Molecular chronicles of cytokine burst in patients with coronavirus disease 2019 (COVID-19) with cardiovascular diseases

Abstract

Central MessageThe strong association between COVID-19 and CVD comorbidity points toward the COVID-19–mediated dysregulation of ACE2 and subsequent activation of multiple proinflammatory signaling pathways.PerspectiveThe molecular associations of ACE2 signaling axis regarding CVDs are interconnected with the major sheddases (ADAM-17 and CTSL), TLRs, and NLRP3 inflammasome, contributing to the overall proinflammatory pool and subsequent cytokine burst leading to aggravated COVID-19–CVD comorbidity. Understanding the potential targets in these associations exhibits immense translational significance.See Commentaries on pages e227 and e228. The strong association between COVID-19 and CVD comorbidity points toward the COVID-19–mediated dysregulation of ACE2 and subsequent activation of multiple proinflammatory signaling pathways. The molecular associations of ACE2 signaling axis regarding CVDs are interconnected with the major sheddases (ADAM-17 and CTSL), TLRs, and NLRP3 inflammasome, contributing to the overall proinflammatory pool and subsequent cytokine burst leading to aggravated COVID-19–CVD comorbidity. Understanding the potential targets in these associations exhibits immense translational significance. See Commentaries on pages e227 and e228. The emergence and pandemic spread of an acute respiratory disease caused due to a novel strain of SARS-Cov-2 (severe acute respiratory syndrome coronavirus 2), COVID-19 (coronavirus disease 2019) continues to threaten the global population. The increased rate of COVID-19 infection has resulted in a global health crisis and caused a huge economic burden in affected nations across the globe. The virus is believed to originate in bats and transmitted to humans possibly through an unknown carrier species in Wuhan, Hubei province, China, sometime in December 2019.1Singhal T. A review of coronavirus disease-2019 (COVID-19).Indian J Pediatr. 2020; 87: 281-286Crossref PubMed Scopus (1750) Google Scholar However, proper scientific evidence is currently unavailable to prove/refute this theory, and extensive investigations have been initiated to unveil this mystery. Also, the entire world is hoping on medical sciences and medical research to tame COVID-19. As of May 10, 2020, about 4.1 million confirmed cases with more than 282,500 deaths have been reported globally. The incidence in most affected countries as of May 10, 2020, include 1.35 million cases and 80,246 deaths in the United States, ∼224,000 cases and 26,478 deaths in Spain, ∼218,000 cases and 30,395 deaths in Italy, ∼215,000 cases and 31,587 deaths in the United Kingdom, and ∼199,000 cases and 1824 deaths in Russia.2COVID-19 Coronavirus (COVID-19) map.https://google.com/covid19-mapDate accessed: May 10, 2020Google Scholar Unfortunately, the number of confirmed cases and mortality are increasing at an alarming rate. In addition, the recent studies revealed the basic reproduction number (R0) of COVID-19 to be around 2.2, which is in the range of 1.4 to 6.5.3Liu Y. Gayle A.A. Wilder-Smith A. Rocklöv J. The reproductive number of COVID-19 is higher compared to SARS coronavirus.J Travel Med. 2020; 27: taaa021Crossref PubMed Scopus (1715) Google Scholar This suggests that each patient with COVID-19 could infect 2.2 people. Fundamentally, the R0 values represent the spread of an infection and R0 > 1 is an indication of population/community spread.4Fraser C. Donnelly C.A. Cauchemez S. Hanage W.P. Van Kerkhove M.D. Hollingsworth T.D. et al.Pandemic potential of a strain of influenza A (H1N1): early findings.Science. 2009; 324: 1557-1561Crossref PubMed Scopus (1515) Google Scholar The incubation period of COVID-19 after the transmission via inhalation or contact with infected droplets from the respiratory tract of infected individual is usually around 2 weeks, and the individual is asymptomatic during the initial incubation phase.1Singhal T. A review of coronavirus disease-2019 (COVID-19).Indian J Pediatr. 2020; 87: 281-286Crossref PubMed Scopus (1750) Google Scholar Moreover, the usual symptoms include fever, dry cough, sore throat, fatigue, weakness, and breathing/swallowing difficulties.5Guo Y.