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

Mubarak Muhammad; Tasneem M. Hassan; Sani S. Baba; Mustapha I. Radda; Mubarak M. Mutawakkil; Majida A. Musa; Sazaly AbuBakar; Shih Keng Loong; Ibrahim Yusuf

doi:10.4081/jphia.2022.1679

Authors

Mubarak Muhammad
mmuhammad6584@stu.ui.edu.ng
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