Abstract Body:
Cardiovascular complications are among the most common diagnoses associated with severe IAV infections. Previous studies have shown that among patients hospitalized with IAV, around 12% had an acute cardiac event, such as acute heart failure or acute ischemic heart disease. Among older patients, even in mild cases of influenza, the risk of acute cardiovascular events increases by two-fold. However, there is little understanding of the basic biological mechanisms linking acute viral infection in the lungs to disease in the heart. Heart stromal cells, particularly fibroblasts, can acquire pro-inflammatory and pro-fibrotic functions and were previously shown to contribute to acute and chronic heart disease. We hypothesize that following an IAV infection, fibroblast activation in the heart initiates acute pathological responses leading to persistent heart disease.
To understand the immune-mediated cardiac effects following severe IAV infections, we used in vitro primary cardiac fibroblasts (CFs) and in vivo mouse models of severe IAV. At both 6 and 9 days after infection, cardiac Troponin T levels were 6-8 fold higher compared to controls, indicating acute damage to cardiomyocytes and heart tissue. We were not able to detect infectious virus or the presence of viral protein in the heart at any time point, suggesting that the cardiac effects of IAV infection do not depend on its replication in the cardiac tissue. Using a multiplex cytokine array, we found that CXCL10, a key mediator in cardiovascular diseases produced by CFs, is significantly upregulated (3-6 fold higher) in the heart at 6 and 9 days after infection, suggesting its role in acute cardiac response during IAV infection. Further, our results showed that at 9 days after infection, interferon-responsive CFs are upregulated by two-fold in the heart, indicating an activated fibroblast state. In vitro studies showed that CFs stimulated by Type I and II interferon resulted in a robust release of CXCL10 from CFs, suggesting their direct involvement in pathogenic response.
Together, these findings indicate that severe IAV infection induces CF activation and production of CXCL10, which may contribute to acute cardiac damage. Future studies will focus on delineating the mechanisms of cardiac inflammation and the spatiotemporal characterization of cardiac damage following severe IAV infection.