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Aspirin and COVID-19. Jun 3rd, 2020

  • June 3, 2020
Covid 19

Maikel Peppelenbosch.

 

Department of Gastroenterology  and Hepatology

Erasmus MC – University Medical Center Rotterdam

PO Box 2040 – NL-3000 CA Rotterdam

The Netherlands

m.peppelenbosch@erasmusmc.nl

 

Salicylic acid, an important active metabolite, which is the most important active metabolite of aspirin, is produced by plants upon infection with pathogens and in particular viruses[i][1]. The production of salicylic acid in turn mediates resistance to viral replication, intercellular spread and systemic movement through so-called pathogenesis-related proteins including the intrigingly-named protein Coronatine Insensitive-1[ii][2],[iii][3]. Although Coronantine refers in this context to a protein produced by a plant pathogen, it is worthwhile to consider whether an anti-viral function of salicylic acid and aspirin has been evolutionary conserved and whether human aspirin may have an anti-coronavirus effect in COVID-19 as well.

 

COVID-19 has entered the human population, either direct or indirect, from a zoonotic reservoir in Chinese horseshoe bats (Rhinolophus sinicus)[iv][4] and as health-care resource has not been able to cope with the resulting morbidity, the resulting societal distress is almost unrivalled[v][5]. The reason that bats serve as reservoirs of a large variety of coronaviruses lies in the strong cell-autonomous innate immunity present in this group of animals, which is sufficient to control disease without elimination through adaptive immunity[vi][6]. In humans, cell autonomous immunity against viruses largely depends on the productions of interferons that upon binding of their cognate receptors activate JAK/STAT signalling in turn leading to the transcription and translation of a group of gene products called interferon stimulated genes, which directly counteract viral replication in the cytoplasm[vii][7]. In bats this pathway is constitutively active. Importantly, it has long been recognised that transactivation of the promotors of interferon stimulated is stimulated by inhibition of cyclooxygenase[viii][8] as prostaglandins inhibit phosphorylation and thus activation of STAT1[ix][9]. As a consequence, aspirin is expected to stimulate cell-autonomous immunity against viral infection and indeed this has been observed for various viruses, including herpes simplex virus[x][10], Hepatis C virus[xi][11], and influenza A virus[xii][12]. Indeed, the upregulation of interferon mediated gene production and associated cell autonomous anti-viral responses has been linked to the remarkable protective effect of aspirin use during 1918 Spanish Influenza virus pandemic[xiii][13]. The fact that coronavirus biology is unusually complex and contains many steps that are targeted by interferon stimulated genes[xiv][14] in conjunction with the proven potential of such immunity to control infection in bats may suggest that regular aspirin use may ameliorate infection following contact with SARS CoV2.

 

In apparent agreement, for other coronaviruses, including SARS CoV-1 and Canine Coronavirus it has been reported that treatment with cyclooxygenase inhibitors strongly counteracts viral replication in cultures of human lung epithelial cell lines[xv][15]. It is thus rational to assume that aspirin use will mitigate clinical course of COVID-19 through stimulation of cell autonomous immunity (but might concomitantly prolong the time individual patients may remain infectious for others) and it will be interesting to see whether clinical observations will confirm this notion.

 

References:

References:

[i][1] Koo YM, Heo AY, Choi HW.Salicylic Acid as a Safe Plant Protector and Growth Regulator. Plant Pathol J. 2020 Feb;36(1):1-10. doi: 10.5423/PPJ.RW.12.2019.0295.

[ii][2] Geng X1, Cheng J, Gangadharan A, Mackey D.  The coronatine toxin of Pseudomonas syringae is a multifunctional suppressor of Arabidopsis defense. Plant Cell. 2012 Nov;24(11):4763-74. doi: 10.1105/tpc.112.105312. Epub 2012 Nov 30.

