Pathogenesis and immune escape potential of SARS-CoV-2 variants of concern.

The biology of RNA viruses, including SARS-CoV-2, is such that mutations constantly arise upon viral replication. The appearance of variants is therefore expected. The more selective pressure is put on the virus, the more frequent mutations are likely to arise. Fortunately, the majority of these mutations will be silent (synonymous mutations) or even harmful and therefore will not provide a growth advantage to the virus and will not be selected for. However, as we have recently experienced with the current pandemic, some mutations confer new properties that allow these variants to have a growth advantage over the original virus. These variants can spread rapidly and become the dominant strains infecting the population. This was experienced first-hand in the current pandemic with several variants, such as B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil), becoming the most common circulating viruses across various geographical areas. All current vaccine efforts are designed based on the original SARS-CoV-2 Wuhan strain. Whether vaccine induced protection is efficacious against variants of concern (VOC) is only partly known. In fact, in vitro results indicate that neutralization of the B.1.351 is much reduced. Similarly, whether these VOC are more or less pathogenic remains to be studied in detail. In the current proposal, we will compare the disease caused by VOC in young and old mice of both sexes. We will also explore potential therapeutic avenues by studying the roles of serotonin and thromboxane flowing infection of mice with the virus. Lastly, we will study the evolution of VOC and determine whether these evolved VOC are more pathogenic and whether they can infect mice that have received the current vaccines.