Exploring NFkB pathway as a potent strategy to mitigate COVID-19 severe morbidity and mortality


Submitted: 7 October 2020
Accepted: 25 April 2022
Published: 12 October 2022
Abstract Views: 216
PDF: 102
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Authors

  • Mubarak Muhammad Department of Physiology, College of Medicine, University of Ibadan, Nigeria. https://orcid.org/0000-0003-0001-5408
  • Tasneem M. Hassan Department of Physiotherapy, Aminu Kano Teaching Hospital, Kano, Nigeria.
  • Sani S. Baba Department of Human Physiology, College of Health Sciences, Bayero University Kano, Nigeria.
  • Mustapha I. Radda Department of Human Physiology, College of Health Sciences, Bayero University Kano, Nigeria.
  • Mubarak M. Mutawakkil Pharmacology and Therapeutics, College of Health Sciences, Bayero University Kano, Nigeria.
  • Majida A. Musa Pharmacology and Therapeutics, College of Health Sciences, Bayero University Kano, Nigeria.
  • Sazaly AbuBakar Tropical Infectious Diseases Research and Education Centre, Higher Institution Centre of Excellence, Universiti of Malaya, Kuala Lumpur, Malaysia.
  • Shih Keng Loong Tropical Infectious Diseases Research and Education Centre, Higher Institution Centre of Excellence, Universiti of Malaya, Kuala Lumpur, Malaysia.
  • Ibrahim Yusuf Department of Pathology, Aminu Kano Teaching Hospital, Kano, Nigeria.

The pandemic of coronavirus disease 2019 (COVID-19), for which there does not appear to be an approved cure, the primary treatment options consist of non-pharmacological preventive measures and supportive treatment that are aimed at halting the progression of the disease. Nuclear factor kappa B (NFkB) presents a promising therapeutic opportunity to mitigate COVID-19-induced cytokine storm and reduce the risk of severe morbidity and mortality resulting from the disease. However, the effective clinical application of NFkB modulators in COVID-19 is hampered by a number of factors that must be taken into consideration. This paper therefore explored the modulation of the NFB pathway as a potential strategy to mitigate the severe morbidity and mortality caused by COVID-19. The paper also discusses the factors that form the barrier, and it offers potential solutions to the various limitations that may impede the clinical use of NFkB modulators against COVID-19. This paper revealed and identified three key potential solutions for the future clinical use of NFkB modulators against COVID-19. These solutions are pulmonary tissue-specific NFkB blockade, agents that target common regulatory proteins of both canonical and non-canonical NFkB pathways, and monitoring clinical indicators of hyperinflammation and cytokine storm in COVID-19 prior to using NFkB modulators.


Berg MK, Yu Q, Salvador CE, et al. Mandated Bacillus Calmette-Guérin (BCG) vaccination predicts flattened curves for the spread of COVID-19. Science Advances 2020; 1-9. DOI: https://doi.org/10.1101/2020.04.05.20054163

Huang C, Wang Y, Li Z, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497-506. DOI: https://doi.org/10.1016/S0140-6736(20)30183-5

Labban L, Thallaj N, Labban A. Assessing the level of awareness and knowledge of covid 19 pandemic among Syrians. Archives of Medicine 2020; 12: 1-8. DOI: https://doi.org/10.36648/1989-5216.12.3.309

Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020; 1-7. DOI: https://doi.org/10.1016/S2213-2600(20)30079-5

Zheng J. SARS-CoV-2: an emerging coronavirus that causes a global threat. International Journal of Biological Sciences 2020; 16: 1678-1685. DOI: https://doi.org/10.7150/ijbs.45053

Singhal T. A review of coronavirus disease-2019 (COVID-19). The Indian Journal of Pediatrics 2020; 87: 281-286. DOI: https://doi.org/10.1007/s12098-020-03263-6

Rodriguez-Morales AJ, Cardona-Ospina JA, Gutierrez-Ocampo E, et al. Clinical laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Medicine and Infectious Disease 2020; 1-13. DOI: https://doi.org/10.1016/j.tmaid.2020.101623

Tay MZ, Poh CM, Rénia L, et al. The trinity of COVID-19: immunity, inflammation and intervention. Nature Reviews Immunology 2020; 20: 363-374. DOI: https://doi.org/10.1038/s41577-020-0311-8

Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. Journal of Autoimmunity 2020; 109: doi:10.1016/j.jaut.2020.102433 DOI: https://doi.org/10.1016/j.jaut.2020.102433

Fung S, Yuen K, Ye Z, et al. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerging Microbes & Infections 2020; 9: 558-570. DOI: https://doi.org/10.1080/22221751.2020.1736644

Tang Y, Liu J, Zhang D, et al. Cytokine storm in COVID-19: the current evidence and treatment strategies. Frontiers in Immunology 2020; 22: 1-13. DOI: https://doi.org/10.3389/fimmu.2020.01708

Bhaskar S, Sinha A, Banach M, et al. Cytokine storm in Covid 19- immunopathological mechanisms, clinical considerations, and therapeutic approaches: The reprogram consortium position paper. Frontiers in Immunology 2020; 11: 1648. DOI: https://doi.org/10.3389/fimmu.2020.01648

Sinha P, Matthay MA, Calfee CS. (2020) Is a “cytokine storm” relevant to COVID-19? JAMA Internal Medicine 2020; doi: https://jamanetwork.com/ DOI: https://doi.org/10.1001/jamainternmed.2020.3313

Ruan Q, Yang K, Wang W. et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Medicine 2020; 46: 846-8. DOI: https://doi.org/10.1007/s00134-020-05991-x

Huang H, Cai S, Li Y, et al. Prognostic factors for COVID-19 pneumonia progression to severe symptom based on the earlier clinical features: a retrospective analysis. medRxiv 2020;doi: 10.1101/2020.03.28.20045989 DOI: https://doi.org/10.1101/2020.03.28.20045989

Hadjadj J, Yatim N, Barnabei L, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.Science 2020; 1-14. DOI: https://doi.org/10.1126/science.abc6027

Chen F, Bower J, Demers JM, et al. Upstream signal transduction of NF-kB activation. Atlas of Genetics and Cytogenetics in Oncology and Haematology 2002; 6: 345-69.

Ahn KS, Aggarwal BB. Transcription factor NF-kappaB: a sensor for smoke and stress signals. Ann N Y AcadSci 2005; 1056: 218-33. DOI: https://doi.org/10.1196/annals.1352.026

Ragab D, Eldin HS, Taeimah M, et al. The covid-19 cytokine storm; what we know so far. Frontiers in Immunology 2020; 11: 1-4. DOI: https://doi.org/10.3389/fimmu.2020.01446

Ferrara JL, Abhyankar S, Gilliland DG. Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1. Transplant Proc 1993; 25: 1216-1217.

Barry SM, Johnson MA, Janossy G. Cytopathology or immunopathology? The puzzle of cytomegalovirus pneumonitis revisited. Bone Marrow Transplant 2000; 26: 591-597. DOI: https://doi.org/10.1038/sj.bmt.1702562

Huang KJ, Su I, Theron M, et al. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol 2005; 75: 185-194. DOI: https://doi.org/10.1002/jmv.20255

Chen G, Wu D, Guo W, et al. Clinical and immunological features in severe and moderate coronavirus disease 2019. J Clin Invest 2020; 130: 2620-2629. DOI: https://doi.org/10.1172/JCI137244

Chen L, Liu H, Liu W, et al. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Chinese Journal of Tuberclosis and Respiratory Diseases 2020; 43: 203-208.

Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: a review. Clinical Immunology 2020;215: 1-7. DOI: https://doi.org/10.1016/j.clim.2020.108427

Ullah A, Araf Y, Sarkar B, et al. Pathogenesis, diagnosis and possible therapeutic options for COVID-19. 2020; doi: https://doi.org/10.20944/preprints202004.0372.v1. DOI: https://doi.org/10.20944/preprints202004.0372.v1

Liu Y, Zhang C, Huang F, et al. 2019-novel coronavirus (2019-nCoV) infections trigger an exaggerated cytokine response aggravating lung injury.http://www.chinaxiv.org/abs/202002.00018.

Chen C, Zhang XR, Ju ZY, et al. Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies. ZhonghuaShaoshangZazhi 2020; 36: E005.

