jilin University, Changchun, China
| | - Jiahuan Chen
- College of Animal Sciences, Jilin University, Changchun, China
| | - Huanyu Zhang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Linquan Li
- College of Animal Sciences, Jilin University, Changchun, China
| | - Hongsheng Ouyang
- College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute of Jilin University, Chongqing, China
| | - Daxin Pang
- College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute of Jilin University, Chongqing, China
| | - Linzhu Ren
- College of Animal Sciences, Jilin University, Changchun, China
| | - Xiaochun Tang
- College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute of Jilin University, Chongqing, China
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15
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Diaz O, Vidalain PO, Ramière C, Lotteau V, Perrin-Cocon L. What role for cellular metabolism in the control of hepatitis viruses? Front Immunol 2022; 13:1033314. [PMID: 36466918 PMCID: PMC9713817 DOI: 10.3389/fimmu.2022.1033314] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/02/2022] [Indexed: 11/26/2023] Open
Abstract
Hepatitis B, C and D viruses (HBV, HCV, HDV, respectively) specifically infect human hepatocytes and often establish chronic viral infections of the liver, thus escaping antiviral immunity for years. Like other viruses, hepatitis viruses rely on the cellular machinery to meet their energy and metabolite requirements for replication. Although this was initially considered passive parasitism, studies have shown that hepatitis viruses actively rewire cellular metabolism through molecular interactions with specific enzymes such as glucokinase, the first rate-limiting enzyme of glycolysis. As part of research efforts in the field of immunometabolism, it has also been shown that metabolic changes induced by viruses could have a direct impact on the innate antiviral response. Conversely, detection of viral components by innate immunity receptors not only triggers the activation of the antiviral defense but also induces in-depth metabolic reprogramming that is essential to support immunological functions. Altogether, these complex triangular interactions between viral components, innate immunity and hepatocyte metabolism may explain why chronic hepatitis infections progressively lead to liver inflammation and progression to cirrhosis, fibrosis and hepatocellular carcinoma (HCC). In this manuscript, we first present a global overview of known connections between the innate antiviral response and cellular metabolism. We then report known molecular mechanisms by which hepatitis viruses interfere with cellular metabolism in hepatocytes and discuss potential consequences on the innate immune response. Finally, we present evidence that drugs targeting hepatocyte metabolism could be used as an innovative strategy not only to deprive viruses of key metabolites, but also to restore the innate antiviral response that is necessary to clear infection.
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Affiliation(s)
- Olivier Diaz
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Pierre-Olivier Vidalain
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Christophe Ramière
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
- Laboratoire de Virologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Vincent Lotteau
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Laure Perrin-Cocon
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
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16
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Kuk MU, Ga YJ, Kim YJ, Park JY, Song ES, Lee H, Lee YH, Ko G, Kim JK, Yeh JY, Kwon HW, Byun Y, Park JT. Metabolic reprogramming as a novel therapeutic target for Coxsackievirus B3. Anim Cells Syst (Seoul) 2022; 26:275-282. [PMID: 36605593 PMCID: PMC9809346 DOI: 10.1080/19768354.2022.2141318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Coxsackievirus B3 (CVB3) is a single-stranded RNA virus that belongs to the Enterovirus genus. CVB3 is a human pathogen associated with serious conditions such as myocarditis, dilated cardiomyopathy, and pancreatitis. However, there are no therapeutic interventions to treat CVB3 infections. In this study, we found that CVB3 induced metabolic alteration in host cells through increasing glycolysis level, as indicated by an increase in the extracellular acidification rate (ECAR). CVB3-mediated metabolic alteration was confirmed by metabolite change analysis using gas chromatography-mass spectrometry (GC-MS). Based on findings, a strategy to inhibit glycolysis has been proposed to treat CVB3 infection. Indeed, glycolysis inhibitors (2-Deoxy-D-glucose, sodium oxide) significantly reduced CVB3 titers after CVB3 infection, indicating that glycolysis inhibitors can be used as effective antiviral agents. Taken together, our results reveal a novel mechanism by which CVB3 infection is controlled by regulation of host cell metabolism.
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Affiliation(s)
- Myeong Uk Kuk
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Yun Ji Ga
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Ye Jin Kim
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Ji Yun Park
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Eun Seon Song
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Haneur Lee
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Yun Haeng Lee
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Gahyun Ko
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Jae Kwang Kim
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Jung-Yong Yeh
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Hyung Wook Kwon
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea,Convergence Research Center for Insect Vectors, Incheon National University, Incheon, Korea, Hyung Wook Kwon Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon22012, Korea; Convergence Research Center for Insect Vectors, Incheon National University, Incheon22012, Korea; Youngjoo Byun College of Pharmacy, Korea University, Sejong30019, Republic of Korea; Joon Tae Park Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon22012, Korea; Convergence Research Center for Insect Vectors, Incheon National University, Incheon22012, Korea
| | - Youngjoo Byun
- College of Pharmacy, Korea University, Sejong, Republic of Korea, Hyung Wook Kwon Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon22012, Korea; Convergence Research Center for Insect Vectors, Incheon National University, Incheon22012, Korea; Youngjoo Byun College of Pharmacy, Korea University, Sejong30019, Republic of Korea; Joon Tae Park Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon22012, Korea; Convergence Research Center for Insect Vectors, Incheon National University, Incheon22012, Korea
| | - Joon Tae Park
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea,Convergence Research Center for Insect Vectors, Incheon National University, Incheon, Korea, Hyung Wook Kwon Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon22012, Korea; Convergence Research Center for Insect Vectors, Incheon National University, Incheon22012, Korea; Youngjoo Byun College of Pharmacy, Korea University, Sejong30019, Republic of Korea; Joon Tae Park Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon22012, Korea; Convergence Research Center for Insect Vectors, Incheon National University, Incheon22012, Korea
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17
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Pouysségur J, Marchiq I, Parks SK, Durivault J, Ždralević M, Vucetic M. 'Warburg effect' controls tumor growth, bacterial, viral infections and immunity - Genetic deconstruction and therapeutic perspectives. Semin Cancer Biol 2022; 86:334-346. [PMID: 35820598 DOI: 10.1016/j.semcancer.2022.07.004] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 07/06/2022] [Accepted: 07/07/2022] [Indexed: 12/16/2022]
Abstract
The evolutionary pressure for life transitioning from extended periods of hypoxia to an increasingly oxygenated atmosphere initiated drastic selections for a variety of biochemical pathways supporting the robust life currently present on the planet. First, we discuss how fermentative glycolysis, a primitive metabolic pathway present at the emergence of life, is instrumental for the rapid growth of cancer, regenerating tissues, immune cells but also bacteria and viruses during infections. The 'Warburg effect', activated via Myc and HIF-1 in response to growth factors and hypoxia, is an essential metabolic and energetic pathway which satisfies nutritional and energetic demands required for rapid genome replication. Second, we present the key role of lactic acid, the end-product of fermentative glycolysis able to move across cell membranes in both directions via monocarboxylate transporting proteins (i.e., MCT1/4) contributing to cell-pH homeostasis but also to the complex immune response via acidosis of the tumor microenvironment. Importantly lactate is recycled in multiple organs as a major metabolic precursor of gluconeogenesis and energy source protecting cells and animals from harsh nutritional or oxygen restrictions. Third, we revisit the Warburg effect via CRISPR-Cas9 disruption of glucose-6-phosphate isomerase (GPI-KO) or lactate dehydrogenases (LDHA/B-DKO) in two aggressive tumors (melanoma B16-F10, human adenocarcinoma LS174T). Full suppression of lactic acid production reduces but does not suppress tumor growth due to reactivation of OXPHOS. In contrast, disruption of the lactic acid transporters MCT1/4 suppressed glycolysis, mTORC1, and tumor growth as a result of intracellular acidosis. Finally, we briefly discuss the current clinical developments of an MCT1 specific drug AZ3965, and the recent progress for a specific in vivo MCT4 inhibitor, two drugs of very high potential for future cancer clinical applications.
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Affiliation(s)
- J Pouysségur
- University Côte d'Azur, (IRCAN), CNRS, INSERM, Centre A, Lacassagne, 06189 Nice, France; Department of Medical Biology, Centre Scientifique de Monaco (CSM), 98000 Monaco.
| | - I Marchiq
- University Côte d'Azur, (IRCAN), CNRS, INSERM, Centre A, Lacassagne, 06189 Nice, France.
| | - S K Parks
- Department of Medical Biology, Centre Scientifique de Monaco (CSM), 98000 Monaco.
| | - J Durivault
- Department of Medical Biology, Centre Scientifique de Monaco (CSM), 98000 Monaco
| | - M Ždralević
- University Côte d'Azur, (IRCAN), CNRS, INSERM, Centre A, Lacassagne, 06189 Nice, France.
