NLRP3 Inflammasome: A Novel Drug Target for Treating Severely Ill COVID-19 Patients

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Several studies indicate that activation of NLRP3 inflammasome is responsible for acute respiratory distress syndrome and/or acute lung injury (ARDS/ALI) seen in severely ill COVID-19 patients which often result in death due to multiple organ failure. This suggests NLRP3 may be playing a very significant role in clinical course. Hence, there is an urgent need to put this hypothesis to test for exploring NLRP3 as a possible drug target to combat COVID-19.

NLRP3 Inflammasome

COVID-19 disease has played havoc around the world affecting the millions of lives and disrupting the entire world economy. Researchers in several countries are working against time to find a cure to combat COVID-19 so that people can be cured quickly and normalcy can be returned. The main strategies being exploited currently include developing novel and repurposing existing drugs1,2 that are based upon, the drug targets identified by studying viral host interactions, targeting viral proteins to arrest viral multiplication and vaccine development. Understand the pathology of COVID-19 disease in further detail by understanding its mechanism of action, can lead to identification of novel drug targets that can be used to develop new and repurpose existing drugs against these targets.

While majority (~80%) of COVID-19 disease patients develop mild fever, cough, experience muscle pain and recover in a span of 14-38 days, most severely ill patients and those who do not recover develop acute respiratory distress syndrome and/or acute lung injury (ARDS/ALI), leading to multiple organ failure resulting in death3. Cytokine storm has been implicated in the development of ARDS/ALI4. This cytokine storm is possibly triggered by the activation of NLRP3 inflammasome (a multimeric protein complex that initiates inflammatory responses upon activation by various stimuli5) by SARS-CoV-2 proteins6-9 which implicates NLRP3 as a major pathophysiological component in the development of ARDS/ALI10-14, that leads to respiratory failure in patients.

NLRP3 plays an important role in the innate immune system. In a normal physiological condition, NLRP3 exists in an inactive state bound by specific proteins in the cytoplasm. Upon activation by stimuli, it triggers inflammatory responses that ultimately causes death of infected cells which are cleared from the system, and NLRP3 returns to its inactive state. NLRP3 inflammasome also contributes to platelet activation, aggregation and thrombus formation in vitro15. However, in a pathophysiological condition such as COVID-19 infection, dysregulated activation of NLRP3 occurs causing a cytokine storm. The release of proinflammatory cytokines causes infiltration of alveoli in the lungs leading to fulminant pulmonary inflammation and subsequent respiratory failure but also may cause thrombosis by rupturing of plaques in vessels due to inflammation. Inflammation of heart muscle has been in a substantial portion of patients hospitalised with COVID-1916.

In addition, NLRP3 inflammasome has been shown, upon specific stimulation, to participate in male infertility pathogenesis via inflammatory cytokine induction in Sertoli cells17.

Therefore, in view of the above-mentioned roles, NLRP3 inflammasome appears to be playing a very significant role in clinical course of severely ill COVID-19 patients. Hence, there is an urgent need to put this hypothesis to test for exploring NLRP3 inflammasome as a drug target to combat COVID-19. This hypothesis is being put to test by Greek scientists who have planned a randomised clinical trial study called GRECCO-19 to investigate inhibitory effects of colchicine on NLRP3 inflammasome18.

In addition, studies on roles of NLRP3 inflammasome will also provide further insights about the pathology and progression of the COVID-19 disease. This will help clinicians better manage patients especially those with co-morbidities such as cardiovascular disease and elderly patients. In elderly patients, the age-related defects in T and B-cells causes increased expression of cytokines, leading to more prolonged proinflammatory responses, potentially leading to poor clinical outcome16.

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References:

1. Soni R., 2020. A Novel Approach to ‘Repurpose’ Existing Drugs For COVID-19. Scientific European. Posted 07 May 2020. Available online at https://www.scientificeuropean.co.uk/a-novel-approach-to-repurpose-existing-drugs-for-COVID-19 Accessed on 08 May 2020.

2. Soni R., 2020. Vaccines for COVID-19: Race Against Time. Scientific European. Posted 14 April 2020. Available online at https://www.scientificeuropean.co.uk/vaccines-for-covid-19-race-against-time Accessed on 07 May 2020.