-R. Cao Q.-D. Hong Z.-S. Tan Y.Y. Chen S.D. Jin H.J. et al.The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak—an update on the status.Mil Med Res. 2020; 7: 11Crossref PubMed Scopus (2472) Google Scholar The disease is mild-to-moderate in healthy individuals; however, is severe-to-fatal in elderly population and those with other comorbidities, including diabetes and cardiovascular diseases (CVDs), leading to pneumonia, acute respiratory distress syndrome, and subsequently to organ failure.1Singhal T. A review of coronavirus disease-2019 (COVID-19).Indian J Pediatr. 2020; 87: 281-286Crossref PubMed Scopus (1750) Google Scholar Supportive treatments are being administered to patients with COVID-19; however, specific antiviral agents are warranted. On January 22, 2020, World Health Organization coined the term COVID-19 and Coronavirus Study Group of the International Committee defined COVID-19 as SARS-CoV-2 on February 11, 2020. Immediately after the outbreak in Wuhan, the Chinese researchers succeeded to isolate and sequence the COVID-19 genome, which opened further research opportunities in COVID-19 management.5Guo Y.-R. Cao Q.-D. Hong Z.-S. Tan Y.Y. Chen S.D. Jin H.J. et al.The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak—an update on the status.Mil Med Res. 2020; 7: 11Crossref PubMed Scopus (2472) Google Scholar Apart from the respiratory system, COVID-19 has a severe pathologic impact on other organs, especially in the cardiovascular system, as evident from the increased risk of mortality and infection among patients with CVD. For instance, a recent case report from Washington State revealed congestive heart failure to be the second most common baseline comorbidity (∼43%) next to the renal failure (47.6%) in subjects with COVID-19.6Arentz M. Yim E. Klaff L. Sharukh L. Francis X.R. Maria C. et al.Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State.JAMA. 2020; 323: 1612-1614Crossref PubMed Scopus (1399) Google Scholar Specifically, cardiac arrhythmias, acute myocardial infarction (MI), myocarditis, and cardiac failure are the potential cardiovascular complications associated with COVID-19 infection.7Zhang J.-J. Dong X. Cao Y.-Y. Yuan Y. Yang Y. Yan Y.-Q. et al.Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.Allergy. February 19, 2020; ([Epub ahead of print])Crossref Scopus (2210) Google Scholar, 8Wang D. Hu B. Hu C. Zhu F. Liu X. Zhang J. et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; 323: 1061-1069Crossref PubMed Scopus (13779) Google Scholar, 9Xu X.-W. Wu X.-X. Jiang X.-G. Xu K.-J. Ying L.-J. Ma C.-L. et al.Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series.BMJ. 2020; 368: m606Crossref PubMed Scopus (1291) Google Scholar Unfortunately, very limited information is available on the underlying molecular mechanisms associated with the aggravated CVD pathology in patients with COVID-19. At this juncture, the major focus of this article is to provide insight into the possible molecular signaling, which may identify target(s) and pave multiple ways to intervene the CVD complications in subjects with COVID-19. COVID-19 belongs to coronaviruses, which are positive-stranded RNA viruses of the order Nidovirales, family Coronaviridae, and the sub-family Orthocoronavirinae. In general, the corona viruses are classified into 4 genera (α-coronavirus, β-coronavirus, δ-coronavirus, and γ-coronavirus).10Chan J.F.-W. To K.K.-W. Tse H. Jin D.-Y. Yuen K.-Y. Interspecies transmission and emergence of novel viruses: lessons from bats and birds.Trends Microbiol. 2013; 21: 544-555Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar The genetic constitution studies and evolutionary analysis support bats and rodents to be the possible source of α-coronavirus and β-coronavirus, whereas δ-coronavirus and γ-coronavirus are expected to be derived from avian species.11Cascella M. Rajnik M. Cuomo A. Dulebohn S.C. Di Napoli R. Features, evaluation and treatment coronavirus (COVID-19).http://www.ncbi.nlm.nih.gov/books/NBK554776/Date accessed: March 31, 2020Google Scholar The characteristic crown-like morphology under the electron microscope due to the presence of spike glycoproteins on their surface covering the envelope