| | - M Vucetic
- Department of Medical Biology, Centre Scientifique de Monaco (CSM), 98000 Monaco
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18
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Sumbalová Z, Kucharská J, Rausová Z, Palacka P, Kovalčíková E, Takácsová T, Mojto V, Navas P, Lopéz-Lluch G, Gvozdjáková A. Reduced platelet mitochondrial respiration and oxidative phosphorylation in patients with post COVID-19 syndrome are regenerated after spa rehabilitation and targeted ubiquinol therapy. Front Mol Biosci 2022; 9:1016352. [PMID: 36339707 PMCID: PMC9634579 DOI: 10.3389/fmolb.2022.1016352] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/06/2022] [Indexed: 08/27/2023] Open
Abstract
European Association of Spa Rehabilitation recommend spa rehabilitation for patients with post COVID-19 syndrome (post C-19). We studied effects of special mountain spa rehabilitation program and its combination with ubiquinol (reduced form of coenzyme Q10-CoQ10) supplementation on pulmonary function, clinical symptoms, endogenous CoQ10 levels, and platelet mitochondrial bioenergetics of patients with post C-19. 36 patients with post C-19 enrolled for rehabilitation in mountain spa resort and 15 healthy volunteers representing the control group were included in this study. 14 patients with post C-19 (MR group) were on mountain spa rehabilitation lasting 16-18 days, 22 patients (MRQ group) were supplemented with ubiquinol (2 × 100 mg/day) during the rehabilitation and additional 12-14 days at home. Clinical symptoms and functional capacity of the lungs were determined in the patients before and after the spa rehabilitation program. Platelet bioenergetics by high-resolution respirometry, plasma TBARS concentration, and CoQ10 concentration in blood, plasma and platelets were evaluated before and after the spa rehabilitation program, and in 8 patients of MRQ group also after additional 12-14 days of CoQ10 supplementation. Pulmonary function and clinical symptoms improved after the rehabilitation program in both groups, 51.8% of symptoms disappeared in the MR group and 62.8% in the MRQ group. Platelet mitochondrial Complex I (CI)-linked oxidative phosphorylation (OXPHOS) and electron transfer (ET) capacity were markedly reduced in both groups of patients. After the rehabilitation program the improvement of these parameters was significant in the MRQ group and moderate in the MR group. CI-linked OXPHOS and ET capacity increased further after additional 12-14 days of CoQ10 supplementation. CoQ10 concentration in platelets, blood and plasma markedly raised after the spa rehabilitation with ubiquinol supplementation, not in non-supplemented group. In the MRQ group all parameters of platelet mitochondrial respiration correlated with CoQ10 concentration in platelets, and the increase in CI-linked OXPHOS and ET capacity correlated with the increase of CoQ10 concentration in platelets. Our data show a significant role of supplemented ubiquinol in accelerating the recovery of mitochondrial health in patients with post C-19. Mountain spa rehabilitation with coenzyme Q10 supplementation could be recommended to patients with post C-19. This study was registered as a clinical trial: ClinicalTrials.gov ID: NCT05178225.
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Affiliation(s)
- Zuzana Sumbalová
- Comenius University in Bratislava, Faculty of Medicine, Pharmacobiochemical Laboratory of 3rd Department of Internal Medicine, Bratislava, Slovakia
| | - Jarmila Kucharská
- Comenius University in Bratislava, Faculty of Medicine, Pharmacobiochemical Laboratory of 3rd Department of Internal Medicine, Bratislava, Slovakia
| | - Zuzana Rausová
- Comenius University in Bratislava, Faculty of Medicine, Pharmacobiochemical Laboratory of 3rd Department of Internal Medicine, Bratislava, Slovakia
| | - Patrik Palacka
- Comenius University in Bratislava, Faculty of Medicine, 2nd Department of Oncology, Bratislava, Slovakia
| | | | | | - Viliam Mojto
- Comenius University in Bratislava, Faculty of Medicine, 3rd Department of Internal Medicine, Bratislava, Slovakia
| | - Plácido Navas
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA and CIBERER, Instituto de Salud Carlos III, Sevilla, Spain
| | - Guillermo Lopéz-Lluch
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA and CIBERER, Instituto de Salud Carlos III, Sevilla, Spain
| | - Anna Gvozdjáková
- Comenius University in Bratislava, Faculty of Medicine, Pharmacobiochemical Laboratory of 3rd Department of Internal Medicine, Bratislava, Slovakia
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19
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Adeyemi OS, Afolabi LB, Rotimi DE, Ofume DS, Adeyanju AA, Awakan OJ, Elebiyo TC. Targeting of Hypoxia for Therapeutic Strategy in the Varied Physiological States. Open Biochem J 2022. [DOI: 10.2174/1874091x-v16-e2208010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Hypoxia-inducible factors (HIFs) are transcription factors that initiate the expression of cellular processes to cope with hypoxic conditions. HIFs are principal regulators of hypoxic adaptation, regulating gene expression involved in glycolysis, erythropoiesis, angiogenesis, proliferation, and stem cell function under low O2. HIFs may play a pivotal role in tumor survival and metastasis in cancer formation and growth. Likewise, HIFs play a key role in microbial pathogenesis, particularly in host-pathogen interaction. Because of the role that HIF-1alpha plays in the biology of cancer and infections, it is a potential therapeutic target not only for malignant growth but also for parasitic infection. Several reports have demonstrated the up-regulation of host cellular HIFs due to infection-induced hypoxia. Hypoxia-inducible pathways have attracted great interest in the down-regulation of prolyl hydroxylase for treating inflammatory diseases and infections by viruses, protozoa, or bacteria, among other pathogens. Interestingly, increasing evidence suggests that HIFs play an important regulatory role in inflammation. For example, in macrophages, HIFs regulate glycolytic energy generation and optimize innate immunity, control pro-inflammatory gene expression, mediate the killing of pathogens and influence cell migration. Therefore, a good understanding of the biochemical mechanism of hypoxia signaling pathways will shed more light on how it could help identify and develop new treatment strategies for cancer and parasitic diseases, including viral, bacterial, fungal and protozoa infections.
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20
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Pająk B, Zieliński R, Manning JT, Matejin S, Paessler S, Fokt I, Emmett MR, Priebe W. The Antiviral Effects of 2-Deoxy-D-glucose (2-DG), a Dual D-Glucose and D-Mannose Mimetic, against SARS-CoV-2 and Other Highly Pathogenic Viruses. Molecules 2022; 27:5928. [PMID: 36144664 PMCID: PMC9503362 DOI: 10.3390/molecules27185928] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 12/15/2022] Open
Abstract
Viral infection almost invariably causes metabolic changes in the infected cell and several types of host cells that respond to the infection. Among metabolic changes, the most prominent is the upregulated glycolysis process as the main pathway of glucose utilization. Glycolysis activation is a common mechanism of cell adaptation to several viral infections, including noroviruses, rhinoviruses, influenza virus, Zika virus, cytomegalovirus, coronaviruses and others. Such metabolic changes provide potential targets for therapeutic approaches that could reduce the impact of infection. Glycolysis inhibitors, especially 2-deoxy-D-glucose (2-DG), have been intensively studied as antiviral agents. However, 2-DG's poor pharmacokinetic properties limit its wide clinical application. Herein, we discuss the potential of 2-DG and its novel analogs as potent promising antiviral drugs with special emphasis on targeted intracellular processes.
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Affiliation(s)
- Beata Pająk
- Independent Laboratory of Genetics and Molecular Biology, Military Institute of Hygiene and Epidemiology, Kozielska 4, 01-163 Warsaw, Poland
- WPD Pharmaceuticals, Zwirki i Wigury 101, 01-163 Warsaw, Poland
| | - Rafał Zieliński
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1901 East Rd., Houston, TX 77054, USA
| | - John Tyler Manning
- Department of Pathology, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
| | - Stanislava Matejin
- Department of Advanced Cardiopulmonary Therapies and Transplantation, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
| | - Slobodan Paessler
- Department of Pathology, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
| | - Izabela Fokt
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1901 East Rd., Houston, TX 77054, USA
| | - Mark R. Emmett
- Department of Pathology, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
| | - Waldemar Priebe
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1901 East Rd., Houston, TX 77054, USA
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21
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Devaux CA, Raoult D. The impact of COVID-19 on populations living at high altitude: Role of hypoxia-inducible factors (HIFs) signaling pathway in SARS-CoV-2 infection and replication. Front Physiol 2022; 13:960308. [PMID: 36091390 PMCID: PMC9454615 DOI: 10.3389/fphys.2022.960308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/02/2022] [Indexed: 11/13/2022] Open
Abstract
Cases of coronavirus disease 2019 (COVID-19) have been reported worldwide. However, one epidemiological report has claimed a lower incidence of the disease in people living at high altitude (>2,500 m), proposing the hypothesis that adaptation to hypoxia may prove to be advantageous with respect to SARS-CoV-2 infection. This publication was initially greeted with skepticism, because social, genetic, or environmental parametric variables could underlie a difference in susceptibility to the virus for people living in chronic hypobaric hypoxia atmospheres. Moreover, in some patients positive for SARS-CoV-2, early post-infection ‘happy hypoxia” requires immediate ventilation, since it is associated with poor clinical outcome. If, however, we accept to consider the hypothesis according to which the adaptation to hypoxia may prove to be advantageous with respect to SARS-CoV-2 infection, identification of the molecular rational behind it is needed. Among several possibilities, HIF-1 regulation appears to be a molecular hub from which different signaling pathways linking hypoxia and COVID-19 are controlled. Interestingly, HIF-1α was reported to inhibit the infection of lung cells by SARS-CoV-2 by reducing ACE2 viral receptor expression. Moreover, an association of the rs11549465 variant of HIF-1α with COVID-19 susceptibility was recently discovered. Here, we review the evidence for a link between HIF-1α, ACE2 and AT1R expression, and the incidence/severity of COVID-19. We highlight the central role played by the HIF-1α signaling pathway in the pathophysiology of COVID-19.
