Pathogenic mechanisms of chronic lung sequelae following respiratory viral infection

SUMMARY The COVID-19 pandemic has brought the world's attention on respiratory viral infections. It is not a question of if another respiratory viral pandemic will arise, but rather when. The diversity of viral pathogens presents a tremendous challenge for designing virus targeted preventions and therapeutics. However, respiratory viruses cause similar lung injury that drives morbidity and mortality. A focus on host mediated lung injury pathways in this context is warranted, as there is potential for therapeutic interventions that would be effective across a range of respiratory viral infections. The COVID-19 pandemic has drawn attention to a poorly characterized phenotype of persistent lung inflammation that lasts well beyond clearance of live virus. Long-COVID and long-Flu are clinical diagnoses that lack an understanding of the molecular underpinnings of disease. In this application, we focus on understanding the mechanism by which respiratory viral infection causes lasting tissue damage covering antigen persistence, presentation, and a positive feedback inflammatory cell network. We propose that the persistent presence of viral antigen in pulmonary endothelial cells is a major driver for the prolonged activation of CD8+ T cells, consequently leading to chronic pulmonary sequelae, through reinforced interaction of CD8+ TRM cells and pro-inflammatory macrophages. This hypothesis will be tested in two Aims: 1) we will investigate the contribution of persistent activation of CD8+ T cells by pulmonary endothelial cells to the development of chronic pulmonary sequelae, and 2) we will interrogate the T cell and macrophage inflammatory axis in persistent inflammation during recovery from respiratory viral infection. To examine these pathways, we will employ the SARS-CoV-2 and influenza virus mouse models, and we will confirm findings using tissue from human patient transbronchial biopsies. Discovery of causative host inflammatory pathways that are critical to post-viral lung sequelae would provide pre-clinical evidence to support clinical trials. If pathogenic mechanisms are indeed similar between multiple respiratory viruses, then host-directed therapeutics would potentially have a tremendous impact. Currently, there are no specific therapies indicated for the treatment of post-viral lung inflammation.