reminiscent of the solar corona gave the name corona virus to this virus family because the word coronam means crown in Latin.11Cascella M. Rajnik M. Cuomo A. Dulebohn S.C. Di Napoli R. Features, evaluation and treatment coronavirus (COVID-19).http://www.ncbi.nlm.nih.gov/books/NBK554776/Date accessed: March 31, 2020Google Scholar COVID-19 is a β-coronavirus, which exists in round, elliptic, and pleomorphic morphology with average diameter of 60 to 140 nm. Moreover, sensitivity to heat and ultraviolet rays are their characteristics. Hence, it is logical that COVID-19 can be effectively inactivated by organic solvents and detergents due to the solubility of constituent lipids from their envelope.11Cascella M. Rajnik M. Cuomo A. Dulebohn S.C. Di Napoli R. Features, evaluation and treatment coronavirus (COVID-19).http://www.ncbi.nlm.nih.gov/books/NBK554776/Date accessed: March 31, 2020Google Scholar COVID-19 shares 89% sequence identity with bat SARS-like-CoVZXC21 and 82% with human SARS-CoV; therefore, it's named SARS-CoV-2.12Chan J.F.-W. Kok K.-H. Zhu Z. Chu H. To K.K. Yuan S. et al.Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan.Emerg Microbes Infect. 2020; 9: 221-236Crossref PubMed Scopus (1755) Google Scholar The phylogenic analysis based on receptor similarities revealed the possibilities of intermediate hosts, including pangolin, turtles, and snakes.13Liu Z. Xiao X. Wei X. Li J. Yang J. Tan H. et al.Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2.J Med Virol. 2020; 92: 595-601Crossref PubMed Scopus (439) Google Scholar The transmission of COVID-19 is human-to-human, mainly among those who has intimate contact with the patients or incubation carriers; however, the transmission routine is still unknown.11Cascella M. Rajnik M. Cuomo A. Dulebohn S.C. Di Napoli R. Features, evaluation and treatment coronavirus (COVID-19).http://www.ncbi.nlm.nih.gov/books/NBK554776/Date accessed: March 31, 2020Google Scholar Symptomatic people have been the predominant source of COVID-19 spread, whereas the risk of transmission by pre-symptomatic/asymptomatic patients is also very high. This suggests that the isolation of patients with COVID-19 and carriers is an ideal preventive measure to control the spread of COVID-19. In addition, aerosol transmission has been reported to be a potent means for COVID-19 transmission, which occurs via the respiratory aerosols discharged by patients while sneezing or coughing.5Guo Y.-R. Cao Q.-D. Hong Z.-S. Tan Y.Y. Chen S.D. Jin H.J. et al.The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak—an update on the status.Mil Med Res. 2020; 7: 11Crossref PubMed Scopus (2472) Google Scholar The nasal droplets carry greater viral load and are reported to spread 1 to 2 meters in diameter and are deposited on surfaces. COVID-19 is capable of surviving on various surfaces for several days; however, it can be destroyed by the disinfectants within a minute.14Kampf G. Todt D. Pfaender S. Steinmann E. Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents.J Hosp Infect. 2020; 104: 246-251Abstract Full Text Full Text PDF PubMed Scopus (2121) Google Scholar The possibilities of COVID-19 transmission via stool and contaminated water have also been hypothesized, which warrant further scientific proof.15Chen H. Guo J. Wang C. Luo J. Yu X. Zhang W. et al.Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records.Lancet Lond Engl. 2020; 395: 809-815Abstract Full Text Full Text PDF PubMed Scopus (2301) Google Scholar Even though the evidence for vertical transplantation is unavailable, a case of postnatal transmission has been reported.15Chen H. Guo J. Wang C. Luo J. Yu X. Zhang W. et al.Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records.Lancet Lond Engl. 2020; 395: 809-815Abstract Full Text Full Text PDF PubMed Scopus (2301) Google Scholar Moreover, it is believed that the proinflammatory microenvironment created by COVID-19 infection results in increased metabolic demand, leading to secondary complications including CVD malfunction.16Rali A.S. Sauer A.J. COVID-19 Pandemic and cardiovascular disease.US Cardiol Rev. 2020; 14: e01Crossref Scopus (12) Google Scholar Hence, this could be the possible explanation for the increased mortality rate in elderly patients and patients who have inflammatory or metabolic disorders. Further studies are required to unveil the underlying molecular pathology. In the current pandemic scenario of COVID-19, it is worthy to mention 2 major virulent strains; the S and L strains. S type is the ancestral strain from which L type was evolved due to the single-nucleotide polymorphism at position 8782. Alternatively, we are lacking proper scientific evidence whether the evolution of L strain occurred in humans or in the intermediate host. Furthermore, the L-type strain (∼70%) exhibits more virulence and is more contagious when compared with the S strain (∼30%).17Tang X. Wu C. Li X. Song Y. Yao X. Wu X. et al.On the origin and continuing evolution of SARS-CoV-2.Natl Sci Rev. 2020; : nwaa036Google Scholar Also, the molecular mechanisms underlying the strain switch are unknown, which recommends further research. COVID-19 is an enveloped positive-stranded RNA virus with a nucleocapsid. The +ssRNA of viral genome is ∼30 kb long and contains a 5′-cap and 3′-poly-A tail, and the COVID-19 strain isolated from Wuhan is 29.9 kb.18Wu F. Zhao S. Yu B. Chen Y.-M. Wang W. Song Z.-G. et al.A new coronavirus associated with human respiratory disease in China.Nature. 2020; 579: 265-269Crossref PubMed Scopus (6151) Google Scholar COVID-19 ssRNA contains 29,891 nucleotides, with 38% G+C content encoding 9860 amino acids, and has 2 untranslated regions and open reading frames (ORFs).12Chan J.F.-W. Kok K.-H. Zhu Z. Chu H. To K.K. Yuan S. et al.Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan.Emerg Microbes Infect. 2020; 9: 221-236Crossref PubMed Scopus (1755) Google Scholar The genome contains 6 to 11 ORFs, where the two-thirds of viral genome is contained in the first ORF (ORF1a/b), which codes for 2 polyproteins (pp1a and pp1ab) and 16 non-structural proteins (Nsps).12Chan J.F.-W. Kok K.-H. Zhu Z. Chu H. To K.K. Yuan S. et al.Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan.Emerg Microbes Infect. 2020; 9: 221-236Crossref PubMed Scopus (1755) Google Scholar,19Song Z. Xu Y. Bao L. Zhang L. Yu P. Qu Y. et al.From SARS to MERS, thrusting coronaviruses into the spotlight.Viruses. 2019; 11: 59Crossref PubMed Scopus (694) Google Scholar The functions and functional domains of the non-structural proteins are displayed in Figure 1, A.12Chan J.F.-W. Kok K.-H. Zhu Z. Chu H. To K.K. Yuan S. et al.Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan.Emerg Microbes Infect. 2020; 9: 221-236Crossref PubMed Scopus (1755) Google Scholar The structural and accessory proteins are coded by the remaining ORFs, including spike glycoprotein (SG), small envelope protein (SEP), nucleocapsid protein (NCP), and matrix protein (MP).20Cui J. Li F. Shi Z.-L. Origin and evolution of pathogenic coronaviruses.Nat Rev Microbiol. 2019; 17: 181-192Crossref PubMed Scopus (2818) Google Scholar The genome of COVID-19 is organized in the order of 5′-orf1/ab (replicase)-structural proteins (SG-SEP-MP-NCP)-3′. Interestingly, COVID-19 lacks the hemagglutinin-esterase gene that is characteristic of β-corona viruses.12Chan J.F.-W. Kok K.-H. Zhu Z. Chu H. To K.K. Yuan S. et al.Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan.Emerg Microbes Infect. 2020; 9: 221-236Crossref PubMed Scopus (1755) Google Scholar The frameshift between ORF1a and ORF1b drives the translation of pp1a and pp1ab which, in turn, are proteolytically processed by viral-encoded chymotrypsin-like protease or main protease. In contrast, the 16 Nsps are processed by papain-like proteases.11Cascella M. Rajnik M. Cuomo A. Dulebohn S.C. Di Napoli R. Features, evaluation and treatment coronavirus (COVID-19).http://www.ncbi.nlm.nih.gov/books/NBK554776/Date accessed: March 31, 2020Google Scholar The expression of COVID-19 proteins is facilitated by replication-transcription complex mediated through subgenomic RNAs. Also, the termination sequences are interspaced between ORFs.21Perlman S. Netland J. Coronaviruses post-SARS: update on replication and pathogenesis.Nat Rev Microbiol. 