[iii][3] Van der Does D, Leon-Reyes A, Koornneef A, Van Verk MC, Rodenburg N, Pauwels L, Goossens A, Körbes AP, Memelink J, Ritsema T, Van Wees SC, Pieterse CM. Salicylic acid suppresses jasmonic acid signaling downstream of SCFCOI1-JAZ by targeting GCC promoter motifs via transcription factor ORA59. Plant Cell. 2013 Feb;25(2):744-6

[iv][4] Ren LL, Wang YM, Wu ZQ, Xiang ZC, Guo L, Xu T, Jiang YZ, Xiong Y, Li YJ, Li XW, Li H, Fan GH, Gu XY, Xiao Y, Gao H, Xu JY, Yang F, Wang XM, Wu C, Chen L, Liu YW, Liu B, Yang J, Wang XR, Dong J, Li L, Huang CL, Zhao JP, Hu Y, Cheng ZS, Liu LL, Qian ZH, Qin C, Jin Q, Cao B, Wang JW. Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study. Chin Med J (Engl). 2020 Feb 11. doi: 10.1097/CM9.0000000000000722.

[v][5] Ji Y, Ma Z, Peppelenbosch MP, Pan Q. Potential association between COVID-19 mortality and health-care resource availability. Lancet Glob Health. 2020 Apr;8(4):e480. doi: 10.1016/S2214-109X(20)30068-1.

[vi][6]Brook CE, Boots M, Chandran K, Dobson AP, Drosten C, Graham AL, Grenfell BT, Müller MA, Ng M, Wang LF, van Leeuwen A. Accelerated viral dynamics in bat cell lines, with implications for zoonotic emergence. Elife. 2020 Feb 3;9. pii: e48401. doi: 10.7554/eLife.48401.

[vii][7] Wang W, Xu L, Su J, Peppelenbosch MP, Pan Q. Transcriptional Regulation of Antiviral Interferon-Stimulated Genes. Trends Microbiol. 2017 Jul;25(7):573-584. doi: 10.1016/j.tim.2017.01.001.

[viii][8] Hannigan GE, Williams BR.  Signal transduction by interferon-alpha through arachidonic acid metabolism. Science. 1991 Jan 11;251(4990):204-7.

[ix][9] Giambartolomei S, Artini M, Almerighi C, Moavero SM, Levrero M, Balsano C. Nonsteroidal anti-inflammatory drug metabolism potentiates interferon alfa signaling by increasing STAT1 phosphorylation. Hepatology. 1999 Aug;30(2):510-6

[x][10] Rajasagi NK, Bhela S, Varanasi SK, Rouse BT. Frontline Science: Aspirin-triggered resolvin D1 controls herpes simplex virus-induced corneal immunopathology. J Leukoc Biol. 2017 Nov;102(5):1159-1171. doi: 10.1189/jlb.3HI1216-511RR. Epub 2017 Jun 5.

[xi][11] Trujillo-Murillo K, Rincón-Sánchez AR, Martínez-Rodríguez H, Bosques-Padilla F, Ramos-Jiménez J, Barrera-Saldaña HA, Rojkind M, Rivas-Estilla AM.  Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways. Hepatology. 2008 May;47(5):1462-72

[xii][12] Coulombe F, Jaworska J, Verway M, Tzelepis F, Massoud A, Gillard J, Wong G, Kobinger G, Xing Z, Couture C4, Joubert P, Fritz JH, Powell WS, Divangahi M. Targeted prostaglandin E2 inhibition enhances antiviral immunity through induction of type I interferon and apoptosis in macrophages. Immunity. 2014 Apr 17;40(4):554-68. doi: 10.1016/j.immuni.2014.02.013. Epub 2014 Apr 10.

[xiii][13] Starko KM. Salicylates and pandemic influenza mortality, 1918-1919 pharmacology, pathology, and historic evidence. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2009; 49: 1405-1410

[xiv][14] Peteranderl C, Herold S. The Impact of the Interferon/TNF-Related Apoptosis-Inducing Ligand Signaling Axis on Disease Progression in Respiratory Viral Infection and Beyond. Front Immunol. 2017 Mar 22;8:313. doi: 10.3389/fimmu.2017.00313.

[xv][15] Amici C, Di Caro A, Ciucci A, Chiappa L, Castilletti C, Martella V, Decaro N, Buonavoglia C, Capobianchi MR, Santoro MG. Indomethacin has a potent antiviral activity against SARS coronavirus. Antivir Ther. 2006;11(8):1021-30.

