The Mechanism Underlying Extrapulmonary Complications of the Coronavirus Disease 2019 and Its Therapeutic Implication

Overview

Journal Signal Transduct Target Ther

Specialties Cell Biology
Pharmacology

Date 2022 Feb 24

PMID 35197452

Authors

Qin Ning

Di Wu

Xiaojing Wang

Dong Xi

Tao Chen

Guang Chen

Hongwu Wang

Huiling Lu

Ming Wang

Lin Zhu

Junjian Hu

Tingting Liu

Ke Ma

Meifang Han

Xiaoping Luo

Affiliations

Soon will be listed here.

Abstract

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.

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References

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223):497-506. PMC: 7159299. DOI: 10.1016/S0140-6736(20)30183-5. View

Zaim S, Chong J, Sankaranarayanan V, Harky A . COVID-19 and Multiorgan Response. Curr Probl Cardiol. 2020; 45(8):100618. PMC: 7187881. DOI: 10.1016/j.cpcardiol.2020.100618. View

Mokhtari T, Hassani F, Ghaffari N, Ebrahimi B, Yarahmadi A, Hassanzadeh G . COVID-19 and multiorgan failure: A narrative review on potential mechanisms. J Mol Histol. 2020; 51(6):613-628. PMC: 7533045. DOI: 10.1007/s10735-020-09915-3. View

Nagele M, Haubner B, Tanner F, Ruschitzka F, Flammer A . Endothelial dysfunction in COVID-19: Current findings and therapeutic implications. Atherosclerosis. 2020; 314:58-62. PMC: 7554490. DOI: 10.1016/j.atherosclerosis.2020.10.014. View

Tang N, Li D, Wang X, Sun Z . Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020; 18(4):844-847. PMC: 7166509. DOI: 10.1111/jth.14768. View

Pei G, Zhang Z, Peng J, Liu L, Zhang C, Yu C . Renal Involvement and Early Prognosis in Patients with COVID-19 Pneumonia. J Am Soc Nephrol. 2020; 31(6):1157-1165. PMC: 7269350. DOI: 10.1681/ASN.2020030276. View

Lim S, Bae J, Kwon H, Nauck M . COVID-19 and diabetes mellitus: from pathophysiology to clinical management. Nat Rev Endocrinol. 2020; 17(1):11-30. PMC: 7664589. DOI: 10.1038/s41574-020-00435-4. View

Mao L, Jin H, Wang M, Hu Y, Chen S, He Q . Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020; 77(6):683-690. PMC: 7149362. DOI: 10.1001/jamaneurol.2020.1127. View

Ashraf U, Abokor A, Edwards J, Waigi E, Royfman R, Hasan S . SARS-CoV-2, ACE2 expression, and systemic organ invasion. Physiol Genomics. 2020; 53(2):51-60. PMC: 7900915. DOI: 10.1152/physiolgenomics.00087.2020. View

10.

Iwasaki M, Saito J, Zhao H, Sakamoto A, Hirota K, Ma D . Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications. Inflammation. 2020; 44(1):13-34. PMC: 7541099. DOI: 10.1007/s10753-020-01337-3. View

11.

Yang L, Liu S, Liu J, Zhang Z, Wan X, Huang B . COVID-19: immunopathogenesis and Immunotherapeutics. Signal Transduct Target Ther. 2020; 5(1):128. PMC: 7381863. DOI: 10.1038/s41392-020-00243-2. View

12.

Boson B, Legros V, Zhou B, Siret E, Mathieu C, Cosset F . The SARS-CoV-2 envelope and membrane proteins modulate maturation and retention of the spike protein, allowing assembly of virus-like particles. J Biol Chem. 2020; 296:100111. PMC: 7833635. DOI: 10.1074/jbc.RA120.016175. View

13.

Siu Y, Teoh K, Lo J, Chan C, Kien F, Escriou N . The M, E, and N structural proteins of the severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking, and release of virus-like particles. J Virol. 2008; 82(22):11318-30. PMC: 2573274. DOI: 10.1128/JVI.01052-08. View

14.

Conceicao C, Thakur N, Human S, Kelly J, Logan L, Bialy D . The SARS-CoV-2 Spike protein has a broad tropism for mammalian ACE2 proteins. PLoS Biol. 2020; 18(12):e3001016. PMC: 7751883. DOI: 10.1371/journal.pbio.3001016. View

15.

Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S . Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020; 581(7807):215-220. DOI: 10.1038/s41586-020-2180-5. View

16.

Li X, Geng M, Peng Y, Meng L, Lu S . Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal. 2020; 10(2):102-108. PMC: 7104082. DOI: 10.1016/j.jpha.2020.03.001. View

17.

Tipnis S, Hooper N, Hyde R, Karran E, Christie G, Turner A . A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000; 275(43):33238-43. DOI: 10.1074/jbc.M002615200. View

18.

Hamming I, Timens W, Bulthuis M, Lely A, Navis G, van Goor H . Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203(2):631-7. PMC: 7167720. DOI: 10.1002/path.1570. View

19.

Geravandi S, Mahmoudi-Aznaveh A, Azizi Z, Maedler K, Ardestani A . SARS-CoV-2 and pancreas: a potential pathological interaction?. Trends Endocrinol Metab. 2021; 32(11):842-845. PMC: 8302839. DOI: 10.1016/j.tem.2021.07.004. View

20.

Yang L, Han Y, Nilsson-Payant B, Gupta V, Wang P, Duan X . A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids. Cell Stem Cell. 2020; 27(1):125-136.e7. PMC: 7303620. DOI: 10.1016/j.stem.2020.06.015. View