Rockx B, Kuiken T, Herfst S, et al. Comparative pathogenesis of COVID-19, MERS and SARS in a non-human primate model. 2020; doi: https://doi.org/10.1101/2020.03.17.995639 DOI: https://doi.org/10.1101/2020.03.17.995639

Tan W, Aboulhosn J. The cardiovascular burden of coronavirus disease 2019 (COVID-19) with a focus on congenital heart disease.International Journal of Cardiology 2020; doi:https://doi.org/10.1016/j.ijcard.2020.03.063 DOI: https://doi.org/10.1016/j.ijcard.2020.03.063

Gao Y, Li T, Han M, et al. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J Med Virol 2020; 92:791-796. DOI: https://doi.org/10.1002/jmv.25770

Sun D, Li H, Lu X, et al. Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center’s observational study. World J Pediatr 2020; 19: 1-9. DOI: https://doi.org/10.1007/s12519-020-00354-4

Wan S, Yi Q, Fan S, et al. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP). medRxiv 2020; doi: https://doi.org/10.1101/2020.02.10.20021832 DOI: https://doi.org/10.1101/2020.02.10.20021832

Feldmann M, Maini NR, Woody NJ, et al. Trials of anti-tumor necrosis factor therapy for COVID-19 are urgently needed. The Lancet 2020; 395: doi:https://doi.org/10.1016/S0140-6736(20)30858-8. DOI: https://doi.org/10.1016/S0140-6736(20)30858-8

Convertino I, Tuccori M, Ferraro S, et al. Exploring pharmacological approaches for managing cytokine storm associated with pneumonia and acute respiratory distress syndrome in COVID-19 patients.Critical Care 2020; 24: 331. DOI: https://doi.org/10.1186/s13054-020-03020-3

Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression The Lancet 2020; 395: 1033-1034. DOI: https://doi.org/10.1016/S0140-6736(20)30628-0

Cao X. COVID-19: immunopathology and its implications for therapy. Nature Reviews Immunology 2020; 20: 269-270. DOI: https://doi.org/10.1038/s41577-020-0308-3

Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. Journal of Infection 2020; 80: 607-613. DOI: https://doi.org/10.1016/j.jinf.2020.03.037

Rosa SGV, Santos WC. Clinical trials on drug repositioning for COVID-19 treatment. Pan American Health Organisation 2020; 44: doi:10.26633/RPSP.2020.40 DOI: https://doi.org/10.26633/RPSP.2020.40

Shi Y, Wang Y, Shao C, et al. COVID-19 infection: the perspectives on immune responses. Cell Death & Differentiation 2020; 27: 1451-1454. DOI: https://doi.org/10.1038/s41418-020-0530-3

Sanders J, Monogue ML, Jodlowski TZ, et al. Pharmacologic treatments for coronavirus disease 2019 (covid-19) a review. JAMA 2020; 323:1824-1836. DOI: https://doi.org/10.1001/jama.2020.6019

Lannaccone G, Scacciavillani R, Buono MGD, et al. Weathering the cytokine storm in COVID-19: therapeutic implications. Cardiorenal Med 2020; doi:10.1159/000509483 DOI: https://doi.org/10.1159/000509483

Birra D, Benucci M, Landolfi L, et al. COVID 19: a clue from innate immunity. Immunologic Research 2020; 68: 161-168. DOI: https://doi.org/10.1007/s12026-020-09137-5

Gautret P, Lagier J, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents 2020; 56:doi:https://doi.org/10.1016/j.ijantimicag.2020.105949 DOI: https://doi.org/10.1016/j.ijantimicag.2020.106063

Saqrane S El Mhammedi MA. Review on the global epidemiological situation and efficacy of chloroquine and hydroxychloroquine for the treatment of COVID-19. New Microbes and New Infections 2020; 35: doi:https://doi.org/10.1016/j.nmni.2020.100680 DOI: https://doi.org/10.1016/j.nmni.2020.100680

Qia A, Wua Y, Dong N, et al. Recombinant human ulinastatin improves immune dysfunction of dendritic cells in septic mice by inhibiting endoplasmic reticulum stress-related apoptosis. International Immunopharmacology 2020; 85: doi: https://doi.org/10.1016/j.intimp.2020.106643 DOI: https://doi.org/10.1016/j.intimp.2020.106643