 

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Daniel José Piñeiro

ASSOCIATE
Name
Daniel José Piñeiro
Academic Affiliations:
Full Professor of Medicine, Universidad de Buenos Aires, Argentina Trustee, Board of Trustees, American College of Cardiology
Professional Setting:
My academic experience includes more than 40 years as a practicing medical doctor, teacher, and researcher. I have fulfilled these appointments in settings of vital social engagement and impact, most notably at the Hospital de Clínicas “José de San Martín” of the Universidad de Buenos Aires, a public hospital with high academic recognition. Additionally, I currently hold the position of Full Professor of Medicine at that same University.
Academic Activities:
  • International Meetings Participations: 180
  • Books-Editor: 1
  • Books Chapters: 39
  • Refereed Full Articles: 118 (listed in Pubmed: 29)
  • Refereed Abstracts: 221
  • Editorial Boards: 10
Profesional Associations:
  • 2005 President, Sociedad Argentina de Cardiología.
  • 2011-2013 President, Inter-American Society of Cardiology.
  • 2011-2013 Member (ex-officio), Board of Directors, World Heart Federation
  • 2017-2018 Member (at large), Board of Directors, World Heart Federation
  • 2018-2021 Trustee, Board of Trustees, American College of Cardiology
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Chia

John Chia

Name
John Chia MBBS (Spore), MRCP (UK), FAMS (Spore)
Academic Affiliations:

Adjunct Associate Professor DUKE-NUS Graduate Medical School,
Consultant Oncologist Curie Oncology Singapore,
Visiting Consultant National Cancer Centre Singapore.

Discipline:

Medical Oncology

Scientific Interests:
  • Aspirin as adjuvant therapy in established cancers
  • Adoptive T cell therapy and Dendritic cell vaccines in the treatment of solid tumors
  • Clinical Trial Design and Management
Declaration of Conflicts of Interest:

In the past 3 years, I have received consultant fees from Tessa Therapeutics, Aslan Pharmaceuticals, Novartis, and AstraZeneca.

I received grant support for investigator-initiated research from:

  • National Medical Research Council Singapore
  • Bayer AG

I hold shares in:  Roche, BMS, AstraZeneca, Incyte, Teva Pharmaceuticals, Trillium Therapeutics, Compugen, Arrowhead pharmaceuticals, Emergex, QuantumDx and Halozyme Therapeutics

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Badimon

Lina Badimon

Name
Lina Badimon BSc, PharmD, PhD, FESC, FAHA
Academic Affiliations:
Director of the Cardiovascular Science Program (ICCC) at the Hospital Santa Creu and San Pau, IIB-Sant Pau; CIBER CV. Director of the Cardiovascular Research Chair of the Autonomous University of Barcelona and Director of the UNESCO Chair in Biomedical Sciences Training and Research.
Discipline:
Pharmacology, Cardiovascular Disease
Scientific Interests:
Cardio-metabolic diseases, thrombosis, atherosclerosis and ischemic heart disease
Declaration of Conflicts of Interest:

I received consultant and speakers fees from Amgen, AstraZeneca, Bayer, Lilly and Sanofi.

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    Ge

    Junbo Ge

    Name

    Junbo Ge

    Ge Junbo, male, was born in Wulian, Shandong province on Nov. 8, 1962. He is the member of Chinese Academy of Sciences, professor and doctoral supervisor. He received his doctor’s degree of Medicine from German Mayence University in 1993 and now works as the director for Shanghai Institute of Cardiovascular Disease and the Center for Stem Cells and Tissue Engineering, Fudan University. He is also the designate chairman of the Cardiovascular Disease Branch of Chinese Medical Association, council member of the Cardiovascular Angiography and Interventions Association, international consultant of the American Heart Association. In Dec. 2013, he was appointed as the vice president of Tongji University.

    Prof. Ge has been engaged in clinical and scientific research work of cardiovascular disease since 1987, and his research area covers the pathogenesis of coronary heart disease, early diagnosis and treatment plan optimization.

