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Review
. 2021 Jan 28:12:593223.
doi: 10.3389/fphys.2021.593223. eCollection 2021.

Pathogenesis of Multiple Organ Injury in COVID-19 and Potential Therapeutic Strategies

Miquéias Lopes-Pacheco  1 , Pedro Leme Silva  2   3   4   5   6   7 , Fernanda Ferreira Cruz  2   3   4   5   6   7 , Denise Battaglini  8 , Chiara Robba  8 , Paolo Pelosi  8   9 , Marcelo Marcos Morales  3   4   5   7   10 , Celso Caruso Neves  3   4   6   7   11 , Patricia Rieken Macedo Rocco  2   3   4   5   6   7
Affiliations
Review

Pathogenesis of Multiple Organ Injury in COVID-19 and Potential Therapeutic Strategies

Miquéias Lopes-Pacheco et al. Front Physiol. .

Abstract

Severe acute respiratory disease coronavirus 2 (SARS-CoV-2, formerly 2019-nCoV) is a novel coronavirus that has rapidly disseminated worldwide, causing the coronavirus disease 2019 (COVID-19) pandemic. As of January 6th, 2021, there were over 86 million global confirmed cases, and the disease has claimed over 1.87 million lives (a ∼2.2% case fatality rate). SARS-CoV-2 is able to infect human cells by binding its spike (S) protein to angiotensin-conversing enzyme 2 (ACE2), which is expressed abundantly in several cell types and tissues. ACE2 has extensive biological activities as a component of the renin-angiotensin-aldosterone system (RAAS) and plays a pivotal role as counter-regulator of angiotensin II (Ang II) activity by converting the latter to Ang (1-7). Virion binding to ACE2 for host cell entry leads to internalization of both via endocytosis, as well as activation of ADAM17/TACE, resulting in downregulation of ACE2 and loss of its protective actions in the lungs and other organs. Although COVID-19 was initially described as a purely respiratory disease, it is now known that infected individuals can rapidly progress to a multiple organ dysfunction syndrome. In fact, all human structures that express ACE2 are susceptible to SARS-CoV-2 infection and/or to the downstream effects of reduced ACE2 levels, namely systemic inflammation and injury. In this review, we aim to summarize the major features of SARS-CoV-2 biology and the current understanding of COVID-19 pathogenesis, as well as its clinical repercussions in the lung, heart, kidney, bowel, liver, and brain. We also highlight potential therapeutic targets and current global efforts to identify safe and effective therapies against this life-threatening condition.