2009; 7: 439-450Crossref PubMed Scopus (1092) Google Scholar The genomic organization and the structural composition of COVID-19 are displayed in Figure 1, A and B. Interestingly, the cumulative action of all structural proteins of COVID-19 and other coronaviruses are not required to assemble the infectious virion, suggesting their additional overlapping functions.22Schoeman D. Fielding B.C. Coronavirus envelope protein: current knowledge.Virol J. 2019; : 16PubMed Google Scholar For instance, most structural proteins are associated with various aspects of viral replication. SG mediates the attachment to the receptor and membrane fusion between COVID-19 and host cells. In addition, the SG binding facilitates viral infusion in the adjacent uninfected cells, suggesting that the activity of SG determines the transmission potential and tropism of COVID-19.23Lu R. Zhao X. Li J. Niu P. Yang B. Wu H. et al.Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.Lancet. 2020; 395: 565-574Abstract Full Text Full Text PDF PubMed Scopus (6913) Google Scholar Based on this observation, it is logical that the syncytia formation is the primary mechanism of direct viral entry between the host cells, destabilizing their neutralizing antibodies.24Fehr A.R. Perlman S. Coronaviruses: an overview of their replication and pathogenesis.Methods Mol Biol Clifton NJ. 2015; 1282: 1-23Crossref PubMed Scopus (147) Google Scholar The SG is composed of S1 and S2 domains. The S1 domain mediates receptor binding employing both N and C terminal ends and the S2 domain drives the fusion of COVID-19 with the host cell membrane.23Lu R. Zhao X. Li J. Niu P. Yang B. Wu H. et al.Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.Lancet. 2020; 395: 565-574Abstract Full Text Full Text PDF PubMed Scopus (6913) Google Scholar The 3-dimensional structural analysis of the S1 domain of COVID-19 revealed the presence of a core domain and an external subdomain. The external subdomain shares more similarities with SARS-COV unveiling angiotensin-converting enzyme 2 (ACE2) as the major receptor for COVID-19.23Lu R. Zhao X. Li J. Niu P. Yang B. Wu H. et al.Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.Lancet. 2020; 395: 565-574Abstract Full Text Full Text PDF PubMed Scopus (6913) Google Scholar Following membrane fusion using the S2 domain, the viral genome is released to the cytosol, where the uncoated viral genome initiates the translation of pp1a and pp1ab. The pp1a and pp1ab code for Nsps required for the assembly of replication transcription complex in double-membrane vesicle.25de Wilde A.H. Snijder E.J. Kikkert M. van Hemert M.J. Host Factors in coronavirus replication.Curr Top Microbiol Immunol. 2018; 419: 1-42PubMed Google Scholar,26Sawicki S.G. Sawicki D.L. Coronavirus transcription: a perspective.Curr Top Microbiol Immunol. 2005; 287: 31-55PubMed Google Scholar Immediately following the assembly, the replication transcription complex initiates the replication of viral RNA to synthesize a battery of subgenomic RNAs encoding the structural and accessory proteins. Finally, employing the host endoplasmic reticulum (ER) and Golgi machinery, the newly formed viral genome and proteins assemble to form viral particle buds. Viral particle buds are virion-containing vesicles that ultimately fuse with the host cell plasma membrane to release the virus.27Hussain S. Pan J. Chen Y. Yang Y. Xu J. Peng Y. et al.Identification of novel subgenomic RNAs and noncanonical transcription initiation signals of severe acute respiratory syndrome coronavirus.J Virol. 2005; 79: 5288-5295Crossref PubMed Scopus (168) Google Scholar,28Perrier A. Bonnin A. Desmarets L. Danneels A. Goffard A. 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Coronavirus envelope protein: current knowledge.Virol J. 2019; : 16PubMed Google Scholar Similarly, as the name implies, SEP is the smallest of the major structural proteins of coronaviruses. The drastic upregulation of SEP inside the host cell has been observed during the replication phase; however, limited amount is incorporated to the envelope.30Venkatagopalan P. Daskalova S.M. Lopez L.A. Dolezal K.A. Hogue B.G. Coronavirus envelope (E) protein remains at the site of assembly.Virology. 2015; 478: 75-85Crossref PubMed Scopus (135) Google Scholar In addition, the SEP has been traced abundantly in ER, Golgi, and ER-Golgi intermediate compartment, suggesting its potential role in virion assembly and budding.31Nieto-Torres J.L. Dediego M.L. Alvarez E. Jiménez-Guardeño J.M. Regla-Nava J.A. 