3. Liming L., Xiaofeng L., et al 2020. An update on the epidemiological characteristics of novel coronavirus pneumonia(COVID-19). Chinese Journal of Epidemiology, 2020,41: Online pre-publishing. DOI:

4. Chousterman BG, Swirski FK, Weber GF. 2017. Cytokine storm and sepsis disease pathogenesis. Seminars in Immunopathology. 2017 Jul;39(5):517-528. DOI: https://doi.org/10.1007/s00281-017-0639-8

5. Yang Y, Wang H, Kouadir M, et al., 2019. Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death and Disease 10, Article number:128 (2019). DOI: https://doi.org/10.1038/s41419-019-1413-8

6. Nieto-Torres JL, Verdiá-Báguena,C., Jimenez-Guardeño JM et al. 2015. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology, 485 (2015), pp. 330-339, DOI: https://doi.org/10.1016/j.virol.2015.08.010

7. Shi CS, Nabar NR, et al 2019. SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes. Cell Death Discovery, 5 (1) (2019) p. 101, DOI: https://doi.org/10.1038/s41420-019-0181-7

8. Siu KL, Yuen KS, et al 2019. Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. FASEB J, 33 (8) (2019), pp. 8865-8877, DOI: https://doi.org/10.1096/fj.201802418R

9. Chen LY, Moriyama, M., et al 2019. Severe Acute Respiratory Syndrome Coronavirus Viroporin 3a Activates the NLRP3 Inflammasome. Frontier Microbiology, 10 (Jan) (2019), p. 50, DOI: https://doi.org/10.3389/fmicb.2019.00050

10. Grailer JJ, Canning BA, et al. 2014. Critical Role for the NLRP3 Inflammasome during Acute Lung Injury. J Immunol, 192 (12) (2014), pp. 5974-5983. DOI: https://doi.org/10.4049/jimmunol.1400368

11. Li D, Ren W, et al, 2018. Regulation of the NLRP3 inflammasome and macrophage pyroptosis by the p38 MAPK signaling pathway in a mouse model of acute lung injury. Mol Med Rep, 18 (5) (2018), pp. 4399-4409. DOI: https://doi.org/10.3892/mmr.2018.9427

12. Jones HD, Crother TR, et al 2014.The NLRP3 inflammasome is required for the development of hypoxemia in LPS/mechanical ventilation acute lung injury. Am J Respir Cell Mol Biol, 50 (2) (2014), pp. 270-280. DOI: https://doi.org/10.1165/rcmb.2013-0087OC

13. Dolinay T, Kim YS, et al 2012. Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am J Respir Crit Care Med, 185 (11) (2012), pp. 1225-1234. DOI: https://doi.org/10.1164/rccm.201201-0003OC

14. Bulgarian Academy of Sciences 2020. News – New clinical evidence confirms the hypothesis of scientists of BAS for the role of NLRP3 inflammasome in the pathogenesis of complications in COVID-19. Posted 29 April 2020. Available online at http://www.bas.bg/en/2020/04/29/new-clinical-evidence-confirms-the-hypothesis-of-scientists-of-bas-for-the-role-of-nlrp3-inflammasome-in-the-pathogenesis-of-complications-in-covid-19/ Accessed on 06 May 2020.

15. Qiao J, Wu X, et al. 2018. NLRP3 Regulates Platelet Integrin ΑIIbβ3 Outside- InSignaling, Hemostasis And Arterial Thrombosis. Haematologica September 2018 103: 1568-1576; DOI: https://doi.org/10.3324/haematol.2018.191700

16. Zhou F, Yu T, et al. 2020. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet (March 2020). DOI: https://doi.org/10.1016/s0140-6736(20)30566-3

17. Hayrabedyan S, Todorova K, Jabeen A, et al. 2016. Sertoli cells have a functional NALP3 inflammasome that can modulate autophagy and cytokine production. Nature Scientific Reports volume 6, Article number: 18896 (2016). DOI: https://doi.org/10.1038/srep18896

18. Deftereos SG, Siasos G, Giannopoulos G, Vrachatis DA, et al. 2020. The Greek study in the effects of colchicine in COVID-19 complications prevention (GRECCO-19 study): Rationale and study design. ClinicalTrials.gov Identifier: NCT04326790. Hellenic Journal of Cardiology (in press). DOI: https://doi.org/10.1016/j.hjc.2020.03.002

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