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    Langley

    Ruth Langley

    Name
    Ruth Langley PhD, FRCP
    Academic Affiliations:
    Professor of Oncology and Clinical Trials, MRC Programme Leader and Chair of the Cancer Group, MRC Clinical Trials Unit at UCL, honorary consultant in medical oncology at the Brighton and Sussex University Hospital.
    Discipline:
    Medical oncologist; trialist
    Scientific Interests:
    • Aspirin
    • Gastro-oesophageal malignancy
    • Transdermal oestrogen in the treatment of prostate cancer
    • Trials methodology
    Declaration of Conflicts of Interest:
    Has received honorarium from Bayer
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    Chan

    Andrew T Chan

    Name
    Andrew T. Chan MD, MPH
    Academic Affiliations:
    Chief, Clinical and Translational Epidemiology Unit, Vice Chair, Division of Gastroenterology, Massachusetts General Hospital, Boston, Co-leader, Cancer Epidemiology Program, Dana-Farber/Harvard Cancer Center, Boston.
    Discipline:
    Gastroenterology
    Scientific Interests:
    • The role of aspirin in the prevention of colorectal cancer and other cancers
    • The role of the gut microbiome in colorectal cancer and other chronic gastrointestinal diseases, including inflammatory bowel disease and diverticulitis
    • The role of diet and lifestyle in colorectal cancer and other chronic gastrointestinal cancers
    Declaration of Conflicts of Interest:

    AACR Honors Dr. Andrew T. Chan With 2019 AACR-Waun Ki Hong Award

    Click here to find the press release.

    I received consultant Bayer and Pfizer, Inc.

    I received grant support for investigator-initiated research from:

    • National Institutes of Health
    • National Cancer Institute
    • Crohn’s and Colitis Foundation
    • Bayer AG
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    Gaziano

    Mike Gaziano

    Name
    J Michael Gaziano MD, MPH
    Academic Affiliations:

    Professor of Medicine, Harvard Medical School; Chief Division of Aging, Brigham and Women’s Hospital; Director of Preventive Cardiology and Director of Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System.
    Discipline: Cardiology and Epidemiology

    Scientific Interests:
    I am a chronic disease epidemiologist with a particular interest in the roles that individual lifestyle choices (diet, exercise, smoking), metabolic factors (obesity, high cholesterol, and hypertension), and biochemical and genetic markers play on the risk of cardiovascular disease and other chronic illnesses. Also, of interest is the impact that vascular disease has on other organ systems, including cognitive dysfunction and renal disease. I have an interest in the design of large-scale trials and observational studies nested in large health care systems using big data analytic techniques.
    Declaration of Conflicts of Interest:

    I received consultant and speaker fees Bayer.

    I received grant support as a principal investigator or co-investigator for research from the VA, DOD, NIH, Merck and Kowa.

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    Pierre A Web Photo

    Pierre Amarenco

    Name

    Pierre Amarenco, MD, FAHA, FAAN

    Academic Affiliations:
    • Professor of Neurology at Paris-Diderot Sorbonne University 
    • Chairman of the Department of Neurology and Stroke Center; Bichat University Hospital
    • Co-Director INSERM Unit-698 “Clinical Research in Atherothrombosis”
    Discipline:

    Neurology and Vascular Neurology

    Scientific Interests:
    • Understanding and preventing stroke and vascular diseases
    • Clinical trials in prevention of vascular diseases
    • Carotid intima-media thickness studies
    • Lipid trials: prevention and therapeutic –protective- evaluation
    Declaration of Conflicts of Interest:

    N/A

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    CarloPatrono

    Carlo Patrono

    CHAIR
    Name
    Carlo Patrono MD, FESC, FRCP
    Academic Affiliations:
    Adjunct Professor of Pharmacology at the Catholic University School of Medicine in Rome (Italy) and at the Perelman School of Medicine of the University of Pennsylvania in Philadelphia (USA).
    Discipline:
    Clinical Pharmacology
    Scientific Interests:
    • Studying platelet activation and inhibition in diabetes mellitus
    • Studying platelet activation and inhibition in myeloproliferative neoplasms
    • Investigating the mechanism of action of low-dose aspirin in preventing colorectal cancer
    Declaration of Conflicts of Interest:

    I received consultant and speakers fees from Acticor Biotech,  Amgen,  Bayer, GlaxoSmithKline,  Tremeau,  Zambon.

    I received grant support for investigator-initiated research from:

    • AIFA (Italian Drug Agency)
    • Bayer AG
    • Cancer Research UK
    • European Commission, FP6 and FP7 Programmes

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