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Affiliation(s)
- Christian Albert Devaux
- Aix-Marseille University, IRD, APHM, MEPHI, Marseille, France
- IHU-Méditerranée Infection, Marseille, France
- Centre National de la Recherche Scientifique, Marseille, France
- *Correspondence: Christian Albert Devaux,
| | - Didier Raoult
- Aix-Marseille University, IRD, APHM, MEPHI, Marseille, France
- IHU-Méditerranée Infection, Marseille, France
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22
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Hypoxia signaling in human health and diseases: implications and prospects for therapeutics. Signal Transduct Target Ther 2022; 7:218. [PMID: 35798726 PMCID: PMC9261907 DOI: 10.1038/s41392-022-01080-1] [Citation(s) in RCA: 183] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/17/2022] [Accepted: 06/23/2022] [Indexed: 02/07/2023] Open
Abstract
Molecular oxygen (O2) is essential for most biological reactions in mammalian cells. When the intracellular oxygen content decreases, it is called hypoxia. The process of hypoxia is linked to several biological processes, including pathogenic microbe infection, metabolic adaptation, cancer, acute and chronic diseases, and other stress responses. The mechanism underlying cells respond to oxygen changes to mediate subsequent signal response is the central question during hypoxia. Hypoxia-inducible factors (HIFs) sense hypoxia to regulate the expressions of a series of downstream genes expression, which participate in multiple processes including cell metabolism, cell growth/death, cell proliferation, glycolysis, immune response, microbe infection, tumorigenesis, and metastasis. Importantly, hypoxia signaling also interacts with other cellular pathways, such as phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-B (NF-κB) pathway, extracellular signal-regulated kinases (ERK) signaling, and endoplasmic reticulum (ER) stress. This paper systematically reviews the mechanisms of hypoxia signaling activation, the control of HIF signaling, and the function of HIF signaling in human health and diseases. In addition, the therapeutic targets involved in HIF signaling to balance health and diseases are summarized and highlighted, which would provide novel strategies for the design and development of therapeutic drugs.
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23
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Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions. J Hepatol 2022; 77:219-236. [PMID: 35157957 DOI: 10.1016/j.jhep.2022.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/12/2022] [Accepted: 01/31/2022] [Indexed: 12/16/2022]
Abstract
HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.
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Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ahmed M Elsharkawy
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, B15 2TH UK; National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
| | - Michele Vacca
- Interdisciplinary Department of Medicine, Università degli Studi di Bari "Aldo Moro", Bari, Italy.
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24
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Allen CNS, Santerre M, Arjona SP, Ghaleb LJ, Herzi M, Llewellyn MD, Shcherbik N, Sawaya BE. SARS-CoV-2 Causes Lung Inflammation through Metabolic Reprogramming and RAGE. Viruses 2022; 14:983. [PMID: 35632725 PMCID: PMC9143006 DOI: 10.3390/v14050983] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 04/29/2022] [Accepted: 05/03/2022] [Indexed: 12/26/2022] Open
Abstract
Clinical studies indicate that patients infected with SARS-CoV-2 develop hyperinflammation, which correlates with increased mortality. The SARS-CoV-2/COVID-19-dependent inflammation is thought to occur via increased cytokine production and hyperactivity of RAGE in several cell types, a phenomenon observed for other disorders and diseases. Metabolic reprogramming has been shown to contribute to inflammation and is considered a hallmark of cancer, neurodegenerative diseases, and viral infections. Malfunctioning glycolysis, which normally aims to convert glucose into pyruvate, leads to the accumulation of advanced glycation end products (AGEs). Being aberrantly generated, AGEs then bind to their receptor, RAGE, and activate several pro-inflammatory genes, such as IL-1b and IL-6, thus, increasing hypoxia and inducing senescence. Using the lung epithelial cell (BEAS-2B) line, we demonstrated that SARS-CoV-2 proteins reprogram the cellular metabolism and increase pyruvate kinase muscle isoform 2 (PKM2). This deregulation promotes the accumulation of AGEs and senescence induction. We showed the ability of the PKM2 stabilizer, Tepp-46, to reverse the observed glycolysis changes/alterations and restore this essential metabolic process.
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Affiliation(s)
- Charles N. S. Allen
- Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (M.S.); (S.P.A.); (L.J.G.); (M.H.); (M.D.L.)
| | - Maryline Santerre
- Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (M.S.); (S.P.A.); (L.J.G.); (M.H.); (M.D.L.)
| | - Sterling P. Arjona
- Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (M.S.); (S.P.A.); (L.J.G.); (M.H.); (M.D.L.)
| | - Lea J. Ghaleb
- Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (M.S.); (S.P.A.); (L.J.G.); (M.H.); (M.D.L.)
| | - Muna Herzi
- Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (M.S.); (S.P.A.); (L.J.G.); (M.H.); (M.D.L.)
| | - Megan D. Llewellyn
- Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (M.S.); (S.P.A.); (L.J.G.); (M.H.); (M.D.L.)
| | - Natalia Shcherbik
- Department for Cell Biology and Neuroscience, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA;
| | - Bassel E. Sawaya
- Molecular Studies of Neurodegenerative Diseases Lab., FELS Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (M.S.); (S.P.A.); (L.J.G.); (M.H.); (M.D.L.)
- Departments of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Cancer and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
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25
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Endothelial Cell Metabolism in Vascular Functions. Cancers (Basel) 2022; 14:cancers14081929. [PMID: 35454836 PMCID: PMC9031281 DOI: 10.3390/cancers14081929] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Recent findings in the field of vascular biology are nourishing the idea that targeting the endothelial cell metabolism may be an alternative strategy to antiangiogenic therapy, as well as a novel therapeutic approach for cardiovascular disease. Deepening the molecular mechanisms regulating how ECs re-adapt their metabolic status in response to the changeable conditions of the tissue microenvironment may be beneficial to develop novel innovative treatments to counteract the aberrant growth of vasculature. Abstract The endothelium is the innermost layer of all blood and lymphatic vessels composed of a monolayer of specialized endothelial cells (ECs). It is regarded as a dynamic and multifunctional endocrine organ that takes part in essential processes, such as the control of blood fluidity, the modulation of vascular tone, the regulation of immune response and leukocyte trafficking into perivascular tissues, and angiogenesis. The inability of ECs to perform their normal biological functions, known as endothelial dysfunction, is multi-factorial; for instance, it implicates the failure of ECs to support the normal antithrombotic and anti-inflammatory status, resulting in the onset of unfavorable cardiovascular conditions such as atherosclerosis, coronary artery disease, hypertension, heart problems, and other vascular pathologies. Notably, it is emerging that the ability of ECs to adapt their metabolic status to persistent changes of the tissue microenvironment could be vital for the maintenance of vascular functions and to prevent adverse vascular events. The main purpose of the present article is to shed light on the unique metabolic plasticity of ECs as a prospective therapeutic target; this may lead to the development of novel strategies for cardiovascular diseases and cancer.
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26
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Allen CNS, Arjona SP, Santerre M, Sawaya BE. Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis. Viruses 2022; 14:602. [PMID: 35337009 PMCID: PMC8955778 DOI: 10.3390/v14030602] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 02/07/2023] Open
Abstract
Metabolic reprogramming is a hallmark of cancer and has proven to be critical in viral infections. Metabolic reprogramming provides the cell with energy and biomass for large-scale biosynthesis. Based on studies of the cellular changes that contribute to metabolic reprogramming, seven main hallmarks can be identified: (1) increased glycolysis and lactic acid, (2) increased glutaminolysis, (3) increased pentose phosphate pathway, (4) mitochondrial changes, (5) increased lipid metabolism, (6) changes in amino acid metabolism, and (7) changes in other biosynthetic and bioenergetic pathways. Viruses depend on metabolic reprogramming to increase biomass to fuel viral genome replication and production of new virions. Viruses take advantage of the non-metabolic effects of metabolic reprogramming, creating an anti-apoptotic environment and evading the immune system. Other non-metabolic effects can negatively affect cellular function. Understanding the role metabolic reprogramming plays in viral pathogenesis may provide better therapeutic targets for antivirals.
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Affiliation(s)
- Charles N. S. Allen
- Molecular Studies of Neurodegenerative Diseases Lab, FELS Cancer Institute for Personalized Medicine Institute, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (S.P.A.); (M.S.)
| | - Sterling P. Arjona
- Molecular Studies of Neurodegenerative Diseases Lab, FELS Cancer Institute for Personalized Medicine Institute, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (S.P.A.); (M.S.)
| | - Maryline Santerre
- Molecular Studies of Neurodegenerative Diseases Lab, FELS Cancer Institute for Personalized Medicine Institute, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (S.P.A.); (M.S.)
| | - Bassel E. Sawaya
- Molecular Studies of Neurodegenerative Diseases Lab, FELS Cancer Institute for Personalized Medicine Institute, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (S.P.A.); (M.S.)
- Departments of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Department of Cancer and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
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27
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Wijayasinghe YS, Bhansali MP, Borkar MR, Chaturbhuj GU, Muntean BS, Viola RE, Bhansali PR. A Comprehensive Biological and Synthetic Perspective on 2-Deoxy-d-Glucose (2-DG), A Sweet Molecule with Therapeutic and Diagnostic Potentials. J Med Chem 2022; 65:3706-3728. [PMID: 35192360 DOI: 10.1021/acs.jmedchem.1c01737] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Glucose, the primary substrate for ATP synthesis, is catabolized during glycolysis to generate ATP and precursors for the synthesis of other vital biomolecules. Opportunistic viruses and cancer cells often hijack this metabolic machinery to obtain energy and components needed for their replication and proliferation. One way to halt such energy-dependent processes is by interfering with the glycolytic pathway. 2-Deoxy-d-glucose (2-DG) is a synthetic glucose analogue that can inhibit key enzymes in the glycolytic pathway. The efficacy of 2-DG has been reported across an array of diseases and disorders, thereby demonstrating its broad therapeutic potential. Recent approval of 2-DG in India as a therapeutic approach for the management of the COVID-19 pandemic has brought renewed attention to this molecule. The purpose of this perspective is to present updated therapeutic avenues as well as a variety of chemical synthetic strategies for this medically useful sugar derivative, 2-DG.