Horby P, Lim WS, Emberson J, et al. Effect of dexamethasone in hospitalized patients with COVID-19 – preliminary report. medRxiv 2020; 1-14. DOI: https://doi.org/10.1101/2020.06.22.20137273

Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: Secondary brain injury. Stroke 2011; 42: 1781-1786. DOI: https://doi.org/10.1161/STROKEAHA.110.596718

Berlo DV, Knaapen AD, Schooten RP, et al. NFkB dependent and independent mechanisms of quartz-induced proinflammation activation of lung epithelial cells. Particle Fibre Toxicology 2010; 7: 1-20. DOI: https://doi.org/10.1186/1743-8977-7-13

Oeckinghaus A, Ghosh S. The NFkB family of transcription factors and its regulation. Cold Spring Harbor Perspective in Biology 2009; 1: 1-14 DOI: https://doi.org/10.1101/cshperspect.a000034

Grumolato L, Liu G, Mong P, et al. Canonical and noncanonicalWnts use a common mechanism to activate completely unrelated coreceptors. Genes Development 2010; 24: 2517-2530. DOI: https://doi.org/10.1101/gad.1957710

Sun SC. The non-canonical NF-KB pathway and inflammation.; Nat Rev Iimmunol 2017; 17(9): 545-558. DOI: https://doi.org/10.1038/nri.2017.52

Bonizzi G, Karin M. (2004). The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends in Immunology 2004; 25: 280-288. DOI: https://doi.org/10.1016/j.it.2004.03.008

Gilmore TD. (2006). Introduction to NF-kappaB: players, pathways, perspectives. Oncogene 2006; 25: 6680-6684. DOI: https://doi.org/10.1038/sj.onc.1209954

Tornatore L, Thotakura AK, Bennett J, et al. The nuclear factor kappa B signaling pathway: integrating metabolism with inflammation. Trends in Cell Biology 2012; 22: 557-566. DOI: https://doi.org/10.1016/j.tcb.2012.08.001

Tergaonkar V. NFkB pathway: A good signaling paradigm and therapeutic target. Int J Biochem Cell Biol 2006; 38: 1647-1653. DOI: https://doi.org/10.1016/j.biocel.2006.03.023

Scheidereit C. IkB kinase complexes: gateways to NFkB activation and transcription. Oncogene 2006; 25: 6685-6705. DOI: https://doi.org/10.1038/sj.onc.1209934

Liao Q, Ye L, Timani KA, et al. Activation of NF-κB by the full-length nucleocapsid protein of the SARS coronavirus.ActaBiochimicaetBiophysicaSinica 2005; 37: 607-612. DOI: https://doi.org/10.1111/j.1745-7270.2005.00082.x

Vitiello M, Galdiero M, Finamore E, et al. NF-kB as a potential therapeutic target in microbial diseases. Molecular BioSystem 2012; 8: 1108-1120. DOI: https://doi.org/10.1039/c2mb05335g

Vrankova S, Barta A, Klimentova J, et al. The regulatory role of nuclear factor kappa B in the heart of hereditary hypertriglyceridemicrat.Oxidative Medicine and Cellular Longevity 2016; 1-6. DOI: https://doi.org/10.1155/2016/9814038

Herrington FD, Carmody RJ, Goodyear CS. Modulation of NF-κB signaling as a therapeutic target in autoimmunity. Journal of Biomolecular Screening 2016; 21: 223-242. DOI: https://doi.org/10.1177/1087057115617456

Biswas DK, Dai S, Cruz A, et al. The nuclear factor kappa B (NF-kB): A potential therapeutic target for estrogen receptor negative breast cancers. PNAS 2001; 98: 10386-10391. DOI: https://doi.org/10.1073/pnas.151257998

Plewka D, Plewka A, Miskiewicz A, et al. Nuclear factor-kappa B as potential therapeutic target in human colon cancer. J Can Res Ther 2018; 14:516-20. DOI: https://doi.org/10.4103/0973-1482.180607

Yan J, Greer JM. NF-kB, a potential therapeutic target for the treatment of multiple sclerosis.CNS & Neurological Disorders - Drug Targets 2008;7: 536-557. DOI: https://doi.org/10.2174/187152708787122941

