The Impact of Pulmonary Influenza Infection on the Pathogenesis of Myocardial Infarction and Heart Failure

Respiratory infections like those caused by influenza A virus (IAV) represent a prominent cause of morbidity and mortality globally. Outside of its well-characterized effects in the lung, IAV infection accelerates cardiovascular disease, leading to an approximate six-fold increase in the likelihood of myocardial infarction (MI). This strongly suggests an essential pulmonary-cardiac immunological crosstalk during infection. Despite these observations, very little is known mechanistically as to how IAV disrupts cardiac homeostasis, damages the heart and promotes cardiovascular disease pathogenesis. Using a combination of innovative mouse models of respiratory infection, myocardial infarction (MI) and heart failure (HF), Dr. Jeffrey Downey will comprehensively probe the hypothesis that IAV translocates from the lung to the heart and induces an antiviral response that damages the heart, leaving it more susceptible to disease. Elucidating how exactly IAV accesses and impacts the heart will not only unravel a novel pulmonary-cardiovascular immunological axis, but will also serve to address an unmet clinical need in countering infection-induced cardiovascular events. This proposal is composed of three aims. In the first aim, we will study the effects of pulmonary IAV infection on the heart, building on preliminary data that show (1) elevated troponin in humans and mice and (2) impaired heart function in mice after infection. We will determine which cells become infected and examine how the virus causes damage, expanding on our preliminary data that suggest direct type I interferon (IFN-I) signaling on cardiomyocytes causes the decline in cardiac function. In the second aim, we will investigate how underlying infection alters the pathogenesis of MI and influences its severity using a unique approach that combines our IAV mouse model with two types of MI. We will moreover genetically target IFN-I signaling in cardiomyocytes and utilize cutting-edge CRISPR/Cas9 technologies to minimize MI risk following infection. Finally, in aim three during the independent phase, Dr. Downey will interrogate the bidirectional influence of anti-IAV immunity on the development and progression of HF, by testing if established HF promotes susceptibility to IAV and if previous infection accelerates HF. Collectively, these studies will greatly expand our understanding of inter-organ inflammatory communication during infection and disease, while also providing greatly needed therapeutic targets. Dr. Downey will primarily conduct this research within the Cardiovascular Research Institute at the esteemed Icahn School of Medicine at Mount Sinai under the primary mentorship of Dr. Filip Swirski, a world-renowned investigator of cardio-immunology, and co-mentorship by Dr. Michael Schotsaert, a leader in virology, microbiology, and vaccinology. Dr. Downey has additionally assembled an elite Advisory Committee comprised of Dr. Mandy Van Leent, a pioneer in non-invasive multiparametric imaging and immunotherapy, and Dr. Deepak Bhatt, the leading expert in interventional cardiology and cardiovascular clinical trials. Together, these mentors will help Dr. Downey foster his own successful research program and facilitate his career as an independent biomedical investigator. Project Number: 1K99HL177314-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Jeffrey Downey | Institution: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, NEW YORK, NY | Award Amount: $167,940 | Activity Code: K99 | Study Section: NHLBI Mentored Transition to Independence Study Section[MTI (MA)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K99HL17731401A1