Mice with covid
Humanized mice get sick with COVID-19 almost like humans
Alexey Torgashev, PCR.news
To study COVID-19, mice expressing the human variant of angiotensin converting enzyme 2 (hACE2) are used today — these are either transgenic animals, or their respiratory pathways express hACE2 temporarily (for example, after transduction by a viral vector that is instilled into the nose). Such animals can be infected with SARS-CoV-2, and the acute viral response, transmission and effectiveness of the vaccine can be tested on them. However, these models do not reproduce the stable immunopathology of patients with severe disease and are not suitable for testing therapeutic agents in severe COVID-19 or in post-acute complications.
In the laboratory of Richard Flavell from Yale University, humanized mice of the MISTRG6 line were used to study severe coronavirus infection and the body's response to drugs that are now actively used — monoclonal antibodies and the immunosuppressor dexamethasone.
MISTRG6 mice were constructed in the same laboratory several years ago by replacing six genes regulating hematopoiesis with human homologues. Such mice can be transplanted with human hematopoietic cells and progenitor cells (human hematopoietic stem and progenitor cells, HSPCs), which as a result creates a complex immune system similar to human in animal organisms.
A model for the study of COVID-19 was obtained as follows: hematopoietic CD34+ cells from human fetal liver tissues were transplanted into the liver of newborn mice MISTRG6. After the adaptation period (after 8 weeks), the hACE2 gene in the adenovirus vector was injected into the trachea of mice. Thus, mice were obtained that were fully prepared to simulate the human immune response to coronavirus infection. Mice were infected with SARS-CoV-2 two weeks after the introduction of a construct with the hACE2 gene.
The condition of the lungs, immune system and viral load in infected mice were checked on the 2nd, 4th, 7th, 14th, 28th and 35th days after infection. The results showed that the model reproduces innate and adaptive immune responses with high accuracy in severe COVID-19. The physiological state of such mice reflects the key features of the main stages of the disease — exudative, proliferative and fibrous. Thus, mice demonstrated weight loss, T-cell lymphopenia, high virus titer, persistent signature of changes in gene expression caused by interferon.
The researchers tested the effect of monoclonal antibodies against SARS-CoV-2 and dexamethasone therapy. In the case of antibodies, treatment was effective only in the early stages of the disease. On the contrary, steroids acted only in the late stages, and in the early stages aggravated the disease, suppressing the immune response.
"If you infect standard laboratory mice with SARS-CoV-2, they will get infected, but they will not get seriously ill. But our humanized mice get sick and just don't get better. Their entire immune system is on fire," he said with satisfaction Richard Flavell, professor of immunobiology at Yale University and lead author of a paper published in Nature Biotechnology (Sefik et al., A humanized mouse model of chronic COVID-19).
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