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Affiliation(s)
- Yasanandana S Wijayasinghe
- Department of Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Kelaniya, Ragama 11010, Sri Lanka
| | | | - Maheshkumar R Borkar
- Department of Pharmaceutical Chemistry, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai 400056, Maharashtra, India
| | - Ganesh U Chaturbhuj
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, Maharashtra, India
| | - Brian S Muntean
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912, United States
| | - Ronald E Viola
- Department of Chemistry and Biochemistry, University of Toledo, Toledo, Ohio 43606, United States
| | - Pravin R Bhansali
- Department of Science, Faculty of Science and Technology, Alliance University, Chikkahagade Cross, Chandapura-Anekal Main Road, Anekal, Bengaluru 562106, Karnataka, India
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28
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Mirzaei R, Sabokroo N, Ahmadyousefi Y, Motamedi H, Karampoor S. Immunometabolism in biofilm infection: lessons from cancer. Mol Med 2022; 28:10. [PMID: 35093033 PMCID: PMC8800364 DOI: 10.1186/s10020-022-00435-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 01/10/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Biofilm is a community of bacteria embedded in an extracellular matrix, which can colonize different human cells and tissues and subvert the host immune reactions by preventing immune detection and polarizing the immune reactions towards an anti-inflammatory state, promoting the persistence of biofilm-embedded bacteria in the host. MAIN BODY OF THE MANUSCRIPT It is now well established that the function of immune cells is ultimately mediated by cellular metabolism. The immune cells are stimulated to regulate their immune functions upon sensing danger signals. Recent studies have determined that immune cells often display distinct metabolic alterations that impair their immune responses when triggered. Such metabolic reprogramming and its physiological implications are well established in cancer situations. In bacterial infections, immuno-metabolic evaluations have primarily focused on macrophages and neutrophils in the planktonic growth mode. CONCLUSION Based on differences in inflammatory reactions of macrophages and neutrophils in planktonic- versus biofilm-associated bacterial infections, studies must also consider the metabolic functions of immune cells against biofilm infections. The profound characterization of the metabolic and immune cell reactions could offer exciting novel targets for antibiofilm therapy.
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Affiliation(s)
- Rasoul Mirzaei
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
| | - Niloofar Sabokroo
- Department of Microbiology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Yaghoub Ahmadyousefi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hamid Motamedi
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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HIF-1α modulates sex-specific Th17/Treg responses during hepatic amoebiasis. J Hepatol 2022; 76:160-173. [PMID: 34599999 DOI: 10.1016/j.jhep.2021.09.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 09/17/2021] [Accepted: 09/21/2021] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS An invasive form of intestinal Entamoeba (E.) histolytica infection, which causes amoebic liver abscess, is more common in men than in women. Immunopathological mechanisms are responsible for the more severe outcome in males. Here, we used a mouse model of hepatic amoebiasis to investigate the contribution of hepatic hypoxia-inducible factor (HIF)-1α to T helper 17 (Th17)/regulatory T cell (Treg) responses in the context of the sex-specific outcome of liver damage. METHODS C57BL/6J mice were infected intrahepatically with E. histolytica trophozoites. HIF-1α expression was determined by qPCR, flow cytometry and immunohistochemistry. Tregs and Th17 cells were analysed by immunohistochemistry and flow cytometry. Finally, male and female hepatocyte-specific Hif1α knockout mice were generated, and the effect of HIF-1α on abscess development, the cytokine milieu, and Th17/Treg differentiation was examined. RESULTS E. histolytica infection increased hepatic HIF-1α levels, along with the elevated frequencies of hepatic Th17 and Treg cells. While the Th17 cell population was larger in male mice, Tregs characterised by increased expression of Foxp3 in female mice. Male mice displayed increased IL-6 expression, contributing to immunopathology; this increase in IL-6 expression declined upon deletion of hepatic HIF-1α. In both sexes, hepatic deletion of HIF-1α reduced the Th17 cell frequency; however, the percentage of Tregs was reduced in female mice only. CONCLUSIONS Hepatic HIF-1α modulates the sex-specific outcome of murine E. histolytica infection. Our results suggest that in male mice, Th17 cells can be modulated by hepatic HIF-1α via IL-6, indicating marked involvement in the immunopathology underlying abscess development. Strong expression of Foxp3 by hepatic Tregs from female mice suggests a potent immunosuppressive function, leading to initiation of liver regeneration. LAY SUMMARY Infection with the parasite Entamoeba histolytica activates immunopathological mechanisms in male mice, which lead to liver abscesses that are larger than those in female mice. In the absence of the protein HIF-1α in hepatocytes, abscess formation is reduced; moreover, the sex difference in abscess size is abolished. These results suggest that HIF-1α modulates the immune response involved in the induction of immunopathology, resulting in differential disease susceptibility in males and females.
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Alfarouk KO, Alhoufie STS, Hifny A, Schwartz L, Alqahtani AS, Ahmed SBM, Alqahtani AM, Alqahtani SS, Muddathir AK, Ali H, Bashir AHH, Ibrahim ME, Greco MR, Cardone RA, Harguindey S, Reshkin SJ. Of mitochondrion and COVID-19. J Enzyme Inhib Med Chem 2021; 36:1258-1267. [PMID: 34107824 PMCID: PMC8205080 DOI: 10.1080/14756366.2021.1937144] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/20/2021] [Accepted: 05/20/2021] [Indexed: 02/08/2023] Open
Abstract
COVID-19, a pandemic disease caused by a viral infection, is associated with a high mortality rate. Most of the signs and symptoms, e.g. cytokine storm, electrolytes imbalances, thromboembolism, etc., are related to mitochondrial dysfunction. Therefore, targeting mitochondrion will represent a more rational treatment of COVID-19. The current work outlines how COVID-19's signs and symptoms are related to the mitochondrion. Proper understanding of the underlying causes might enhance the opportunity to treat COVID-19.
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Affiliation(s)
- Khalid Omer Alfarouk
- Research Center, Zamzam University College, Khartoum, Sudan
- Department of Evolutionary Pharmacology and Tumor Metabolism, Hala Alfarouk Cancer Center, Khartoum, Sudan
- Al-Ghad International College for Applied Medical Sciences, Al-Madinah Al-Munwarah, Saudi Arabia
| | - Sari T. S. Alhoufie
- Medical Laboratories Technology Department, College of Applied Medical Sciences, Taibah University, Al-Madinah Al-Munwarah, Saudi Arabia
| | | | | | - Ali S. Alqahtani
- College of Applied Medical Sciences, Najran University, Najran, Saudi Arabia
| | | | - Ali M. Alqahtani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Saad S. Alqahtani
- Pharmacy Practice Research Unit, Clinical Pharmacy Department, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | | | - Heyam Ali
- Faculty of Pharmacy, University of Khartoum, Khartoum, Sudan
| | - Adil H. H. Bashir
- Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan
| | | | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, Bari, Italy
| | - Rosa A. Cardone
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, Bari, Italy
| | | | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, Bari, Italy
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Ahmed D, Humphrey A, Roy D, Sheridan ME, Versey Z, Jaworski A, Edwards A, Donner J, Abizaid A, Willmore W, Kumar A, Golshani A, Cassol E. HIF-1α Regulation of Cytokine Production following TLR3 Engagement in Murine Bone Marrow-Derived Macrophages Is Dependent on Viral Nucleic Acid Length and Glucose Availability. THE JOURNAL OF IMMUNOLOGY 2021; 207:2813-2827. [PMID: 34740958 DOI: 10.4049/jimmunol.2001282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 09/16/2021] [Indexed: 12/24/2022]
Abstract
Hypoxia-inducible factor-1α (HIF-1α) is an important regulator of glucose metabolism and inflammatory cytokine production in innate immune responses. Viruses modulate HIF-1α to support viral replication and the survival of infected cells, but it is unclear if this transcription factor also plays an important role in regulating antiviral immune responses. In this study, we found that short and long dsRNA differentially engage TLR3, inducing distinct levels of proinflammatory cytokine production (TNF-α and IL-6) in bone marrow-derived macrophages from C57BL/6 mice. These responses are associated with differential accumulation of HIF-1α, which augments NF-κB activation. Unlike TLR4 responses, increased HIF-1α following TLR3 engagement is not associated with significant alterations in glycolytic activity and was more pronounced in low glucose conditions. We also show that the mechanisms supporting HIF-1α stabilization may differ following stimulation with short versus long dsRNA and that pyruvate kinase M2 and mitochondrial reactive oxygen species play a central role in these processes. Collectively, this work suggests that HIF-1α may fine-tune proinflammatory cytokine production during early antiviral immune responses, particularly when there is limited glucose availability or under other conditions of stress. Our findings also suggest we may be able to regulate the magnitude of proinflammatory cytokine production during antiviral responses by targeting proteins or molecules that contribute to HIF-1α stabilization.
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Affiliation(s)
- Duale Ahmed
- Department of Biology, Carleton University, Ottawa, Ontario, Canada.,Department of Health Sciences, Carleton University, Ottawa, Ontario, Canada
| | - Allan Humphrey
- Department of Health Sciences, Carleton University, Ottawa, Ontario, Canada.,Apoptosis Research Centre, The Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
| | - David Roy
- Department of Health Sciences, Carleton University, Ottawa, Ontario, Canada
| | | | - Zoya Versey
- Department of Health Sciences, Carleton University, Ottawa, Ontario, Canada
| | - Allison Jaworski
- Department of Health Sciences, Carleton University, Ottawa, Ontario, Canada
| | - Alex Edwards
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - James Donner
- Department of Health Sciences, Carleton University, Ottawa, Ontario, Canada
| | - Alfonso Abizaid
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - William Willmore
- Institute of Biochemistry, Carleton University, Ottawa, Ontario, Canada
| | - Ashok Kumar
- Department of Pathology, The Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada; and.,Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Ashkan Golshani
- Department of Biology, Carleton University, Ottawa, Ontario, Canada
| | - Edana Cassol
- Department of Health Sciences, Carleton University, Ottawa, Ontario, Canada;
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32
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Ren Z, Yu Y, Chen C, Yang D, Ding T, Zhu L, Deng J, Xu Z. The Triangle Relationship Between Long Noncoding RNA, RIG-I-like Receptor Signaling Pathway, and Glycolysis. Front Microbiol 2021; 12:807737. [PMID: 34917069 PMCID: PMC8670088 DOI: 10.3389/fmicb.2021.807737] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/09/2021] [Indexed: 12/11/2022] Open
Abstract
Long noncoding RNA (LncRNA), a noncoding RNA over 200nt in length, can regulate glycolysis through metabolic pathways, glucose metabolizing enzymes, and epigenetic reprogramming. Upon viral infection, increased aerobic glycolysis providzes material and energy for viral replication. Mitochondrial antiviral signaling protein (MAVS) is the only protein-specified downstream of retinoic acid-inducible gene I (RIG-I) that bridges the gap between antiviral immunity and glycolysis. MAVS binding to RIG-I inhibits MAVS binding to Hexokinase (HK2), thereby impairing glycolysis, while excess lactate production inhibits MAVS and the downstream antiviral immune response, facilitating viral replication. LncRNAs can also regulate antiviral innate immunity by interacting with RIG-I and downstream signaling pathways and by regulating the expression of interferons and interferon-stimulated genes (ISGs). Altogether, we summarize the relationship between glycolysis, antiviral immunity, and lncRNAs and propose that lncRNAs interact with glycolysis and antiviral pathways, providing a new perspective for the future treatment against virus infection, including SARS-CoV-2.
