A Comprehensive Review of Viral Characteristics, Transmission, Pathophysiology, Immune Response, and Management of SARS-CoV-2 and COVID-19 as a Basis for Controlling the Pandemic

Abstract

COVID-19 emerged from China in December 2019 and during 2020 spread to every continent including Antarctica. The coronavirus, SARS-CoV-2, has been identified as the causative pathogen, and its spread has stretched the capacities of healthcare systems and negatively affected the global economy. This review provides an update on the virus, including the genome, the risks associated with the emergence of variants, mode of transmission, immune response, COVID-19 in children and the elderly, and advances made to contain, prevent and manage the disease. Although our knowledge of the mechanics of virus transmission and the immune response has been substantially demystified, concerns over reinfection, susceptibility of the elderly and whether asymptomatic children promote transmission remain unanswered. There are also uncertainties about the pathophysiology of COVID-19 and why there are variations in clinical presentations and why some patients suffer from long lasting symptoms-"the long haulers." To date, there are no significantly effective curative drugs for COVID-19, especially after failure of hydroxychloroquine trials to produce positive results. The RNA polymerase inhibitor, remdesivir, facilitates recovery of severely infected cases but, unlike the anti-inflammatory drug, dexamethasone, does not reduce mortality. However, vaccine development witnessed substantial progress with several being approved in countries around the globe.

Keywords: COVID vaccines; COVID-19; SARS-CoV-2; drugs; immune response; pathophysiology; transmission.

Figure 1

Origin and dynamics of SARS-CoV-2. SARS-CoV-2 is suspected to originate from bats (8, 9). It is unclear if the virus is transmitted to humans directly from bats or via intermediate hosts such as cats, pangolins, ferrets, minks or other animals. Infection with SARS-CoV-2 in cats, dogs, tigers, and lions were suggested to originate from human carriers (10). SARS-CoV-2 transmission from humans to minks and from minks to humans was detected in the Netherlands and Denmark (11, 12). However, human to human transmission remains the main route of transmission during the current pandemic (13).

Figure 2

SARS-CoV-2: mechanism of entry, replication, and dissemination. (A) Entry and replication of SARS-CoV-2 inside the host cells. The virus spike glycoprotein binds to the cellular receptor ACE2. This binding induces conformational changes at the receptor binding domain (RBD) that expose co-receptors to bind with transmembrane protease serine-2 (TMPRSS2), with the help of cellular endosomes it facilitates viral internalization via endocytosis. Internalization results in uncoating of viral genomic RNA into the cytoplasm. Genomic RNA binds to the host ribosome, which leads to formation of polyproteins that contain transcription complex, including the viral RNA-dependent RNA polymerase (RdRP). The RdRP generates viral genomic RNA and several subgenomic mRNAs, which will be translated into relevant viral proteins. The translated proteins translocate into endoplasmic reticulum (ER) membranes and transit through the ER-to-Golgi intermediate compartment (ERGIC), where interaction with encapsidated, newly produced genomic RNA results in budding into the lumen of secretory vesicular compartments. The newly formed viral particles (virions) are subsequently released out of the cells via exocytosis. (B) Viremia and dissemination into body organs: Initial replication takes place in the upper respiratory tract, followed by the migration of the virus to the lungs. A primary viremia occurs after establishment of infection and replication in the lung pneumocytes. This viremia disseminates the virus throughout the body via blood stream where another cycle of viral replication takes places and ensuing viremia leads to further dissemination (for more details and references see section SARS-CoV-2 Genome Structure: Role in Infectivity and Virulence and Replication Cycle and Pathophysiology of the review). ACE2, Angiotensin-converting enzyme 2; RdRP, RNA-dependent RNA polymerase. ER, Endoplasmic reticulum; ERGIC, ER-Golgi Intermediate Compartment.

Figure 3

The mechanism of action of different therapeutics against COVID-19. (A) illustrates the mode of action of drugs targeting COVID-19 including chloroquine (CQ) and hydroxychloroquine (HCQ), which have multiple putative sites of action: (i). ACE2 receptor for SARS-CoV-2; (ii). increasing the pH of the endolysosome; and (iii). suppression of the immune response. Sites of action of TMPRSS2 inhibitors such as camostat, famotidine, and furin inhibitors are shown; famotidine is also a putative inhibitor of the 3CL/PLpro proteases; ivermectin is a putative TMPRSS2 inhibitor that also inhibits the importin (IMP) α-β complex and viral replication; while remdesivir inhibits viral RNA polymerase. (B) Dexamethasone suppresses expression of pro-inflammatory cytokines. (C) Summary of role of convalescent plasma and monoclonal antibody therapy. (D) Ivermectin inhibits the heterodimeric importin (IMP) α/β complex via binding directly to IMPα preventing nuclear import of key viral proteins (for more details and references, see section COVID-19 therapeutics).