SARS-CoV-2: One Year in the Pandemic. What Have We Learned, the New Vaccine Era and the Threat of SARS-CoV-2 Variants

Abstract

Since the beginning of 2020, the new pandemic caused by SARS-CoV-2 and named coronavirus disease 19 (COVID 19) has changed our socio-economic life. In just a few months, SARS-CoV-2 was able to spread worldwide at an unprecedented speed, causing hundreds of thousands of deaths, especially among the weakest part of the population. Indeed, especially at the beginning of this pandemic, many reports highlighted how people, suffering from other pathologies, such as hypertension, cardiovascular diseases, and diabetes, are more at risk of severe outcomes if infected. Although this pandemic has put the entire academic world to the test, it has also been a year of intense research and many important contributions have advanced our understanding of SARS-CoV-2 origin, its molecular structure and its mechanism of infection. Unfortunately, despite this great effort, we are still a long way from fully understanding how SARS-CoV-2 dysregulates organismal physiology and whether the current vaccines will be able to protect us from possible future pandemics. Here, we discuss the knowledge we have gained during this year and which questions future research should address.

Keywords: ACE2; COVID19; SARS-CoV-2; coronavirus; kinin-kallikrein system; renin angiotensin aldosterone system.

Figure 1

SARS-CoV-2 origin and molecular structure. The natural reservoir of the new betacoronavirus Sars-CoV-2 has been demonstrated to be bats and thought to spread to humans through an intermediate host. The viral RNA is associated with the N proteins that are involved in the key process of infection such as transcription, replication, and packaging. The lipid membrane that protects the viral RNA contains structural proteins such as membrane (M) and envelope proteins (E). The spike glycoprotein (S), through its receptor-binding domain, is responsible for the recognition of the host cell receptor. The picture shows a simplification of the viral genome.

Figure 2

Schematic representation of spike variants. (A) Brazilian mutation called P.1, that shares three mutations in the RBD domain of spike protein with South African variants (N501Y, E484K and K417T); P.1 has 17 amino acid changes, nine of which are in its spike protein (L18F, T20N, P26S, D138Y, R190S, H655Y). (B) English mutation called B1.1.7 has a mutation (N501Y) in the RBD of the spike protein like P.1 and B1.351 variants. Additionally, amino acid deletions were found within the N-terminal domain (NTD) of spike protein, important for efficient entry into host cells. (C) South African mutation called B1. 351, shows a mutation in spike protein (N501Y, E484K and K417T) and several changes in NTD spike domain (A570D, D614G, P681H), including amino acid deletion (del144). [14] Created with BioRender.com.

Figure 3

Mechanism of infection. SARS-CoV-2 recognizes the host cell by binding with the Angiotensin- converting enzyme 2 (ACE2) via Spike glycoprotein S1 unit. The priming of the Spike glycoprotein can be mediated by the TMPRSS2 protease that allows virus/membrane fusion guided by the S2 unit. Alternatively, the virus can enter the cell by using the endocytic pathway where Chatepsin-L cleaves the S protein allowing also in this case the priming of the late endosome membrane with the S2 unit. The viral RNA will undergo transcription and replication. The new viral particle will be built in the ER-Golgi intermediate compartment (ERGIC) and released by exocytosis.

Figure 4

Immune response activation due to SARS-CoV-2 infection. The presence of virus particles in the cell, such as the viral RNA, is recognized by the Toll-Like and RIG-I/MAD5 pathway and will initiate signaling cascades resulting in the translocation of NF-kb and IRF3/7 into the nucleus and the transcription of pro-inflammatory cytokines that are responsible for recruiting immune cells to the site of infection (left).

Figure 5

SARS-CoV-2 dependent ACE2 internalization as a possible cause of the cytokine storm. The binding of SARS-CoV-2 to ACE2 can cause its internalization and a decreased level on the plasma membrane. This leads to an increase in AngII and DEABK/LDEABK causing vasoconstriction, apoptosis, oxidative stress, and an overproduction of proinflammatory cytokines through their receptor AT1R and BRB1.

Figure 6

Map of COVID19 clinical trials. This map has been obtained by using clinicaltrial.gov searching for COVID-19 clinical trials for the age 65 and above.