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Affiliation(s)
- Zhihua Ren
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yueru Yu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Chaoxi Chen
- College of Life Since and Technology, Southwest Minzu University, Chengdu, China
| | - Dingyong Yang
- College of Animal Husbandry and Veterinary Medicine, Chengdu Agricultural College, Chengdu, China
| | - Ting Ding
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ling Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Junliang Deng
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Zhiwen Xu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
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Abstract
Cellular activities are finely regulated by numerous signaling pathways to support specific functions of complex life processes. Viruses are obligate intracellular parasites. Each step of viral replication is ultimately governed by the interaction of a virus with its host cells. Because of the demands of viral replication, the nutritional needs of virus-infected cells differ from those of uninfected cells. To improve their chances of survival and replication, viruses have evolved to commandeer cellular processes, including cell metabolism, augmenting these processes to support their needs. This article summarizes recent findings regarding virus-induced alterations to major cellular metabolic pathways focusing on how viruses modulate various signaling cascades to induce these changes. We begin with a general introduction describing the role played by signaling pathways in cellular metabolism. We then discuss how different viruses target these signaling pathways to reprogram host metabolism to favor the viral needs. We highlight the gaps in understanding metabolism-related virus-host interactions and discuss how studying these changes will enhance our understanding of fundamental processes involved in metabolic regulation. Finally, we discuss the potential to harness these processes to combat viral diseases, as well as other diseases, including metabolic disorders and cancers.
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34
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Das A, Patra M, Dhangadamajhi G. Association of rs11549465 (C1772T) variant of hypoxia-inducible factor-1α with Covid-19 susceptibility. A population-based epidemiological study. Hum Cell 2021; 34:1937-1940. [PMID: 34426956 PMCID: PMC8382105 DOI: 10.1007/s13577-021-00601-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 08/19/2021] [Indexed: 12/19/2022]
Affiliation(s)
- Anamika Das
- Agricultural and Food Engineering Department, Indian Institute of Technology, Kharagpur, 721302, West Bengal, India
| | - Maheswari Patra
- Department of Biotechnology, Maharaja Sriram Chandra Bhanjadeo University, Baripada, 757003, Odisha, India
| | - Gunanidhi Dhangadamajhi
- Department of Biotechnology, Maharaja Sriram Chandra Bhanjadeo University, Baripada, 757003, Odisha, India.
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35
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Chen Z, Wang C, Feng X, Nie L, Tang M, Zhang H, Xiong Y, Swisher SK, Srivastava M, Chen J. Interactomes of SARS-CoV-2 and human coronaviruses reveal host factors potentially affecting pathogenesis. EMBO J 2021; 40:e107776. [PMID: 34232536 PMCID: PMC8447597 DOI: 10.15252/embj.2021107776] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 06/27/2021] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
Host-virus protein-protein interactions play key roles in the life cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We conducted a comprehensive interactome study between the virus and host cells using tandem affinity purification and proximity-labeling strategies and identified 437 human proteins as the high-confidence interacting proteins. Further characterization of these interactions and comparison to other large-scale study of cellular responses to SARS-CoV-2 infection elucidated how distinct SARS-CoV-2 viral proteins participate in its life cycle. With these data mining, we discovered potential drug targets for the treatment of COVID-19. The interactomes of two key SARS-CoV-2-encoded viral proteins, NSP1 and N, were compared with the interactomes of their counterparts in other human coronaviruses. These comparisons not only revealed common host pathways these viruses manipulate for their survival, but also showed divergent protein-protein interactions that may explain differences in disease pathology. This comprehensive interactome of SARS-CoV-2 provides valuable resources for the understanding and treating of this disease.
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Affiliation(s)
- Zhen Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chao Wang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xu Feng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Litong Nie
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mengfan Tang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Huimin Zhang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yun Xiong
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Samuel K Swisher
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mrinal Srivastava
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Junjie Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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36
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Immunometabolism Modulation in Therapy. Biomedicines 2021; 9:biomedicines9070798. [PMID: 34356862 PMCID: PMC8301471 DOI: 10.3390/biomedicines9070798] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/02/2021] [Accepted: 07/06/2021] [Indexed: 02/07/2023] Open
Abstract
The study of cancer biology should be based around a comprehensive vision of the entire tumor ecosystem, considering the functional, bioenergetic and metabolic state of tumor cells and those of their microenvironment, and placing particular importance on immune system cells. Enhanced understanding of the molecular bases that give rise to alterations of pathways related to tumor development can open up new therapeutic intervention opportunities, such as metabolic regulation applied to immunotherapy. This review outlines the role of various oncometabolites and immunometabolites, such as TCA intermediates, in shaping pro/anti-inflammatory activity of immune cells such as MDSCs, T lymphocytes, TAMs and DCs in cancer. We also discuss the extraordinary plasticity of the immune response and its implication in immunotherapy efficacy, and highlight different therapeutic intervention possibilities based on controlling the balanced systems of specific metabolites with antagonistic functions.
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37
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Burtscher J, Burtscher M, Millet GP. The central role of mitochondrial fitness on antiviral defenses: An advocacy for physical activity during the COVID-19 pandemic. Redox Biol 2021; 43:101976. [PMID: 33932869 PMCID: PMC8062414 DOI: 10.1016/j.redox.2021.101976] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 04/06/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
Mitochondria are central regulators of cellular metabolism, most known for their role in energy production. They can be "enhanced" by physical activity (including exercise), which increases their integrity, efficiency and dynamic adaptation to stressors, in short "mitochondrial fitness". Mitochondrial fitness is closely associated with cardiorespiratory fitness and physical activity. Given the importance of mitochondria in immune functions, it is thus not surprising that cardiorespiratory fitness is also an integral determinant of the antiviral host defense and vulnerability to infection. Here, we first briefly review the role of physical activity in viral infections. We then summarize mitochondrial functions that are relevant for the antiviral immune response with a particular focus on the current Coronavirus Disease (COVID-19) pandemic and on innate immune function. Finally, the modulation of mitochondrial and cardiorespiratory fitness by physical activity, aging and the chronic diseases that represent the most common comorbidities of COVID-19 is discussed. We conclude that a high mitochondrial - and related cardiorespiratory - fitness should be considered as protective factors for viral infections, including COVID-19. This assumption is corroborated by reduced mitochondrial fitness in many established risk factors of COVID-19, like age, various chronic diseases or obesity. We argue for regular analysis of the cardiorespiratory fitness of COVID-19 patients and the promotion of physical activity - with all its associated health benefits - as preventive measures against viral infection.
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Affiliation(s)
- Johannes Burtscher
- Institute of Sport Sciences, University of Lausanne, CH-1015, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, CH-1015, Lausanne, Switzerland.
| | | | - Grégoire P Millet
- Institute of Sport Sciences, University of Lausanne, CH-1015, Lausanne, Switzerland
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38
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Viral Infection Modulates Mitochondrial Function. Int J Mol Sci 2021; 22:ijms22084260. [PMID: 33923929 PMCID: PMC8073244 DOI: 10.3390/ijms22084260] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/14/2021] [Accepted: 04/15/2021] [Indexed: 02/08/2023] Open
Abstract
Mitochondria are important organelles involved in metabolism and programmed cell death in eukaryotic cells. In addition, mitochondria are also closely related to the innate immunity of host cells against viruses. The abnormality of mitochondrial morphology and function might lead to a variety of diseases. A large number of studies have found that a variety of viral infections could change mitochondrial dynamics, mediate mitochondria-induced cell death, and alter the mitochondrial metabolic status and cellular innate immune response to maintain intracellular survival. Meanwhile, mitochondria can also play an antiviral role during viral infection, thereby protecting the host. Therefore, mitochondria play an important role in the interaction between the host and the virus. Herein, we summarize how viral infections affect microbial pathogenesis by altering mitochondrial morphology and function and how viruses escape the host immune response.
