The PCSK9 protein holds a dual key to countering COVID-19 infection
The team of Dr. Nabil G. Seidah, Director of the Neuroendocrine Biochemistry Research Unit at the Montreal Clinical Research Institute (IRCM), has uncovered another important mechanism of COVID-19 infection that could help improve the medical management of the disease.
With this study, recently published in the journal Viruses, Dr. Seidah's team is the first to establish, among other things, a direct relationship between the PCSK9 protein, cholesterol and SARS-CoV-2 infection. When SARS-CoV-2 enters the body, the virus binds to the ACE2 receptor in the airways via its surface glycoprotein S, known as Spike. Vaccines against Spike are currently being administered worldwide to prevent viral infection.
Yet, Dr. Seidah's study shows that PCSK9, a protein that regulates LDL cholesterol, known as "bad cholesterol," also plays a role in SARS-CoV-2 infection. The research team found that PCSK9 appears to provide an unsuspected dual pathway to counteract COVID-19. The findings may explain why patients who take statins, which decrease intracellular cholesterol synthesis while increasing PCSK9 synthesis, would be protected in part from long-term hospitalization.
First, PCSK9 appears to reduce the establishment of the infection. In fact, by regulating circulating cholesterol, PCSK9 also leads to the cellular degradation of ACE2 that SARS-CoV-2 needs to enter the respiratory tract, thus reducing the infection. Second, once the infection has taken hold, inhibiting PCSK9 helps control the lethal inflammation associated with COVID-19. PCSK9 therefore appears to be partially responsible for the increase in inflammation once the infection is established. In fact, the main role of the enzyme ACE2 is to generate a strong anti-inflammatory molecule called angiotensin 1-7. Accordingly, by blocking PCSK9, the team observed an increase in the level of ACE2.
“In a COVID-19 context, PCSK9 appears to play an important and paradoxical dual role. On the one hand, it limits the infection, but on the other hand, it contributes to its worsening, explains Dr. Seidah. This new understanding could make a big difference in the medical management of severe cases of COVID-19 that require hospitalization due to the strong inflammatory response induced by coronavirus infection.”
These results are timely as they corroborate the findings of a recent clinical study in which U.S. clinicians administered a PCSK9 inhibitory monoclonal antibody to 60 patients with severe respiratory disease caused by COVID-19. These clinicians observed a significant decrease in the inflammatory disorders and half of the patients were rapidly able to leave the intensive care unit.
Acknowledgements
This work was successful in large part because of a close collaboration between members of Dr. Seidah and Dr. Eric Cohen’s laboratories at the IRCM.
It was made possible in part by two CIHR grants.
