Influenza infection is estimated to cause one billion annual infections globally. While most infections result in symptoms that are mild and self-resolving, some infections may trigger consequences in the heart including cardiomyocyte death leading to desynchronized contraction.
The connection between influenza and cardiovascular conditions has been well documented, however, the mechanisms connecting the respiratory infection to heart function are unclear.
“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,” said senior author Filip Swirski, PhD, director of the Cardiovascular Research Institute at the Icahn School of Medicine at Mount Sinai.
Swirski’s team at the Icahn school of Medicine at Mount Sinai aimed to elucidate this connection, studying both human and mouse hearts to clarify the link between influenza infection and cardiac disease.
The study is published in a paper titled, “Influenza hijacks circulating myeloid cells to inflict IFN-I-fueled damage in the heart” was published in Immunity.
In humans, the team evaluated 35 autopsies of patients who died of influenza while hospitalized. They found that over 85% of these patients had at least one significant cardiovascular comorbidity including hypertension, atherosclerosis, or cardiac fibrosis.
They used mice to dive deeper into the mechanisms driving cardiac damage by influenza infection. Mice infected with influenza were observed to have a new type of white blood cell, pro-dendritic cell 3, migrate from the lung to the heart. Once in the heart, the virus escaped pro-dendritic cell 3, infecting cardiomyocytes and triggering production of large amounts of type 1 interferon in the heart, compromising heart function.
“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,” explained first author Jeffrey Downey, PhD, of the Icahn School of Medicine at Mount Sinai. “This process causes production of the damaging type 1 interferon that comes with considerable collateral damage to the heart.”
“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,” said Swirski. “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.”
Therapeutic efforts to preserve the anti-viral function of interferon in the lungs, while preserving heart function, the team attempted to dampen the function of interferon 1 receptor exclusively in cardiomyocytes. Continuing research in collaboration with Lior Zangi, PhD, associate professor at the Icahn school of Medicine at Mount Sinai, is underway to investigate alternative delivery methods outside of direct injection which was used in the proof-of-concept study.
In addition to developing safe and effective therapies for influenza-induced cardiac events, the team is also focused on clarifying more details of the function of the pro-dendritic cell 3, and how it might be used in the therapeutic development endeavors.
“Pathogens are constantly emerging and evolving, which means our strategies to combat them must evolve as well,” said Swirski. “Better understanding of influenza pathogenesis and immune pathways that are activated throughout the body will help fuel the next stage of advanced care.”