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39
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Nunes EDC, de Filippis AMB, Pereira TDES, Faria NRDC, Salgado Á, Santos CS, Carvalho TCPX, Calcagno JI, Chalhoub FLL, Brown D, Giovanetti M, Alcantara LCJ, Barreto FK, de Siqueira IC, Canuto GAB. Untargeted Metabolomics Insights into Newborns with Congenital Zika Infection. Pathogens 2021; 10:468. [PMID: 33924291 PMCID: PMC8070065 DOI: 10.3390/pathogens10040468] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 03/17/2021] [Accepted: 03/22/2021] [Indexed: 12/13/2022] Open
Abstract
Zika virus (ZIKV), an emerging virus belonging to the Flaviviridae family, causes severe neurological clinical complications and has been associated with Guillain-Barré syndrome, fetal abnormalities known collectively as congenital Zika syndrome, and microcephaly. Studies have shown that ZIKV infection can alter cellular metabolism, directly affecting neural development. Brain growth requires controlled cellular metabolism, which is essential for cell proliferation and maturation. However, little is known regarding the metabolic profile of ZIKV-infected newborns and possible associations related to microcephaly. Furthering the understanding surrounding underlying mechanisms is essential to developing personalized treatments for affected individuals. Thus, metabolomics, the study of the metabolites produced by or modified in an organism, constitutes a valuable approach in the study of complex diseases. Here, 26 serum samples from ZIKV-positive newborns with or without microcephaly, as well as controls, were analyzed using an untargeted metabolomics approach involving gas chromatography-mass spectrometry (GC-MS). Significant alterations in essential and non-essential amino acids, as well as carbohydrates (including aldohexoses, such as glucose or mannose) and their derivatives (urea and pyruvic acid), were observed in the metabolic profiles analyzed. Our results provide insight into relevant metabolic processes in patients with ZIKV and microcephaly.
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Affiliation(s)
- Estéfane da C. Nunes
- Departamento de Química Analítica, Instituto de Química, Universidade Federal da Bahia, Rua Barao de Jeremoabo, 147, Salvador, BA 40170-115, Brazil; (E.d.C.N.); (T.d.E.S.P.)
| | - Ana M. B. de Filippis
- Laboratório de Flavivírus, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil, 4365, Manguinhos, Rio de Janeiro, RJ 21040-900, Brazil; (A.M.B.d.F.); (F.L.L.C.); (D.B.); (M.G.); (L.C.J.A.)
| | - Taiane do E. S. Pereira
- Departamento de Química Analítica, Instituto de Química, Universidade Federal da Bahia, Rua Barao de Jeremoabo, 147, Salvador, BA 40170-115, Brazil; (E.d.C.N.); (T.d.E.S.P.)
| | - Nieli R. da C. Faria
- Laboratório de Flavivírus, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil, 4365, Manguinhos, Rio de Janeiro, RJ 21040-900, Brazil; (A.M.B.d.F.); (F.L.L.C.); (D.B.); (M.G.); (L.C.J.A.)
| | - Álvaro Salgado
- Laboratório de Genética Celular e Molecular, Universidade Federal de Minas Gerais, Avenida Presidente Antônio Carlos, 6627, Belo Horizonte, MG 31270-901, Brazil;
| | - Cleiton S. Santos
- Instituto Gonçalo Moniz, Fiocruz, Rua Waldemar Falcão, 121, Salvador, BA 40295-010, Brazil;
| | - Teresa C. P. X. Carvalho
- Maternidade de Referência Professor José Maria de Magalhães Neto, SESAB, Rua Marquês de Maricá, Salvador, BA 40310-000, Brazil; (T.C.P.X.C.); (J.I.C.)
| | - Juan I. Calcagno
- Maternidade de Referência Professor José Maria de Magalhães Neto, SESAB, Rua Marquês de Maricá, Salvador, BA 40310-000, Brazil; (T.C.P.X.C.); (J.I.C.)
| | - Flávia L. L. Chalhoub
- Laboratório de Flavivírus, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil, 4365, Manguinhos, Rio de Janeiro, RJ 21040-900, Brazil; (A.M.B.d.F.); (F.L.L.C.); (D.B.); (M.G.); (L.C.J.A.)
| | - David Brown
- Laboratório de Flavivírus, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil, 4365, Manguinhos, Rio de Janeiro, RJ 21040-900, Brazil; (A.M.B.d.F.); (F.L.L.C.); (D.B.); (M.G.); (L.C.J.A.)
| | - Marta Giovanetti
- Laboratório de Flavivírus, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil, 4365, Manguinhos, Rio de Janeiro, RJ 21040-900, Brazil; (A.M.B.d.F.); (F.L.L.C.); (D.B.); (M.G.); (L.C.J.A.)
- Laboratório de Genética Celular e Molecular, Universidade Federal de Minas Gerais, Avenida Presidente Antônio Carlos, 6627, Belo Horizonte, MG 31270-901, Brazil;
| | - Luiz C. J. Alcantara
- Laboratório de Flavivírus, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil, 4365, Manguinhos, Rio de Janeiro, RJ 21040-900, Brazil; (A.M.B.d.F.); (F.L.L.C.); (D.B.); (M.G.); (L.C.J.A.)
- Laboratório de Genética Celular e Molecular, Universidade Federal de Minas Gerais, Avenida Presidente Antônio Carlos, 6627, Belo Horizonte, MG 31270-901, Brazil;
| | - Fernanda K. Barreto
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Rua Hormindo Barros, 58, Vitória da Conquista, BA 45029-094, Brazil
| | - Isadora C. de Siqueira
- Instituto Gonçalo Moniz, Fiocruz, Rua Waldemar Falcão, 121, Salvador, BA 40295-010, Brazil;
| | - Gisele A. B. Canuto
- Departamento de Química Analítica, Instituto de Química, Universidade Federal da Bahia, Rua Barao de Jeremoabo, 147, Salvador, BA 40170-115, Brazil; (E.d.C.N.); (T.d.E.S.P.)
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Sumbria D, Berber E, Mathayan M, Rouse BT. Virus Infections and Host Metabolism-Can We Manage the Interactions? Front Immunol 2021; 11:594963. [PMID: 33613518 PMCID: PMC7887310 DOI: 10.3389/fimmu.2020.594963] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 12/16/2020] [Indexed: 01/08/2023] Open
Abstract
When viruses infect cells, they almost invariably cause metabolic changes in the infected cell as well as in several host cell types that react to the infection. Such metabolic changes provide potential targets for therapeutic approaches that could reduce the impact of infection. Several examples are discussed in this review, which include effects on energy metabolism, glutaminolysis and fatty acid metabolism. The response of the immune system also involves metabolic changes and manipulating these may change the outcome of infection. This could include changing the status of herpesviruses infections from productive to latency. The consequences of viral infections which include coronavirus disease 2019 (COVID-19), may also differ in patients with metabolic problems, such as diabetes mellitus (DM), obesity, and endocrine diseases. Nutrition status may also affect the pattern of events following viral infection and examples that impact on the pattern of human and experimental animal viral diseases and the mechanisms involved are discussed. Finally, we discuss the so far few published reports that have manipulated metabolic events in-vivo to change the outcome of virus infection. The topic is expected to expand in relevance as an approach used alone or in combination with other therapies to shape the nature of virus induced diseases.
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Affiliation(s)
- Deepak Sumbria
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, United States
| | - Engin Berber
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, United States.,Department of Virology, Faculty of Veterinary Medicine, Erciyes University, Kayseri, Turkey
| | - Manikannan Mathayan
- Center for Drug Discovery and Development, Sathyabama Institute of Science and Technology, Chennai, India
| | - Barry T Rouse
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, United States
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41
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Millet GP, Debevec T, Brocherie F, Burtscher M, Burtscher J. Altitude and COVID-19: Friend or foe? A narrative review. Physiol Rep 2021; 8:e14615. [PMID: 33340275 PMCID: PMC7749581 DOI: 10.14814/phy2.14615] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 09/22/2020] [Accepted: 09/23/2020] [Indexed: 12/11/2022] Open
Abstract
Recent reports suggest that high-altitude residence may be beneficial in the novel coronavirus disease (COVID-19) implicating that traveling to high places or using hypoxic conditioning thus could be favorable as well. Physiological high-altitude characteristics and symptoms of altitude illnesses furthermore seem similar to several pathologies associated with COVID-19. As a consequence, high altitude and hypoxia research and related clinical practices are discussed for potential applications in COVID-19 prevention and treatment. We summarize the currently available evidence on the relationship between altitude/hypoxia conditions and COVID-19 epidemiology and pathophysiology. The potential for treatment strategies used for altitude illnesses is evaluated. Symptomatic overlaps in the pathophysiology of COVID-19 induced ARDS and high altitude illnesses (i.e., hypoxemia, dyspnea…) have been reported but are also common to other pathologies (i.e., heart failure, pulmonary embolism, COPD…). Most treatments of altitude illnesses have limited value and may even be detrimental in COVID-19. Some may be efficient, potentially the corticosteroid dexamethasone. Physiological adaptations to altitude/hypoxia can exert diverse effects, depending on the constitution of the target individual and the hypoxic dose. In healthy individuals, they may optimize oxygen supply and increase mitochondrial, antioxidant, and immune system function. It is highly debated if these physiological responses to hypoxia overlap in many instances with SARS-CoV-2 infection and may exert preventive effects under very specific conditions. The temporal overlap of SARS-CoV-2 infection and exposure to altitude/hypoxia may be detrimental. No evidence-based knowledge is presently available on whether and how altitude/hypoxia may prevent, treat or aggravate COVID-19. The reported lower incidence and mortality of COVID-19 in high-altitude places remain to be confirmed. High-altitude illnesses and COVID-19 pathologies exhibit clear pathophysiological differences. While potentially effective as a prophylactic measure, altitude/hypoxia is likely associated with elevated risks for patients with COVID-19. Altogether, the different points discussed in this review are of possibly some relevance for individuals who aim to reach high-altitude areas. However, due to the ever-changing state of understanding of COVID-19, all points discussed in this review may be out of date at the time of its publication.