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A detailed understanding regarding the structural proteins and Nsps would open novel avenues in the development of potential therapeutic/diagnostic targets to effectively manage COVID-19; however, further research on proteomics, genomics, and metabolomics is warranted to accomplish this goal. The biological events associated with COVID-19 infection are displayed in Figure 2, and further detailed information is described in the sections to follow. Upon entry to the host cells, the coronaviruses are detected by the conventional pattern-recognition receptors as viral RNA acts as pathogen-associated molecular patterns. Generally, multiple intracellular Toll-like receptors (TLRs), including TLR3, TLR7, TLR8, and TLR9, detect viral genome in the endosomal vesicles.33Wu J. Chen Z.J. Innate immune sensing and signaling of cytosolic nucleic acids.Annu Rev Immunol. 2014; 32: 461-488Crossref PubMed Scopus (756) Google Scholar In addition, the viral genome in the cytosol is recognized by the cytosolic receptors, including retinoic-acid inducible gene I, melanoma differentiation-associated gene 5, and cyclic-GMP-AMP synthase.5Guo Y.-R. Cao Q.-D. Hong Z.-S. Tan Y.Y. Chen S.D. Jin H.J. et al.The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak—an update on the status.Mil Med Res. 2020; 7: 11Crossref PubMed Scopus (2472) Google Scholar The binding of viral ligands with the receptors initiates the recruitment and assembly of adaptor proteins, including TIR-domain-containing adaptor protein including interferon (IFN)-β, mitochondrial antiviral-signaling protein, and stimulator of IFN genes protein that trigger the activation of transcription factor nuclear factor-κB (NF-κB) and IFN regulatory factor 3 via MyD88 adapter.34Seth R.B. 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The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.Nat Immunol. 2010; 11: 373-384Crossref PubMed Scopus (6161) Google Scholar,37Takeuchi O. Akira S. Innate immunity to virus infection.Immunol Rev. 2009; 227: 75-86Crossref PubMed Scopus (906) Google Scholar However, dysregulation of innate immune response against virus results in immunopathology, as evident from the cytokine burst in patients with COVID-19. Evidently, the inflammatory mediators/cytokines/chemokines including interleukin (IL)-1, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-13, IL-17, granulocyte-colony stimulating factor, macrophage colony-stimulating factor, IFN-γ–induced protein 10, monocyte chemoattractant protein 1, IFN-γ, tumor necrosis factor-α (TNF-α), and others are drastically upregulated in patients with COVID-19. Also, the postmortem specimen from a patient with COVID-19 displayed extreme inflammatory events in the lung alveoli and exhibited severe lung injury.5Guo Y.-R. Cao Q.-D. Hong Z.-S. Tan Y.Y. Chen S.D. Jin H.J. et al.The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak—an update on the status.Mil Med Res. 2020; 7: 11Crossref PubMed Scopus (2472) Google Scholar Together, COVID-19 infects the respiratory mucosa and epithelium followed by invasion to other cell types and subsequently elicits adverse immune responses leading to cytokine burst, which ultimately leads to a critical clinical condition or even death. Like other β-coronaviruses, COVID-19 elicits a lethal cytokine burst, leading to human mortality. Even though inflammation is the first line of defense against viral infections, the hyperinflammation favors pro-viral features, including the spread of virus to other organs especially via the infiltrated immune cells and circulatory fluids.38Gram A.M. Frenkel J. Ressing M.E. Inflammasomes and viruses: cellular defence versus viral offence.J Gen Virol. 2012; 93: 2063-2075Crossref PubMed Scopus (56) Google Scholar Among the highly upregulated proinflammatory cytokines with the predominance of IL-1β5Guo Y.-R. Cao Q.-D. Hong Z.-S. Tan Y.Y. Chen S.D. Jin H.J. et al.The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak—an update on the status.Mil Med Res. 2020; 7: 11Crossref PubMed Scopus (2472) Google Scholar suggest the involvement of Nod-like receptor p