Researchers discovered the nucleocapsid protein of SARS-CoV-2 triggers hyperinflammation in immune cells, potentially leading to vascular leakage in the heart and brain.
RT’s Three Key Takeaways:
- Pro-inflammatory Mechanism: The SARS-CoV-2 nucleocapsid protein suppresses early antiviral defenses while simultaneously overactivating inflammatory pathways in macrophages, according to a study from UCLA.
- Vascular Damage: Overactivated macrophages release signals that cause vascular leakage in endothelial cell models of the heart and brain, providing a potential mechanism for severe COVID-19 complications.
- Therapeutic Target: Targeting the nucleocapsid protein with new therapies or vaccines could help prevent hyperinflammation and protect blood vessel barriers in patients with severe infections.
UCLA researchers identified a previously unrecognized mechanism by which the SARS-CoV-2 nucleocapsid protein drives the immune system into a dangerous inflammatory state, according to a study published in Science Advances.
While the spike protein has been the primary focus of vaccine research and public attention, the nucleocapsid protein is a structural component responsible for packaging and protecting the virus’s genetic material. The study found that this protein also plays a dual role in how the virus interacts with the immune system.
“Coronaviruses are notorious for encoding proteins that antagonize the body’s natural antiviral defenses,” said Melody Li, an associate professor of microbiology, immunology and molecular genetics and member of the UCLA Broad Stem Cell Research Center, in a news release. “When SARS-CoV-2 first appeared, almost nothing was known about it, so we wanted to find out whether it was using the same playbook.”
The research team, led by Li, investigated how the nucleocapsid protein behaves inside macrophages. These immune cells are responsible for patrolling tissues and releasing chemical signals, such as cytokines and chemokines, to coordinate the body’s defense against infection.
The study found that the protein acts as a “double-edged sword.” While it suppresses the signals that trigger an early antiviral response, it simultaneously amplifies inflammatory pathways within macrophages. This overactivation can lead to tissue-damaging immune responses.
“We set out looking for a protein that suppresses the immune response, and we found the opposite,” said Zhenlan Yao, co-first author of the study and a former postdoctoral researcher in Li’s lab, in a news release. “It was surprising, but it lines up with what we already know about COVID-19: The virus dampens the immune response early on, then overactivates it later — and that’s when a lot of the tissue damage happens.”
The researchers compared nucleocapsid proteins across several variants and other pathogenic coronaviruses, including SARS-CoV-1 and MERS-CoV. They found the pro-inflammatory effect was consistent, with the Delta variant’s version proving the most inflammatory.
When macrophages become overactivated, they release signals that impact nearby tissues, including the endothelial cells that line blood vessels. To test this impact, the team used human cell-based models of the blood-brain barrier and the coronary artery lining.
When exposed to signals from macrophages producing the Delta variant’s nucleocapsid protein, the heart barrier model experienced significant vascular leakage. These findings suggest a mechanism for the cardiac injury and neurological complications observed in severe cases of COVID-19.
The study suggests that targeting the nucleocapsid protein could lead to more precise treatments for severe COVID-19. While broad anti-inflammatory drugs like corticosteroids are currently used to dampen inflammation, a therapy or vaccine targeting this specific protein could potentially rein in hyperinflammation while protecting the blood vessel barriers essential for brain and heart healthcare.
“It’s critical to keep studying COVID-19 so that we can constantly improve patient care — not everyone responds well to vaccines, and people who are immunocompromised often have limited treatment options,” said Pablo Alvarez, co-first author of the study and a former graduate student in Li’s lab, in a news release. “These studies can also help us prepare for future coronavirus outbreaks.”
