SARS-CoV-2 Infection: New Molecular, Phylogenetic, and Pathogenetic Insights. Efficacy of Current Vaccines and the Potential Risk of Variants

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly discovered coronavirus responsible for the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 has rapidly become a public health emergency of international concern. Although remarkable scientific achievements have been reached since the beginning of the pandemic, the knowledge behind this novel coronavirus, in terms of molecular and pathogenic characteristics and zoonotic potential, is still relatively limited. Today, there is a vaccine, or rather several vaccines, which, for the first time in the history of highly contagious infectious diseases that have plagued mankind, has been manufactured in just one year. Currently, four vaccines are licensed by regulatory agencies, and they use RNA or viral vector technologies. The positive effects of the vaccination campaign are being felt in many parts of the world, but the disappearance of this new infection is still far from being a reality, as it is also threatened by the presence of novel SARS-CoV-2 variants that could undermine the effectiveness of the vaccine, hampering the immunization control efforts. Indeed, the current findings indicate that SARS-CoV-2 is adapting to transmission in humans more efficiently, while further divergence from the initial archetype should be considered. In this review, we aimed to provide a collection of the current knowledge regarding the molecular, phylogenetic, and pathogenetic insights into SARS-CoV-2. The most recent findings obtained with respect to the impact of novel emerging SARS-CoV-2 variants as well as the development and implementation of vaccines are highlighted.

Keywords: COVID-19; CoV; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; coronavirus disease 2019; coronaviruses; spike protein; vaccine; variants; zoonosis.

Figure 1

Known structures for SARS-CoV-2 proteins and mutation position of SARS-CoV-2 spike protein. (A) Schematic representation of genomic organization of SARS-CoV-2. (B) When available, the three-dimensional (3D) structure models were obtained from Protein Data Bank (PDB) database (https://www.rcsb.org/, accessed 11 August 2021). A cartoon representation for each available protein and/or protein complexes is shown. (C,D) Structural domain and mutation position of SARS-CoV-2 spike protein. The 3D structure of SARS-CoV-2 spike protein (6VYB, RCSB Protein Data Bank) is shown in up (C) and down (D) conformations. SARS-CoV-2 spike regions carrying mutations are RDB and SD1-2_S1-S2_S2 regions (labeled in green). (C) R346K, K417T, K417N, L452R, N501Y, D614G, H655Y, and G669S mutations are shown in the up conformation, while A701V mutation is not observable with this protein orientation. (D) R346K, K417T, K417N, L452R, N501Y, D614G, H655Y, G669S, and A701V mutations are observable in the down conformation. Due to protein orientation reasons, the localization of S477N, T478K, V483A, E484K, E484Q, Q677H, P681H, and P681R mutations is not visible with both up and down conformations.

Figure 2

SARS-CoV-2 life cycle. (1) Binding between S glycoprotein and ACE2 receptor on the surface of host cell. (2) The fusion peptide undergoes conformational changes allowing SARS-CoV-2 fusion and entry into the cell cytoplasm. (3) Release of SARS-CoV-2 single-stranded positive RNA genome. (4) Viral genome is immediately transcribed by host cell ribosomes. (5) The translated RNA encodes polyproteins (pp1a and pp1ab) and the viral RNA-dependent RNA polymerase NSP12. (6) NSP12 produces full-length negative-sense copies of SARS-CoV-2 RNA. (7) The negative-sense RNA genome is employed as a template for generating the new positive-sense genomes. (8) The translation of the viral RNA occurs in the endoplasmic reticulum of host cells and leads to the synthesis of structural proteins. (9) Structural proteins move into the Golgi intermediate compartment where viral assembly occurs. (10) The mature viral progeny germinates from the intermediate compartment of the Golgi, and it is released as secretory vesicles. (11) SARS-CoV-2 virions are secreted by exocytosis.

Figure 3

SARS-CoV-2 spillover to humans hypotheses. Spillover to humans can result from three different processes: zoonoses in which pathogens are transmitted from the animal reservoir directly (such as Rhabdovirus or Chlamydia psittaci) or indirectly (e.g., via vectors such as Borrelia burgdorferi) to humans causing disease. Emerging infectious diseases in which pathogens can evolve from animals and cause an emerging disease of human infection that is characterized by human-to-human transmission independent of animals (e.g., Ebola virus and HIV). Anthropozoonosis which is an infection transmitted from human to animal (such as Mycobacterium tuberculosis infection). Some pathogens may fall into more than one category: MERS and H5N1 are both zoonoses and emerging infectious diseases. The SARS-CoV-2 infection has characteristics of both an emerging infectious disease and an anthropozoonosis, but from this point of view, it is not considered a zoonosis because no animal is found as a reservoir, and human infection can only occur by human-to-human transmission.

Figure 4

SARS-CoV-2 infection. Angiotensin-converting enzyme 2 (ACE2) expression is also found in respiratory and pulmonary tract cells (alveolar monocytes and macrophages), with the possibility of severe acute respiratory distress syndrome (ARDS) and in heart, kidneys, brain, endothelium, and liver, in which organ failure and thromboembolism may occur.