SARS-CoV-2: pathogenesis, therapeutics, variants, and vaccines

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in December 2019 with staggering economic fallout and human suffering. The unique structure of SARS-CoV-2 and its underlying pathogenic mechanism were responsible for the global pandemic. In addition to the direct damage caused by the virus, SARS-CoV-2 triggers an abnormal immune response leading to a cytokine storm, culminating in acute respiratory distress syndrome and other fatal diseases that pose a significant challenge to clinicians. Therefore, potential treatments should focus not only on eliminating the virus but also on alleviating or controlling acute immune/inflammatory responses. Current management strategies for COVID-19 include preventative measures and supportive care, while the role of the host immune/inflammatory response in disease progression has largely been overlooked. Understanding the interaction between SARS-CoV-2 and its receptors, as well as the underlying pathogenesis, has proven to be helpful for disease prevention, early recognition of disease progression, vaccine development, and interventions aimed at reducing immunopathology have been shown to reduce adverse clinical outcomes and improve prognosis. Moreover, several key mutations in the SARS-CoV-2 genome sequence result in an enhanced binding affinity to the host cell receptor, or produce immune escape, leading to either increased virus transmissibility or virulence of variants that carry these mutations. This review characterizes the structural features of SARS-CoV-2, its variants, and their interaction with the immune system, emphasizing the role of dysfunctional immune responses and cytokine storm in disease progression. Additionally, potential therapeutic options are reviewed, providing critical insights into disease management, exploring effective approaches to deal with the public health crises caused by SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2; cytokine storm; immunity; treatment; vaccine; variants.

Figure 1

The function of the renin-angiotensin system (RAS). Angiotensin II predominantly exerts its role via activating the AT1 receptor, whereas angiotensin (1-7) [Ang (1-7)] binds to the Mas receptor to exert the opposing effects. The final homeostatic effect of the RAS depends on the balance of the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/AT1R axis with the ACE2/Ang (1-7)/Mas receptor axis.

Figure 2

SARS-CoV-2 entry and immune activation. SARS-CoV-2 enters the cell by binding to angiotensin-converting enzyme 2 (ACE2) through transmembrane serine protease 2 (TMPRSS2)-enhanced endocytosis. Furin can also facilitate viral entry. The pathogen-associated molecular patterns (PAMPs) of SARS-CoV-2 are recognized by endosomal pattern recognition receptors, including Toll-like receptors (TLRs), which activate interferon regulatory factor (IRF) genes and nuclear factor kappa B (NF-κB). Pyroptosis of host cells releases damage-associated molecular patterns (DAMPs), which neighboring epithelial cells, endothelial cells, and alveolar macrophages recognize, triggering the production of pro-inflammatory cytokines and chemokines, such as interleukin (IL)-6, interferon γ-induced protein 10 (IP-10), macrophage inflammatory protein 1α (MIP1α), MIP1β and monocyte chemoattractant protein 1 (MCP1). These cytokines and chemokines attract monocytes, macrophages, and T cells to the site of infection, promoting further inflammation and establishing a pro-inflammatory feedback loop.

Figure 3

Immunopathology of SARS-CoV-2 infection. Patients with mild to moderate COVID-19 can clear the virus with a healthy immune response, while those with severe infection show immune dysfunction, characterized by relatively increased levels of neutrophils and monocytes and decreased levels of effector T lymphocytes. SARS-CoV-2 infection induces an excess of cytokines, which contribute to hyper-inflammation as constituents of the “cytokine storm” in severe disease (e.g., IL-6, IP-10, IL-1β, TNF-α, and MCP-1), whereas others are particularly important for viral clearance in mild to moderate disease (e.g., IFN-α and IFN-γ). SARS-CoV-2 infection also induces the release of neutrophil extracellular traps (NETs), and excessive formation of NETs leads to a strong pro-coagulant response. Lymphopenia may be caused by hemophagocytosis, reduced hematopoiesis and increased apoptosis/pyroptosis.