Jha NK, Jha SK, Kar R, et al. Nuclear factor-kappa β as a therapeutic target for Alzheimer’s disease. Journal of Neurochemistry 2019; 150: 113-137. DOI: https://doi.org/10.1111/jnc.14687

Roman-Blas JA, Jimenez SA. NF-kB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis.OsteoArthritis and Cartilage 2006; 14: 839-848. DOI: https://doi.org/10.1016/j.joca.2006.04.008

Pinto R, Herold S, Cakarova L, et al. Inhibition of influenza virus-induced NF-kappaB and Raf/MEK/ERK activation can reduce both virus titers and cytokine expression simultaneously in vitro and in vivo. Antiviral Research 2011; 92: 45-56. DOI: https://doi.org/10.1016/j.antiviral.2011.05.009

Wiesener N, Zimmer C, Jarasch-Althof N, et al. Therapy of experimental influenza virus infection with pyrrolidinedithiocarbamate. Med MicrobiolImmunol 2011; doi: 10.1007/s00430-010-0182-

Zang N, Xie X, Deng Y, et al. Resveratrol-mediated gamma interferon reduction prevents airwayinflammation and airway hyperresponsiveness in respiratory syncytialvirus-infected immunocompromised mice. J Virol 2011; 85:13061-13068. DOI: https://doi.org/10.1128/JVI.05869-11

DeDiego ML, Nieto-Torres JL, Regla-Nava JA, et al. Inhibition of NF-kappaB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival. Journal of Virology 2014; 88: 913-924. DOI: https://doi.org/10.1128/JVI.02576-13

Elkhodary MSM. Treatment of COVID-19 by controlling the activity of the nuclear factor- kappa B. Cell Biology 2020; 9: 109-121. DOI: https://doi.org/10.4236/cellbio.2020.92006

Catanzaro M, Fagiani F, Racchi M, et al. Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. Signal Transduction and Targeted Therapy 2020; 5: 1-10. DOI: https://doi.org/10.1038/s41392-020-0191-1

Fitzgerald KA, Kagan JC. Toll-like receptors and the control of immunity. Cell 2020; 180:1044-66. DOI: https://doi.org/10.1016/j.cell.2020.02.041

Zhang X, Zhu Z, Jiao W, et al. Ulinastatin treatment for acute respiratory distress syndrome in China: a meta-analysis of randomized controlled trials. Pulmonary Medicine 2019; 19: 196. DOI: https://doi.org/10.1186/s12890-019-0968-6

Barnes PJ, Karin M. Nuclear factor-kB: a pivotal transcription factor in chronic inflammatory diseases. The New England Journal of Medicine 1997; 336: 1066-1071. DOI: https://doi.org/10.1056/NEJM199704103361506

Bowie A, O’Neill LA. Oxidative stress and nuclear factor-kB activation: a reassessment of the evidence in the light of recent discoveries. Biochemical Pharmacology 2000; 59: 13-23. DOI: https://doi.org/10.1016/S0006-2952(99)00296-8

Shi H, Berger EA. Characterization of site-specific phosphorylation of NF-κB p65 in retinal cells in response to high glucose and cytokine polarization. Mediators of Inflammation 2018; 1-15. DOI: https://doi.org/10.1155/2018/3020675

Muhammad M. Tumor necrosis factor alpha: a major cytokine of brain neuroinflammation. Croatia: IntechOpen 2019; 1-14. DOI: https://doi.org/10.5772/intechopen.85476

Gilmore TD, Herscovitch M. Inhibitors of NF-kB signaling: 785 and counting. Oncogene 2006; 25: 6887-6899. DOI: https://doi.org/10.1038/sj.onc.1209982

Muhammad, M., Hassan, T. M., Baba, S. S., Radda, M. I., Mutawakkil, M. M., Musa, M. A., AbuBakar, S., Loong, S. K., & Yusuf, I. (2022). Exploring NFkB pathway as a potent strategy to mitigate COVID-19 severe morbidity and mortality. Journal of Public Health in Africa, 13(3). https://doi.org/10.4081/jphia.2022.1679

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