Overlooked Coronavirus Protein May Drive Cytokine Storm, Cardiac Injury in Severe COVID-19

Six years after the height of the COVID-19 pandemic, researchers continue to uncover new ways SARS-CoV-2 damages the body. A study published in Science Advances by investigators at the University of California, Los Angeles (UCLA), describes a previously unrecognized function of the nucleocapsid (N) protein—a structural component of the virus that has received far less attention than the spike protein driving most vaccine development.^1,2

The N protein's primary role is to package and protect the virus's genetic material, and it has long been known to suppress the body's early antiviral defenses. However, the new findings show that within macrophages, the same protein can simultaneously fuel dangerous, excessive inflammation.^1,2

Study Design and Key Findings

The research team investigated whether SARS-CoV-2's N protein manipulated the innate immune system the same way as N proteins from SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Using macrophage-like cells, the investigators found that N amplifies extracellular RNA sensing through Toll-like receptors (TLRs) while dampening intracellular sensing pathways typically responsible for antiviral interferon responses.^1,2

“We set out looking for a protein that suppresses the immune response, and we found the opposite," said Zhenlan Yao, PhD, co-first author of the study and assistant project scientist at UCLA.² The effect was conserved across pathogenic betacoronaviruses, although each virus appeared to drive inflammation through distinct downstream mechanisms.¹

Among SARS-CoV-2 variants tested, the Delta variant's N protein proved to be the most inflammatory, driving its effects in part through interactions with cyclic GMP-AMP synthase (cGAS), a key DNA-sensing protein. Cytokine profiling further revealed that N protein disrupts the secretion of inflammatory mediators in a variant-specific manner.¹

Vascular Leakage Implicates Cardiac Complications

To explore the clinical relevance of these findings, researchers exposed 2 human cell–based models—representing the blood-brain barrier and the coronary artery lining—to fluid containing signals from macrophages producing the Delta variant's N protein. The coronary artery endothelial barrier broke down significantly, a phenomenon known as vascular leakage.^1,2

Because the heart relies on tight, selective blood vessel linings for normal function, this finding offers a possible mechanistic explanation for the cardiac injury observed in severe COVID-19 cases. Cardiovascular complications, including endothelial dysfunction and myocardial inflammation, have also been increasingly implicated in long COVID, with several reviews describing persistent vascular injury as a central driver of ongoing symptoms such as chest pain and exercise intolerance.^1,3,4

Rethinking Treatment for Severe and Long COVID-19

Currently, severe COVID-19 cases are often managed with broad anti-inflammatory agents, such as corticosteroids, which dampen harmful inflammation but do not specifically target the viral mechanisms believed to be driving it. While corticosteroids like dexamethasone have demonstrated benefit in reducing mortality and complications in hospitalized patients, their systemic immunosuppressive effects carry a wide range of adverse effects and do not address the specific viral machinery responsible for hyperinflammation.⁵

According to study authors, a therapy or vaccine that specifically targets the N protein could offer a more precise way to rein in hyperinflammation, potentially protecting the vascular barriers that support brain and heart health without the drawbacks of broad immunosuppression. Because macrophages play a similarly dual role in many infections beyond COVID-19, the researchers noted that this mechanism could have implications extending well beyond SARS-CoV-2.²

Clinical Takeaways for Pharmacists

For pharmacists managing patients with a history of severe COVID-19 or persistent post-viral cardiovascular symptoms, these findings underscore the biological plausibility of a distinct viral mechanism behind endothelial injury, separate from direct viral invasion of cardiac tissue. Although a nucleocapsid-targeted therapeutic is likely years away from clinical use, the study adds to a growing body of evidence supporting more mechanism-specific approaches to managing COVID-19–associated inflammation and its cardiovascular sequelae.^1,3,4,5

The study authors noted that continued investigation into COVID-19 pathophysiology remains critical, particularly for immunocompromised patients and others who may not respond fully to existing vaccines or treatments.²

REFERENCES

1. Yao Z, Alvarez PA, Chavez C, et al. SARS-CoV-2 nucleocapsid induces hyperinflammation and vascular leakage through the Toll-like receptor signaling axis in macrophages. Sci Adv. 2026;12(32). doi:10.1126/sciadv.aea2780

2. A lesser-known SARS-CoV-2 protein may offer clues to long COVID symptoms. News release. EurekAlert. August 5, 2026. Accessed August 24, 2026. https://www.eurekalert.org/news-releases/1139021

3. Zhang T, Li Z, Mei Q, et al. Cardiovascular outcomes in long COVID-19: a systematic review and meta-analysis. Front Cardiovasc Med. 2025;12:1450470.doi:10.3389/fcvm.2025.1450470

4. Thomas D, Yang P, Wu J, Sayed N. Decoding long COVID-associated cardiovascular dysfunction: mechanisms, models, and new approach methodologies. J Mol Cell Cardiol. 2025;209:37-50. doi: 10.1016/j.yjmcc.2025.09.008

5. Que Y, Hu C, Wan K, et al. Cytokine release syndrome in COVID-19: a major mechanism of morbidity and mortality. Int Rev Immunol. 2022;41(2):217-230. doi:10.1080/08830185.2021.1884248