Keywords: ACE2; SARS-CoV-2; coronavirus; lung; multiple organ dysfunction; pathophysiology; therapy; viral infection.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
ACE2 expression in the human body. Tissue distribution of angiotensin-converting enzyme 2 (ACE2) expression and potential targets for direct cytotoxicity induced by SARS-CoV-2 infection.
FIGURE 2
FIGURE 2
Genome and structure of SARS-CoV-2. (A) Full-length single-strand (ss)RNA genome of SARS-CoV-2 demonstrating open-reading frames (ORFs) 1a and 1b, which encode non-structural proteins, and the position of genes that encode main structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N). (B) Schematic representation of a SARS-CoV-2 viral particle. (C) Ribbon diagram of the open conformation of SARS-CoV-2 spike protein. This structure has been deposited on the Protein Data Bank under accession number 6VYB (SARS-CoV-2 spike ectodomain structure).
FIGURE 3
FIGURE 3
Simplified diagram of the renin-angiotensin-aldosterone system. Angiotensinogen is cleaved by renin to angiotensin I (Ang I). Ang I is then converted by angiotensin-converting enzyme (ACE) to Ang II, which interacts with the AT1 receptor (AT1-R), or is cleaved by ACE2 to Ang (1-7), which interacts with Mas receptor. The ACE2/Ang (1-7)/Mas axis exerts counter-regulatory effects to the ACE/Ang II/AT1-R axis in multiple organs. ACE2 can also convert Ang I to Ang (1-9), which is then cleaved to Ang (1-7) by ACE. However, ACE2 converts Ang II to Ang (1-7) with higher efficiency than it converts Ang I to Ang (1-9).
FIGURE 4
FIGURE 4
SARS-CoV-2 infection and replication. (1) SARS-CoV-2 spike protein is primed by the type II transmembrane serine protease (TMPRSS2) and interacts with the angiotensin-converting enzyme 2 (ACE2) expressed on the surface of host cells, allowing binding and entry of the virus via clathrin-dependent endocytosis. Concomitantly, ADAM17 is activated and leads to cleavage of ACE2 in its soluble form. (2) The SARS-CoV-2 virion uses host ribosomes to produce viral RNA-dependent RNA polymerase (3). This viral polymerase then initiates replication of the SARS-CoV-2 genome (4) and transcription of subgenomic structures (5). The spike, membrane, and envelope subgenomic transcripts use the endoplasmic reticulum for translation of these viral structural proteins (6), while the viral genome joins the nucleocapsid. (7) All viral structures are exported to the endoplasmic-reticulum-Golgi intermediated compartment (ERGIC), where new viral particles are assembled. (8) After the formation of mature virions, these are exported inside Golgi vesicles to the extracellular compartment via exocytosis. (9) These new viruses are now able to infect adjacent ACE2-expressing cells or enter the bloodstream and infect other tissues.
FIGURE 5
FIGURE 5
Pathogenesis of COVID-19. Five main pathological mechanisms are implicated in COVID-19 development and progression: (1) SARS-CoV-2 spike protein is primed by the type II transmembrane serine protease (TMPRSS2) and interacts with angiotensin-converting enzyme 2 (ACE2) expressed on the cell surface of epithelial cells, inducing direct cytotoxicity; (2) The interaction of SARS-CoV-2 with ACE2 causes downregulation of ACE2 expression, thus preventing cleavage of angiotensin II (Ang II) to Ang (1-7) and resulting in dysregulation of the renin-angiotensin-aldosterone system; (3) excessive acute inflammatory responses are elicited, with overproduction of pro-inflammatory cytokines and chemokines; (4) SARS-CoV-2 exerts direct cytotoxic effects on endothelial cells, leading to recruitment of pro-inflammatory cells and activation of the coagulation cascade, with intravascular thrombus formation; and (5) extensive tissue destruction with interstitial thickening, fibroblast proliferation, and fibrosis.
FIGURE 6
FIGURE 6
Multiple organ injury in COVID-19. SARS-CoV-2 infection can potentially cause multiple clinical manifestations and affect several organs, including the lungs, heart, blood vessels, kidney, intestine, liver, brain, and reproductive system.
FIGURE 7
FIGURE 7
Clinical trials of COVID-19 therapeutics registered on the U.S. National Institutes of Health Clinical Trials Platform. As of December 7th, 2020, there were 4,094 registered clinical trials to evaluate the safety and efficacy of therapeutic approaches for COVID-19. (A) Distribution based on study phase: I (13.3%), II (32.9%), III (19.6%), and IV (4.1%). (B) Distribution based on region: North America (28.9%), Central/South America (6.5%), Africa (5.2%), Europe (37.9%), Middle East (6.5%), Asia (12.5%), Oceania (0.9%). (C) Distribution of 1,520 clinical trials based on therapeutic approaches under investigation: vaccines (20.4%), TMPRSS2 inhibitors (1.4%), recombinant soluble ACE2 and human monoclonal antibodies against SARS-CoV-2 (4.5%), agents with known or purported antiviral activity (ribavirin, favipiravir, remdesivir, lopinavir, umifenovir, ivermectin, nitazoxanide, chloroquine/hydroxychloroquine) (36.7%), convalescent plasma (CP) therapy (11.2%), IL-6/IL-1/JAK inhibitors (8.2%), corticosteroids (5.2%), adjuvant therapies (low-molecular-weight heparin, bevacizumab, recombinant human DNase) (7.7%), and mesenchymal stromal cell (MSC)-based therapies (4.6%).
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