Pathogenesis of COVID-19: ACE2, Cytokine Storm and Extrapulmonary Manifestations

  • Muhammad Naeem National University of Medical Sciences, Rawalpindi
  • Abdul Muhaymin Muhaymin Preston Institute of Nanoscience and Technology, Preston University Kohat, Islamabad
  • Hyder Wajid Abbasi Pakistan Institute of Medical Sciences, Islamabad
  • Naeem Ullah National Institute of Child Health, Karachi
  • Adnan Haider National University of Medical Sciences, Rawalpindi
  • Syed Babar Jamal National University of Medical Sciences, Rawalpindi
  • Fazli Subhan National University of Medical Sciences, Rawalpindi
Keywords: ACE2, COVID-19 Pathogenesis, Cytokines Storm, Extrapulmonary Manifestations.

Abstract

The coronavirus disease 19 (COVID-19) is a global pandemic of the twenty-first century and currently fourth
wave is creating fear and panic worldwide. It is caused by severe acute respiratory syndrome coronavirus 2
(SARS-COV-2), a highly contagious viral infection of humans. The COVID-19 can be spread mainly through
respiratory droplet particles and in contact with a COVID-19 infected person. Clinical manifestation of COVID-19
patients includes cough, fever, diarrhea, loss of taste and smell. In critical cases of COVID-19, the development
of pneumonia and dyspnea leads to acute respiratory distress syndrome that may cause the death of the
patient. It is well established that Angiotensin-Converting Enzyme 2 (ACE2) receptors on alveolar cells act as an
entry gate for the SARS-COV-2. However, ACE2 is also highly expressed in multiple extrapulmonary vital organs
such as the gastrointestinal system, cardiovascular system, kidney, etc. Therefore, the direct viral entry in these
organs can be a likely pathway of injury. In addition, decoupling of immune responses leads to the cytokines
storm, which might contribute to the injury of extrapulmonary organs. In this review, we report the multiple
organ pathogenesis and clinical manifestations of COVID-19 patients, which could aid clinicians and researchers
in prioritizing therapeutics remedies and developing research for all vital body systems involved.

References

Ginsburg AS, Klugman KP. COVID-19 pneumonia and the appropriate use of antibiotics. Lancet Glob Heal [Internet]. 2020; 8: e1453–4.

Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet. 2020; 395: 470–3.

Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China. 2019. N Engl J Med. 2020.

WHO. Coronavirus disease 2019 (COVID-19) Situation R e p o r t – 2 3 [ I n t e r n e t ] . A v a i l a b l e f r o m :

h t t p s : / / w w w . w h o . i n t / d o c s / d e f a u l t - source/coronaviruse/situation-reports/20200212-sitrep-

-ncov.pdf?sfvrsn=41e9fb78_4

WHO. Rolling updates on coronavirus disease (COVID-19)

[ I n t e r n e t ] . A v a i l a b l e f r o m :https://www.who.int/emergencies/diseases/novelcoronavirus-

/events-as-they-happen

Cucinotta D, Vanelli M. WHO declares COVID-19 a pandemic. Acta bio-medica Atenei Parm. 2020; 91: 157–60.

Worldometer. COVID-19 CORONAVIRUS PANDEMIC [ I n t e r n e t ] . A v a i l a b l e f r o m :

https://www.worldometers.info/coronavirus/

Woo PCY, Lau SKP, Lam CSF, Lai KKY, Huang Y, Lee P, et al. Comparative analysis of complete genome sequences of three avian coronaviruses reveals a novel group 3c coronavirus. J Virol. 2009; 83: 908–17.

Su S, Wong G, Shi W, Liu J, Lai ACK, Zhou J, et al. Epidemiology, genetic recombination, and pathogenesis of

coronaviruses. Trends Microbiol. 2016; 24: 490–502.

De Wit E, Van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol. 2016; 14: 523.

Lau SKP, Woo PCY, Li KSM, Huang Y, Tsoi HW, Wong BHL, et al. Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. Proc Natl Acad Sci. 2005; 102:14040–5.

Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol. 2019; 17: 181–92.

Guan Y, Zheng BJ, He YQ, Liu XL, Zhuang ZX, Cheung CL, et al. Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science. 2003; 302: 276–8.

Li F. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol. 2016; 3: 237–61.

Perlman S, Netland J. Coronaviruses post-SARS: update on replication and pathogenesis. Nat Rev Microbiol. 2009; 7:439–50.

Belouzard S, Chu VC, Whittaker GR. Activation of the SARS coronavirus spike protein via sequential proteolytic

cleavage at two distinct sites. Proc Natl Acad Sci. 2009; 106: 5871–6.