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Affiliation(s)
| | - Tadej Debevec
- Faculty of SportUniversity of LjubljanaLjubljanaSlovenia
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42
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Almaeen AH, Alduraywish AA, Mobasher MA, Almadhi OIM, Nafeh HM, El-Metwally TH. Oxidative stress, immunological and cellular hypoxia biomarkers in hepatitis C treatment-naïve and cirrhotic patients. Arch Med Sci 2021; 17:368-375. [PMID: 33747272 PMCID: PMC7959056 DOI: 10.5114/aoms.2019.91451] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 11/13/2019] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Hepatitis C virus (HCV) is the main cause of chronic liver disease, with calamitous complications. Its highest rate is recorded in Egypt. This study investigated whether oxidative stress, immunological chaos and cellular hypoxia are implicated in the pathophysiology of the disease. MATERIAL AND METHODS This cross-sectional study aimed to evaluate the changes in blood oxidative stress, cellular hypoxia/angiogenesis and cellular immunological biomarkers in hospital-diagnosed treatment-naïve HCV-infected Upper Egyptian chronic liver disease patients vs. healthy controls (n = 40). The consecutively included patients comprised 120 with normal serum enzymes (HCV-NE) and 130 with high serum enzymes (HCV-HE), along with 120 cirrhotic patients. RESULTS Oxidative stress biomarkers - malondialdehyde (MDA), total peroxides and oxidative stress index (OSI) - were significantly lower in controls vs. each of the patient groups. Cirrhotic patients presented the highest levels. However, total antioxidants (TAO) showed non-significant differences among the four groups. The cellular hypoxia/angiogenesis biomarkers - lactate, vascular endothelial cell growth factor (VEGF) and its soluble receptor 1 (sVEGFR1) - vs. controls were massively increased in patient groups. VEGF was lowest while sVEGFR1 was highest among cirrhotic patients. Immunological biomarkers, - granulocyte/monocyte-colony stimulating factor (GM-CSF) and total immunoglobulin G (IgG) - were massively increased in patient groups vs. controls. GM-CSF was lowest in HCV-HE and IgG was highest in cirrhotic patients. sVEGFR1 correlated with the progression towards cirrhosis. CONCLUSIONS Oxidative stress is implicated in the progress of HCV infection with marked induction of cellular hypoxia and dysfunctional angiogenesis, and a futile immunological reaction. sVEGFR1 level correlated with progression towards HCV-induced liver fibrosis.
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Affiliation(s)
| | | | - Maysa Ahmed Mobasher
- Department of Pathology, Jouf University College of Medicine, Sakaka, Saudi Arabia
| | - Omar I. M. Almadhi
- College of Medicine, Jouf University College of Medicine, Sakaka, Saudi Arabia
| | - Hanan M. Nafeh
- Department of Tropical Medicine and Gastroenterology, Assiut University, Faculty of Medicine, Assiut, Egypt
| | - Tarek Hassan El-Metwally
- Department of Pathology, Jouf University College of Medicine, Sakaka, Saudi Arabia
- Department of Medical Biochemistry, Assiut University, Faculty of Medicine, Assiut, Egypt
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43
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AbdelMassih A, Yacoub E, Husseiny RJ, Kamel A, Hozaien R, El Shershaby M, Rajab M, Yacoub S, Eid MA, Elahmady M, Gadalla M, Mokhtar S, Hassan AA, Abou-Zeid AS, Hussein M, Aboushadi N, Emad N, Zahra N, Hassan A, Hussein E, Ibrahim N, El Nahhas N, Elahmady T, Khallaf M, Mustafa H, Anis N, Albehairy M, Hanna F, Moris L, Ye J. Hypoxia-inducible factor (HIF): The link between obesity and COVID-19. ACTA ACUST UNITED AC 2020; 22:100317. [PMID: 33521378 PMCID: PMC7832240 DOI: 10.1016/j.obmed.2020.100317] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 12/23/2020] [Accepted: 12/27/2020] [Indexed: 01/10/2023]
Abstract
The COVID-19 death toll has involved to date more than 1 million confirmed deaths. The death rate is even higher in the obese COVID-19 patients, as a result of hypoxia, due to the interplay between adipose tissue hypoxia and obstructive sleep apnea. The discrepancy of manifestations seen in COVID-19 seems to be mediated by a differential immune response rather than a differential viral load. One of the key players of the immune response is HIF. HIF-1β is a stable constitutively expressed protein in the nucleus; and under hypoxic changes, its activity is unaffected, whereas the HIF-α subunit has a short half-life and because of its degradation by an enzyme known as propyl hydroxylase; under hypoxic conditions, propyl hydroxylase gets deactivated thus leading to the stabilization of HIF-1α. As mentioned before, HIF-1α expression is triggered by hypoxic states, this crippling condition will aggravate the pro-inflammatory characteristics of HIF-1α. The vast majority of decompensated COVID19 cases manifest with drastic lung injury and severe viral pneumonia, the infection-induced hypoxia will the existing hypoxia in obesity. This will additionally augment HIF-1α levels that will provoke the already existing cytokines' storm to fulminant. Consequently, this will directly correlate the effect of a hypoxic environment with the increase of HIF-1α level. HIFɑ exists in two main isoforms HIF-1α and HIF-2α. HIF-1α and HIF-2α act in distinct ways in how they work on different target genes. For example, HIF-2α may act on hemopoietin genes (heme-regulating genes); while HIF-1α acts on EPO. HIF-1α release seems to be markedly augmented in obesity due to adipose tissue hypoxia and obstructive sleep apnea resulting in cyclic hypoxia. HIF-1α can also be secreted by direct viral proteolytic effects. Whereas, HIF-2α is stimulated by chronic hypoxia. HIF-1α exerts detrimental effects on the immune system, characterized by unopposed pro-inflammation at the macrophages, dendritic cells, T cells, and complement levels resulting in cytokines' storm, which is linked to the poor outcomes of COVID-19. On the other hand, HIF-2α role is regulatory and largely opposes the actions mediated by HIF-1α. In view of this, inhibiting HIF-1α release or switching its production to HIF-2α by natural products such as resveratrol or by synthetic drugs, offer a good therapeutic strategy that can prevent COVID-19 worst outcome in infected patients. The approach of breaking the vicious circle between lung damage-induced hypoxia and HIF-1α pro-inflammatory stimulant through drugs is considered to be extremely promising as a therapeutic manner to combat further deterioration of COVID19 cases.
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Affiliation(s)
- Antoine AbdelMassih
- Pediatric Cardiology Unit, Pediatrics' Department, Faculty of Medicine, Cairo University, Egypt.,Pediatric Cardio-Oncology Department, Children Cancer Hospital of Egypt, 57357, Egypt
| | - Elaria Yacoub
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt
| | - Reem J Husseiny
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt
| | - Aya Kamel
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt
| | - Rafeef Hozaien
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt
| | - Meryam El Shershaby
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt
| | - Maram Rajab
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt
| | - Shenoda Yacoub
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt
| | - Maryam A Eid
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | - Maryam Elahmady
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | - Mahenar Gadalla
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | - Sherouk Mokhtar
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | - Alaa A Hassan
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | - Aya S Abou-Zeid
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | - Mahinour Hussein
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | - Nour Aboushadi
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | - Nadine Emad
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | - Nihal Zahra
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | - Aya Hassan
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | - Engy Hussein
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | - Nourhan Ibrahim
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | - Nadine El Nahhas
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt.,Faculty of Dentistry, New Giza University, New Giza, Egypt
| | | | - Mohamed Khallaf
- Residency Training Program, Faculty of Medicine, Cairo University, Egypt
| | - Hadeel Mustafa
- Research Accessibility Team (students' and Interns' Research Program), Faculty of Medicine, Cairo University, Egypt
| | - Nancy Anis
- Pediatric Cardiology Unit, Pediatrics' Department, Faculty of Medicine, Cairo University, Egypt
| | | | - Farid Hanna
- Residency Training Program, Faculty of Medicine, Cairo University, Egypt
| | - Laila Moris
- Residency Training Program, Faculty of Medicine, Al Mansoura University, Egypt
| | - Jianping Ye
- Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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Reyes A, Corrales N, Gálvez NMS, Bueno SM, Kalergis AM, González PA. Contribution of hypoxia inducible factor-1 during viral infections. Virulence 2020; 11:1482-1500. [PMID: 33135539 PMCID: PMC7605355 DOI: 10.1080/21505594.2020.1836904] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/15/2020] [Accepted: 10/11/2020] [Indexed: 12/15/2022] Open
Abstract
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays critical roles during the cellular response to hypoxia. Under normoxic conditions, its function is tightly regulated by the degradation of its alpha subunit (HIF-1α), which impairs the formation of an active heterodimer in the nucleus that otherwise regulates the expression of numerous genes. Importantly, HIF-1 participates in both cancer and infectious diseases unveiling new therapeutic targets for those ailments. Here, we discuss aspects related to the activation of HIF-1, the effects of this transcription factor over immune system components, as well as the involvement of HIF-1 activity in response to viral infections in humans. Although HIF-1 is currently being assessed in numerous clinical settings as a potential therapy for different diseases, up to date, there are no clinical studies evaluating the pharmacological modulation of this transcription factor as a possible new antiviral treatment. However, based on the available evidence, clinical trials targeting this molecule are likely to occur soon. In this review we discuss the role of HIF-1 in viral immunity, the modulation of HIF-1 by different types of viruses, as well as the effects of HIF-1 over their life cycle and the potential use of HIF-1 as a new target for the treatment of viral infections.
