Unveiling the Pathologic Response of Cardiac Fibroblasts During Aspergillus fumigatus Pulmonary Infections

Abstract

Various adverse cardiovascular events have been associated with lung damage as a result of pathological infections followed by chronic inflammation. In this context, several recent studies report severe cardiovascular complications after pulmonary infection by SARS‐CoV‐2. Therefore, determining the physiological link between abnormal pulmonary and cardiac function is an emerging clinical need in the cardiovascular field. The main limitation of these studies has been the lack of specific genetic tools and mouse models to study the cellular and molecular mechanisms that regulate the lung‐heart interactions. To induce lung damage we utilized a common airborne environmental fungus, Aspergillus fumigatus (AF), which is an opportunistic pathogen that establishes pathological infection in the lung if the immune system is compromised. However, in immunocompetent animals, transient stress to the lung is still detectable before clearance via immune cells. Our lab has discovered that pulmonary fibroblasts (PFs), typically associated with the maintenance and production of the extracellular matrix, activate in response to inhaled AF spores and modulate the immune response. Moreover, we have also observed activation of cardiac fibroblasts (CFs) in response to the pulmonary AF infection. Therefore, we hypothesized that pulmonary infection leads to cardiac stress, resulting in the activation and pathological response of CFs, and subsequently result in myocardial remodeling, fibrosis, and disease. To test our hypothesis we used our recently developed and described in vivo cre‐loxP lineage tracing mouse lines to specifically tag and manipulate all activated fibroblast during infection, clearing and reinfection. Our data show that CFs can activate after an acute inhalation of AF spores which are quickly cleared in immunocompetent mice with no pathological lung damage. Moreover, subsequent asymptomatic chronic AF infections result in the accumulation of PF and CF pathologic activation. These results reveal a cellular novel link between pulmonary infection and its impact on cardiovascular events.