Novel receptor, mutation, vaccine, and establishment of coping mode for SARS-CoV-2: current status and future

Abstract

Since the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant pneumonia in December 2019, the cumulative number of infected people worldwide has exceeded 670 million, with over 6.8 million deaths. Despite the marketing of multiple series of vaccines and the implementation of strict prevention and control measures in many countries, the spread and prevalence of SARS-CoV-2 have not been completely and effectively controlled. The latest research shows that in addition to angiotensin converting enzyme II (ACE2), dozens of protein molecules, including AXL, can act as host receptors for SARS-CoV-2 infecting human cells, and virus mutation and immune evasion never seem to stop. To sum up, this review summarizes and organizes the latest relevant literature, comprehensively reviews the genome characteristics of SARS-CoV-2 as well as receptor-based pathogenesis (including ACE2 and other new receptors), mutation and immune evasion, vaccine development and other aspects, and proposes a series of prevention and treatment opinions. It is expected to provide a theoretical basis for an in-depth understanding of the pathogenic mechanism of SARS-CoV-2 along with a research basis and new ideas for the diagnosis and classification, of COVID-19-related disease and for drug and vaccine research and development.

Keywords: COVID-19 vaccines; Omicron variant; attachment factors; entry receptors; heterologous booster immunization; small molecule antiviral drugs.

FIGURE 1

Structure, RNA genome and encoding protein of SARS-CoV-2. SARS-CoV-2 contains spike (S) protein, envelope (E) protein, membrane (M) protein and nucleocapsid (N) protein. The S, E, and M proteins are embedded in the bilayer phospholipid envelope, and the RNA genome is located in the center, wrapped by N protein. The RNA genome of SARS-CoV-2 consists of 15 open reading frames (ORFs), which can encode 16 non-structural proteins (Nsp1-16), 4 structural proteins (S, E, M, and N) and 9 auxiliary proteins (ORF3a, ORF3b, ORF6, ORF7a, ORF7b, ORF8, ORF9b, ORF9c, and ORF10). As the most important surface protein of SARS CoV-2, S protein is mainly composed of S1 and S2 functional subunits and plays a key role in the process of virus invasion and replication. (S1, receptor-binding subunit; S2, membrane fusion subunit; NTD, N-terminal domain; RBM, receptor binding motif; RBD, receptor binding domain; CDT1&CDT2, C-terminal domain; FP, furin peptide; HR1&HR2, heptad repeats; CH, central helix; CD, connector domain; TM, transmembrane domain; CT, cytoplasmic tail).

FIGURE 2

Invasion and release mechanism of SARS-CoV-2 based on ACE2 receptor. The host cells infected by SARS-CoV-2 mainly include virus adsorption, invasion, genetic material release, genome replication and transcription, assembly, budding and other processes. As a key protein for SARS-CoV-2 to recognize host cells, spike protein has a strong binding force with the cell membrane surface receptor ACE2. There are two fusion pathways for SARS-CoV-2 to invade host cells, one is viral envelope-endosome membrane fusion pathway mediated by endocytosis, and the other is viral envelope-cell membrane fusion pathway. When the viral genome is released into the cytoplasm of the host cells, it will induce the endoplasmic reticulum to form a replication organelle with a double membrane structure, complete genome RNA replication and structural protein synthesis, and assemble and generate new viral particles at the endoplasmic reticulum of the host cells, which will be transported by golgi to the host cell membrane and released to the outside of the cell by exocytosis. The whole process is critical to the survival and pathogenicity of SARS-CoV-2, and requires the participation of host cell proteases such as Furin, TMPRSS2 and Cathepsin L. (ACE2, angiotensin-converting enzyme II; TMPRSS2, transmembrane serine protease 2; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum- golgi intermediate compartment).

FIGURE 3

Composition of different types of COVID-19 vaccines and the mechanism of protective immune response induced by them. (A) Different types of COVID-19 vaccines. a. Inactivated virus vaccine: Use physical and chemical methods to inactivate SARS-CoV-2 and add specific adjuvants. The inactivated virus injected into the body has no pathogenicity but only retains immunogenicity. b. mRNA vaccine: Lipid nanoparticles are used as delivery carriers to introduce mRNA expressing spike (S) protein into the body to produce neutralization reaction. c. Virus vector vaccine: Integrate S protein gene into adenovirus genome to construct recombinant adenovirus vaccine, and then inject it into muscle. d. Protein subunit vaccine: The S protein or its subunit fragment prepared in vitro is mixed with a specific adjuvant and injected into the human body to induce the immune response of the body. Then stimulate the immune system to produce specific immune response against SARS-CoV-2. (B) The human immune system will produce immune response against the invading vaccine components. When COVID-19 vaccine is injected into the body, it can be internalized by antigen presenting cells, and S protein or its subunit fragments can be transmitted or synthesized in the cytoplasm. If the target antigen is decomposed into small fragments by the proteasome complex, MHC-I molecules can present the antigen fragments to the cell surface to facilitate the recognition of CD8⁺cytotoxic T cells. Activated cytotoxic T cells kill infected cells by secreting lymphokines such as perforin and granzyme. If the target antigen secreted is reabsorbed by cells, it will be degraded by lysosomes and presented to CD4⁺helper T cells through MHC-II molecules on the cell surface. B cells will be activated by the stimulation of antigen, proliferate and differentiate into plasma cells, secrete specific antibodies, and the antibodies can combine with SARS-CoV-2 to make them lose their infectivity. At the same time, they will guide macrophages to phagocytosis and eliminate pathogens. In addition, both memory T cells and memory B cells have the ability to recognize specific antigens. If they encounter the same target antigen invasion again in the future, they can be quickly activated to kill the invading pathogens. (LNP, lipid nanoparticle; APC, antigen-presenting cell; MHC, major histocompatibility complex; BCR, B cell receptor).