A research paper that has just been peer reviewed and published in Nature has described how disrupting an immune pathway that is upregulated in aging decreases the lethality of COVID-19 in a mouse model.
Mice with COVID-19
As the researchers explain, normal mice do not use the same angiotensin converting enzyme 2 (ACE2) as humans, which makes them naturally resistant to SARS-CoV-2, the virus that causes COVID-19 [1]. Therefore, to develop a mouse model of the disease, the researchers had to choose between two options: they could use gene editing or similar techniques to cause the mice to express the human version of ACE2, or they could alter the virus to infect mice.
The researchers chose the latter option. After making one small mutation to the virus’ genome, they were able to infect mice, and repeatedly passaging the virus through mouse lungs caused it to mutate further towards greater virulence and lethality in mice. This is not the first lab to mutate SARS-CoV-2 for mouse research, and the mutations that occurred in this virus were similar to those found in previous research [2].
Two days after infection, the virus was found in all the organs in the body, but in four days, it was found only in the lungs and heart. Interestingly, while it did not kill young C57BL/6 (Black 6) mice, the most common mouse strain used in research, it killed many young BALB/c albino mice, along with middle-aged Black 6 mice, approximately a week after infection.
A pathway enhanced with aging
Previous research had found that a specific prostaglandin pathway, which increases susceptibility to the original SARS virus, was increased with age [3]. It involves prostaglandin D2 (PGD2), a phospholipase known as PLA2G2D, and PTGDR, a PGD2 receptor. This pathway is known to be upregulated by oxidative stress and inflammaging, the increased inflammation associated with age.
This pathway is critical to SARS-CoV-2 infection as well. Testing on middle-aged Black 6 mice, the researchers infected 9 mice that did not express PTGDR, 9 other mice that did not express PLA2G2D, and a control group of 8 wild-type mice. Five of the PTGDR-negative mice perished a week after infection, all of the wild-type mice perished within 8 days, and every single one of the PLA2G2D-negative mice survived the disease.
The researchers attempted to interfere with this pathway by administering indomethacin, a non-steroidal anti-inflammatory drug. However, this approach was found to be ineffective.
Therefore, they turned to aspiprant, a drug that is known to specifically target the PGD2 pathway in humans. Beginning to administer the drug two days after infection and continuing for six days, they found that it was nearly miraculous in their mouse model. While the murine version of SARS-CoV-2 killed all of the ten control mice, only a single one of the dozen treated mice died. This made the survival rate of middle-aged Black 6 mice very similar to that of young mice.
Additionally, aspiprant reduced lung fluids, better preserved body weight, and partially prevented abnormal lung thickening.
Conclusion
Unlike other recently published murine research, this approach is already being explored in a Phase 2 human trial, as asapiprant has already been thoroughly tested for safety in trials for allergic rhinitis. Five of the authors of this paper are employees of BIOAGE Labs, the company conducting this human trial. If it proves successful, this approach will demonstrate that counteracting pathways that are upregulated in aging is a viable approach towards fighting infectious disease.
Literature
[1] Wan, Y., Shang, J., Graham, R., Baric, R. S., & Li, F. (2020). Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. Journal of virology, 94(7), e00127-20.
[2] Leist, S. R., Dinnon III, K. H., Schäfer, A., Longping, V. T., Okuda, K., Hou, Y. J., … & Baric, R. S. (2020). A mouse-adapted SARS-CoV-2 induces acute lung injury and mortality in standard laboratory mice. Cell, 183(4), 1070-1085.
[3] Vijay, R., Hua, X., Meyerholz, D. K., Miki, Y., Yamamoto, K., Gelb, M., … & Perlman, S. (2015). Critical role of phospholipase A2 group IID in age-related susceptibility to severe acute respiratory syndrome–CoV infection. Journal of Experimental Medicine, 212(11), 1851-1868.
