13th February 2023

Ever since the global COVID-19 pandemic emerged, research has focused on identifying effective vaccines and therapies to combat the disease. In this article, Margarida Saraiva explains how a BSAC grant enabled her and her team to conduct research to help better understand SARS-CoV-2, which will hopefully help to develop more effective treatments.

When it comes to studying SARS-CoV-2, mouse models of infection are very useful, owing to their tractability. Because most variants of SARS-CoV-2 do not infect wild-type mice, a transgenic model which contains the human ACE2 receptor (the cell entry point for the virus) was created. This model, the k18-hACE2 mouse, which was originally developed in 2007 to study SARS-CoV, became extremely useful to help us understand infections by SARS-CoV-2. The more we understand the progression of the infection and how our immune system reacts to it, the more prepared we will be to continue tackling COVID-19.

With the help of a BSAC grant, we developed a study to establish in a systematic way how different SARS-CoV-2 variants of concern impacted the severity of disease and the immune response in k18-hACE2 mice. Our goal was to understand the relative virulence of different viral variants and how that correlated with distinct immune responses. We decided to perform the study with three well-known SARS-CoV-2 variants (alpha, B.1.1.7; delta, B.1.617.2; and omicron, BA.1.18/B.1.1.529.1.18), which caused successive waves of COVID-19 in the world.

Overall, our study demonstrated an increasing order of virulence from the omicron to the delta and the alpha SARS-CoV-2 variants, which was seen across a diversity of parameters. Interestingly, we found that this distinct virulence profile is reflected in the immune response seen in the lungs (the site of infection), in the blood (that carries immune cells around the body), and even in the bone marrow and thymus (important organs for the production and maturation of immune cells). Thus, a major conclusion of our study is that severe SARS-CoV-2 infections do perturb the immune system at very different locations and levels.

Additionally, by establishing correlations between the severity of the disease and the impact of the infection on the immune response, we offer a series of parameters that can be used in the future as read-outs for the efficacy of vaccines and therapies being tested in this mouse model. Finally, because of the multidisciplinary of our team (that included immunology, infection and veterinary specialists), we were also able to provide a detailed description of the clinical evolution and scoring of SARS-CoV-2 infection in the k18-hACE2 mice, which we believe will facilitate future works in the field and improve animal welfare.

More details can be found in our paper: Gonçalves, Couto et al. “SARS-CoV-2 variants induce distinct disease and impact in the bone marrow and thymus of mice.”

This project was made possible through an unrestricted grant from Pfizer.

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