Mount Sinai researchers have identified a cellular mechanism linking infections from influenza A viruses (IAVs) to cardiovascular disease, providing critical insights on how influenza can damage the heart and increase the risk of a heart attack or other major cardiovascular event.
Through its work with mouse models and human data, the team also provided evidence that a cutting-edge modified mRNA treatment that dampens an interferon signalling pathway in the heart can significantly mitigate cardiac damage following viral infection while preserving the protective antiviral response of the immune system. The study was recently published in the journal Immunity.
“We have known for years that the frequency of heart attacks increases during flu season, yet outside of clinical intuition, scant evidence exists of the underlying mechanisms of that phenomenon,” says Filip Swirski PhD, Director of the Cardiovascular Research Institute at the Icahn School of Medicine at Mount Sinai and the senior author of the study. “Studies like ours are now shedding valuable light on immune system pathways, like the antiviral cytokine type 1 interferon (IFN-1), that factor into damage to the heart following severe influenza infection. These findings offer great promise for the development of new therapies, which are desperately needed since there are currently no viable clinical options to prevent cardiac damage.”
Influenza A viruses are responsible for an estimated 1 billion infections globally each year, ranging from seasonal flu outbreaks locally to pandemics globally. While most infections are mild and self-resolving, in some cases they can become severe or even fatal, particularly when the virus travels to the heart and triggers the death of cardiomyocytes, specialised muscle cells that are responsible for the rhythmic contraction and relaxation of the heart. Pictured above is a transmission electron micrograph of influenza A virus, late passage
The Mount Sinai team studied autopsies of 35 hospitalised patients who died of influenza and found that more than 85% had at least one significant cardiovascular comorbidity, such as hypertension, and that the majority had multiple comorbidities, including atherosclerosis and cardiac fibrosis, underscoring cardiovascular disease as a major driver of influenza mortality.
The research team also uncovered the mechanism by which cardiac damage occurs. They learned, for example, that a novel subset of white blood cells, known as pro-dendritic cell 3, becomes infected in the lung and, after traveling to the heart, produces large amounts of type 1 interferon. This, instead of fulfilling its mission of clearing the virus from the heart, triggers the death of cardiomyocytes, impairing cardiac output.
“We found that the pro-dendritic cell 3 acts as the ‘Trojan horse’ of the immune system during influenza infection, becoming infected in the lung, trafficking the virus to the heart, and disseminating it to cardiomyocytes. This process causes production of the damaging type 1 interferon that comes with considerable collateral damage to the heart,” explains Jeffrey Downey PhD, a member of Dr Swirski’s laboratory who served as lead author of the study. “The hopeful news for patients is that by injecting a novel mod-RNA therapeutic that modulates the IFN-1 signalling pathway, we reduced levels of cardiac damage, as evidenced by lower troponin, and improved cardiac function, as measured by higher left ventricular ejection fraction.”
As part of its ongoing research, Dr Swirski’s team is collaborating with Lior Zangi PhD, Associate Professor of Medicine (Cardiology), and Genetics and Genomic Sciences, at the Icahn school of Medicine at Mount Sinai, to investigate the use of a safe and effective systemic delivery method of the mod-RNA therapeutic to the heart’s muscle cells, instead of the direct injection method used in its proof-of-concept study. Additional work is focused on the pro-dendritic cell 3 itself: why is it so susceptible to influenza and how could its protective capacity be fully harnessed to potentially minimise heart damage exacerbated by cardiovascular disease?
- Downey J, Oliveira-Coelho A, Kiss MG, et al. Influenza hijacks myeloid cells to inflict type-I interferon-fueled damage in the heart. Immunity. Published online 9 February, 2026. doi:10.1016/j.immuni.2025.12.011