Burkard C, Verheije MH, Wicht O, van Kasteren SI, van Kuppeveld FJ, Haagmans BL, et al. Coronavirus cell entry occurs through the endo-/lysosomal pathway in a proteolysis-dependent manner. PLoS Pathog. 2014; 10:

e1004502.

Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV

of the same clade. Antiviral Res [Internet]. 2020; 176: 104742.

Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003; 426: 450–4.

Belouzard S, Millet JK, Licitra BN, Whittaker GR. Mechanisms of coronavirus cell entry mediated by the viral

spike protein. Viruses. 2012; 4: 1011–33.

Albini A, Di Guardo G, Noonan DM, Lombardo M. The SARSCoV- 2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor-and angiotensin II receptor blocker-based cardiovascular therapies. Internal and emergency medicine. 2020; 15: 759-66.

Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human

transmission. Sci China Life Sci. 2020; 63: 457–60.

Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: an

analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020; 94: e00127-20.

Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020; 5: 562–9.

Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020; 581: 221–4.

e Silva ACS, Flynn JT. The renin–angiotensin–aldosterone system in 2011: role in hypertension and chronic kidney disease. Pediatr Nephrol. 2012; 27: 1835–45.

Göbölös L, Rácz I, Hogan M, Remsey-Semmelweis E, Atallah B, AlMahmeed W, et al. The role of renin-angiotensin system activated phagocytes in the SARS-CoV-2 coronavirus infection. J Vasc Surg [Internet]. 2021; 73: 1889–97.

Hamming I, Cooper ME, Haagmans BL, Hooper NM, Korstanje R, Osterhaus ADME, et al. The emerging role of

ACE2 in physiology and disease. J Pathol A J Pathol Soc Gt Britain Irel. 2007; 212: 1–11.

Li X, Geng M, Peng Y, Meng L, Lu S. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal

[Internet]. 2020; 10: 102–8.

Totura AL, Whitmore A, Agnihothram S, Schäfer A, Katze MG, Heise MT, et al. Toll-like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. MBio. 2015; 6: 1–14.

Renu K, Prasanna PL, Gopalakrishnan AV. Coronaviruses pathogenesis, comorbidities and multi-organ damage – A review. Life Sci. 2020; 255: 117839.

Li L, Huang Q, Wang DC, Ingbar DH, Wang X. Acute lung injury in patients with COVID-19 infection. Clin Transl Med. 2020; 10: 20–7.

Zhao Y, Zhao Z, Wang Y, Zhou Y, Ma Y, Zuo W. Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. BioRxiv. 2020.

Gu J, Gong E, Zhang B, Zheng J, Gao Z, Zhong Y, et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med. 2005; 202: 415–24.

Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ van, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol A J Pathol Soc Gt Britain Irel. 2004; 203: 631–7.

Naeem M, Ullah S, Haider A, Awan UA, Ullah S, Hussain KK. Recent Development in Diagnosis and Treatment of COVID- 19 Pandemic. Life Sci. 2020; 1 (supplement): 14.

Connelly D. Targeting COVID-19: the drugs being fast tracked through clinical trials and how they work. Pharm J. 2020; 304: 312–3.

Biorender Software [Internet]. [cited 2021 Sep 3]. Available from: https://biorender.com

Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020.

Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020; 18: 1094–9.

Lopes-Pacheco M, Silva PL, Cruz FF, Battaglini D, Robba C, Pelosi P, et al. Pathogenesis of Multiple Organ Injury in COVID-19 and Potential Therapeutic Strategies. Front Physiol. 2021; 12: 1–23.

Wang 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: 1061–9.

Young BE, Ong SWX, Kalimuddin S, Low JG, Tan SY, Loh J, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. Jama. 2020; 323: 1488–94.

Gao QY, Chen YX, Fang JY. 2019 novel coronavirus infection and gastrointestinal tract. J Dig Dis. 2020; 21: 125–6.

Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020; 382: 929–36.

Pan L, Mu M, Yang P, Sun Y, Wang R, Yan J, et al. Clinical characteristics of COVID-19 patients with digestive

symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. Am J Gastroenterol. 2020; 115.

Lamers MM, Beumer J, van der Vaart J, Knoops K, Puschhof J, Breugem TI, et al. SARS-CoV-2 productively infects human gut enterocytes. Science. 2020; 369: 50-4.

Liu WW, Yuan C, Yu M, Li P, Yan J. Detection of novel coronavirus by rt-pcr in stool specimen from asymptomatic child, china. Emerg Infect Dis. 2020; 26: 1337-9.

Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology. 2020; 158: 1831-3.

Gu J, Han B, Wang J. COVID-19: gastrointestinal manifestations and potential fecal–oral transmission.

Gastroenterology. 2020; 158: 1518–9.

Li M, Wang B, Zhang M, Rantalainen M, Wang S, Zhou H, et al. Symbiotic gut microbes modulate human metabolic phenotypes. Proc Natl Acad Sci. 2008; 105: 2117–22.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395: 497–506.

Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular Implications of Fatal Outcomes of Patients

with Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020; 5: 811–8.

Wong CK, Lam CWK, Wu AKL, Ip WK, Lee NLS, Chan IHS, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004; 136: 95–103.

Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020; 17: 259–60.

Meo SA, Alhowikan AM, Khlaiwi TAL, Meo IM, Halepoto DM, Iqbal M, et al. Novel coronavirus 2019-nCoV: Prevalence, biological and clinical characteristics comparison with SARS-CoV and MERS-CoV. Eur Rev Med Pharmacol Sci. 2020; 24: 2012–9.

Li Z, Wu M, Yao J, Guo J, Liao X, Song S, et al. Caution on Kidney Dysfunctions of COVID-19 Patients. medRxiv. 2020; 1–25.

Wu R, Wang L, Kuo HCD, Shannar A, Peter R, Chou PJ, et al. An update on current therapeutic drugs treating COVID-19. Curr Pharmacol Reports. 2020; 6: 56-70.

Shao M, Li XM, Liu F, Tian T, Luo J, Yang Y. Acute kidney injury is associated with severe infection and fatality in patients with COVID-19: A systematic review and meta-analysis of 40 studies and 24,527 patients. Pharmacol Res [Internet]. 2020; 161: 105107.

Ding Y, He LI, Zhang Q, Huang Z, Che X, Hou J, et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission

pathways. J Pathol A J Pathol Soc Gt Britain Irel. 2004; 203: 622–30.

Naicker S, Yang CW, Hwang SJ, Liu BC, Chen JH, Jha V. The Novel Coronavirus 2019 epidemic and kidneys. Kidney Int. 2020; 97: 824–8.

Ren X, Wang S, Chen X, Wei X, Li G, Ren S, et al. Multiple expression assessments of ace2 and tmprss2 sars-cov-2 entry molecules in the urinary tract and their associations with clinical manifestations of covid-19. Infect Drug Resist. 2020; 13: 3977–90.

Chau T, Lee K, Yao H, Tsang T, Chow T, Yeung Y, et al. SARS-associated viral hepatitis caused by a novel

coronavirus: report of three cases. Hepatology. 2004; 39: 302–10.

Alsaad KO, Hajeer AH, Al Balwi M, Al Moaiqel M, Al Oudah N, Al Ajlan A, et al. Histopathology of Middle East respiratory s y n d r o m e c o r o n o v i r u s ( M E R S - C o V ) infection–clinicopathological and ultrastructural study. Histopathology. 2018; 72: 516–24.

Zhang C, Shi L, Wang FS. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol

[Internet]. 2020; 5: 428–30.

Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020; 382: 1708–20.

Guan GW, Gao L, Wang JW, Wen XJ, Mao TH, Peng SW, et al. Exploring the mechanism of liver enzyme abnormalities in patients with novel coronavirus-infected pneumonia.

Zhonghua gan zang bing za zhi= Zhonghua ganzangbing zazhi= Chinese J Hepatol. 2020; 28: E002.

Chai X, Hu L, Zhang Y, Han W, Lu Z, Ke A, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. BioRxiv. 2020.

Fotuhi M, Mian A, Meysami S, Raji CA. Neurobiology of COVID-19. J Alzheimer's Dis. 2020; 76: 3–19.

Ksiazek TG, Dean Erdman DPH, Cynthia S. Goldsmith MS, Zak SR, Perset T, et al. A Novel Coronavirus Associated with Severe Acute Respiratory Syndrome Thomas. N Engl J Med. 2020; 348: 1953–66.

Saad M, Omrani AS, Baig K, Bahloul A, Elzein F, Matin MA, et

al. Clinical aspects and outcomes of 70 patients with Middle

East respiratory syndrome coronavirus infection: A single center experience in Saudi Arabia. Int J Infect Dis. 2014; 29: 301–6.

Ellul MA, Benjamin L, Singh B, Lant S, Michael BD, Easton A, et al. Neurological associations of COVID-19. Lancet Neurol [Internet]. 2020; 19: 767–83.

Mercante G, Ferreli F, de Virgilio A, Gaino F, Di Bari M, Colombo G, et al. Prevalence of taste and smell dysfunction in coronavirus disease 2019. JAMA Otolaryngol - Head Neck Surg. 2020; 146: 723–8.

Medeiros BC. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young We. 2009; 2008–9.

Paterson RW, Brown RL, Benjamin L, Nortley R, Wiethoff S, Bharucha T, et al. The emerging spectrum of COVID-19 neurology: Clinical, radiological and laboratory findings. Brain. 2020; 143: 3104–20.

Published
2021-09-28
Section
Review Article