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Affiliation(s)
- Antonia Reyes
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Nicolás Corrales
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Nicolás M. S. Gálvez
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susan M. Bueno
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento De Endocrinología, Facultad De Medicina, Escuela De Medicina, Pontificia Universidad Católica De Chile, Santiago, Chile
| | - Pablo A. González
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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45
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Jahani M, Dokaneheifard S, Mansouri K. Hypoxia: A key feature of COVID-19 launching activation of HIF-1 and cytokine storm. JOURNAL OF INFLAMMATION-LONDON 2020; 17:33. [PMID: 33139969 PMCID: PMC7594974 DOI: 10.1186/s12950-020-00263-3] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 10/20/2020] [Indexed: 12/12/2022]
Abstract
COVID-19, disease caused by the new coronavirus, SARS-CoV-2, appeared in the end of 2019 and was rapidly spread in most countries. This respiratory virus has different symptoms from moderate to severe, and results in lung pneumonia following acute respiratory distress syndrome (ARDS) and patient’s death in severe cases. ARDS is a severe form of acute lung injury that is caused by high inflammatory response of the innate immunity cells. Hypoxia is the common feature in the inflammatory sites with having various impacts on this condition by induction of some factors such as hypoxia inducible factor-1α (HIF-1α). HIF-1α regulates some important cellular processes including cell proliferation, metabolism and angiogenesis. Furthermore, this factor is activated during the immune responses and plays important roles in the inflammation site by inducing pro-inflammatory cytokines production through immune cells. So, in this study the possible effect of the HIF-1α on the COVID-19 pathogenesis with emphasizes on its role on innate immunity response has been discussed.
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Affiliation(s)
- Mozhgan Jahani
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sadat Dokaneheifard
- Department of Human Genetics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136 USA
| | - Kamran Mansouri
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Molecular Medicine, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
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46
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Liu PJ, Balfe P, McKeating JA, Schilling M. Oxygen Sensing and Viral Replication: Implications for Tropism and Pathogenesis. Viruses 2020; 12:E1213. [PMID: 33113858 PMCID: PMC7693908 DOI: 10.3390/v12111213] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 10/19/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022] Open
Abstract
The ability to detect and respond to varying oxygen tension is an essential prerequisite to life. Several mechanisms regulate the cellular response to oxygen including the prolyl hydroxylase domain (PHD)/factor inhibiting HIF (FIH)-hypoxia inducible factor (HIF) pathway, cysteamine (2-aminoethanethiol) dioxygenase (ADO) system, and the lysine-specific demethylases (KDM) 5A and KDM6A. Using a systems-based approach we discuss the literature on oxygen sensing pathways in the context of virus replication in different tissues that experience variable oxygen tension. Current information supports a model where the PHD-HIF pathway enhances the replication of viruses infecting tissues under low oxygen, however, the reverse is true for viruses with a selective tropism for higher oxygen environments. Differences in oxygen tension and associated HIF signaling may play an important role in viral tropism and pathogenesis. Thus, pharmaceutical agents that modulate HIF activity could provide novel treatment options for viral infections and associated pathological conditions.
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47
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Gatti P, Ilamathi HS, Todkar K, Germain M. Mitochondria Targeted Viral Replication and Survival Strategies-Prospective on SARS-CoV-2. Front Pharmacol 2020; 11:578599. [PMID: 32982760 PMCID: PMC7485471 DOI: 10.3389/fphar.2020.578599] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 08/14/2020] [Indexed: 12/11/2022] Open
Abstract
SARS-CoV-2 is a positive sense RNA coronavirus that constitutes a new threat for the global community and economy. While vaccines against SARS-CoV-2 are being developed, the mechanisms through which this virus takes control of an infected cell to replicate remains poorly understood. Upon infection, viruses completely rely on host cell molecular machinery to survive and replicate. To escape from the immune response and proliferate, viruses strategically modulate cellular metabolism and alter subcellular organelle architecture and functions. One way they do this is by modulating the structure and function of mitochondria, a critical cellular metabolic hub but also a key platform for the regulation of cellular immunity. This versatile nature of mitochondria defends host cells from viruses through several mechanisms including cellular apoptosis, ROS signaling, MAVS activation and mitochondrial DNA-dependent immune activation. These events are regulated by mitochondrial dynamics, a process by which mitochondria alter their structure (including their length and connectivity) in response to stress or other cues. It is therefore not surprising that viruses, including coronaviruses hijack these processes for their survival. In this review, we highlight how positive sense RNA viruses modulate mitochondrial dynamics and metabolism to evade mitochondrial mediated immune response in order to proliferate.
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Affiliation(s)
- Priya Gatti
- Groupe de Recherche en Signalisation Cellulaire and Département de Biologie, Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada
- Centre d’Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada
| | - Hema Saranya Ilamathi
- Groupe de Recherche en Signalisation Cellulaire and Département de Biologie, Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada
- Centre d’Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada
| | - Kiran Todkar
- Groupe de Recherche en Signalisation Cellulaire and Département de Biologie, Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada
- Centre d’Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada
| | - Marc Germain
- Groupe de Recherche en Signalisation Cellulaire and Département de Biologie, Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada
- Centre d’Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada
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48
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Liu PJ, Harris JM, Marchi E, D'Arienzo V, Michler T, Wing PAC, Magri A, Ortega-Prieto AM, van de Klundert M, Wettengel J, Durantel D, Dorner M, Klenerman P, Protzer U, Giotis ES, McKeating JA. Hypoxic gene expression in chronic hepatitis B virus infected patients is not observed in state-of-the-art in vitro and mouse infection models. Sci Rep 2020; 10:14101. [PMID: 32839523 PMCID: PMC7445281 DOI: 10.1038/s41598-020-70865-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 07/31/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. The prolyl hydroxylase domain (PHD)-hypoxia inducible factor (HIF) pathway is a key mammalian oxygen sensing pathway and is frequently perturbed by pathological states including infection and inflammation. We discovered a significant upregulation of hypoxia regulated gene transcripts in patients with chronic hepatitis B (CHB) in the absence of liver cirrhosis. We used state-of-the-art in vitro and in vivo HBV infection models to evaluate a role for HBV infection and the viral regulatory protein HBx to drive HIF-signalling. HBx had no significant impact on HIF expression or associated transcriptional activity under normoxic or hypoxic conditions. Furthermore, we found no evidence of hypoxia gene expression in HBV de novo infection, HBV infected human liver chimeric mice or transgenic mice with integrated HBV genome. Collectively, our data show clear evidence of hypoxia gene induction in CHB that is not recapitulated in existing models for acute HBV infection, suggesting a role for inflammatory mediators in promoting hypoxia gene expression.
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Affiliation(s)
- Peter Jianrui Liu
- Nuffield Department of Medicine Research Building, University of Oxford, Oxford, OX3 7LF, UK
| | - James M Harris
- Nuffield Department of Medicine Research Building, University of Oxford, Oxford, OX3 7LF, UK
| | - Emanuele Marchi
- Medawar Building, University of Oxford, South Parks Road, Oxford, OX1 3SY, UK
| | - Valentina D'Arienzo
- Nuffield Department of Medicine Research Building, University of Oxford, Oxford, OX3 7LF, UK
| | - Thomas Michler
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Trogerstrasse 30, 81675, Munich, Germany
| | - Peter A C Wing
- Nuffield Department of Medicine Research Building, University of Oxford, Oxford, OX3 7LF, UK
| | - Andrea Magri
- Nuffield Department of Medicine Research Building, University of Oxford, Oxford, OX3 7LF, UK
| | - Ana Maria Ortega-Prieto
- Section of Molecular Virology, Department of Infectious Diseases, Imperial College London, London, W2 1PG, UK
| | - Maarten van de Klundert
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Trogerstrasse 30, 81675, Munich, Germany
| | - Jochen Wettengel
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Trogerstrasse 30, 81675, Munich, Germany
| | - David Durantel
- Cancer Research Center of Lyon (CRCL), INSERM U1052, and University of Lyon (UCBL1), Lyon, France
| | - Marcus Dorner
- Section of Molecular Virology, Department of Infectious Diseases, Imperial College London, London, W2 1PG, UK
| | - Paul Klenerman
- Medawar Building, University of Oxford, South Parks Road, Oxford, OX1 3SY, UK
| | - Ulrike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Trogerstrasse 30, 81675, Munich, Germany
| | - Efstathios S Giotis
- Section of Molecular Virology, Department of Infectious Diseases, Imperial College London, London, W2 1PG, UK
- School of Life Sciences, University of Essex, Colchester, C04 3SQ, UK
| | - Jane A McKeating
- Nuffield Department of Medicine Research Building, University of Oxford, Oxford, OX3 7LF, UK.
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49
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Metabolic Reprogramming of Host Cells in Response to Enteroviral Infection. Cells 2020; 9:cells9020473. [PMID: 32085644 PMCID: PMC7072837 DOI: 10.3390/cells9020473] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/13/2020] [Accepted: 02/17/2020] [Indexed: 12/15/2022] Open
Abstract
Enterovirus 71 (EV71) infection is an endemic disease in Southeast Asia and China. We have previously shown that EV71 virus causes functional changes in mitochondria. It is speculative whether EV71 virus alters the host cell metabolism to its own benefit. Using a metabolomics approach, we demonstrate that EV71-infected Vero cells had significant changes in metabolism. Glutathione and its related metabolites, and several amino acids, such as glutamate and aspartate, changed significantly with the infectious dose of virus. Other pathways, including glycolysis and tricarboxylic acid cycle, were also altered. A change in glutamine/glutamate metabolism is critical to the viral infection. The presence of glutamine in culture medium was associated with an increase in viral replication. Dimethyl α-ketoglutarate treatment partially mimicked the effect of glutamine supplementation. In addition, the immunoblot analysis revealed that the expression of glutamate dehydrogenase (GDH) and trifunctional carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) increased during infection. Knockdown of expression of glutaminase (GLS), GDH and CAD drastically reduced the cytopathic effect (CPE) and viral replication. Furthermore, we found that CAD bound VP1 to promote the de novo pyrimidine synthesis. Our findings suggest that virus may induce metabolic reprogramming of host cells to promote its replication through interactions between viral and host cell proteins.
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Autophagy in hepatitis B or C virus infection: An incubator and a potential therapeutic target. Life Sci 2020; 242:117206. [DOI: 10.1016/j.lfs.2019.117206] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 12/17/2019] [Accepted: 12/17/2019] [Indexed: 12/12/2022]
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