Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): a Systemic Infection

Abstract

To date, seven identified coronaviruses (CoVs) have been found to infect humans; of these, three highly pathogenic variants have emerged in the 21st century. The newest member of this group, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected at the end of 2019 in Hubei province, China. Since then, this novel coronavirus has spread worldwide, causing a pandemic; the respiratory disease caused by the virus is called coronavirus disease 2019 (COVID-19). The clinical presentation ranges from asymptomatic to mild respiratory tract infections and influenza-like illness to severe disease with accompanying lung injury, multiorgan failure, and death. Although the lungs are believed to be the site at which SARS-CoV-2 replicates, infected patients often report other symptoms, suggesting the involvement of the gastrointestinal tract, heart, cardiovascular system, kidneys, and other organs; therefore, the following question arises: is COVID-19 a respiratory or systemic disease? This review aims to summarize existing data on the replication of SARS-CoV-2 in different tissues in both patients and ex vivo models.

Keywords: COVID-19; SARS-CoV-2; coronavirus; disease; infection; organoids; organs; systemic.

FIG 1

Schematic structure of the SARS-CoV-2 virion.

FIG 2

The entry of human coronaviruses into the host cell. Coronaviruses first interact with an adhesion molecule (e.g., heparan sulfate proteoglycans [HSPGs] for HCoV-NL63 [32], SARS-CoV [33], and [possibly] SARS-CoV-2 [409]; N-acetyl-9-O-acetylneuraminic acid [Neu5Ac] for HCoV-HKU1 and HCoV-OC43 [34]; or carcinoembryonic antigen-related cell adhesion molecule 5 [CEACAM5] for MERS-CoV [35]). Next, the virus interacts with the entry receptor (aminopeptidase N [APN] for HCoV-229E [36]; dipeptidyl peptidase 4 [DPP4] for MERS-CoV [37]; 9-O-acetylated sialic acid for HCoV-OC43 [39]; or angiotensin-converting enzyme 2 [ACE2] for HCoV-NL63, SARS-CoV, and SARS-CoV-2 [40]). Recently, neuropilin 1 (NRP1) was reported to enhance the SARS-COV-2 entry (41, 42). To enter the cell, the S protein requires proteolytic priming, which may occur on the cell surface (TMPRSS2, TMPRSS4, kallikrein 13) or after endosomal entry (cathepsin B [catB] and cathepsin L [catL]) (43–50, 410–414).

FIG 3

Cell types and their localization within the human respiratory tract.

FIG 4

Cell types and their localization in the human intestine.

FIG 5

Cell types and their localization in the cardiovascular system.

FIG 6

Organs affected by COVID-19. The solid and dotted lines indicate direct and indirect viral replication, respectively.