Mechanisms of Recovery from Viral Pneumonia

Recovery from viral pneumonia is a clinically important yet understudied process. Infection with a virus such as influenza A virus or severe acute respiratory syndrome coronavirus 2 can cause severe viral pneumonia, which damages the lower respiratory tract to induce acute respiratory distress syndrome (ARDS). Despite advances in supportive care and treatment with antiviral medications, viral pneumonia–induced ARDS carries a mortality rate approaching 40%. Most ARDS deaths occur days to weeks after ARDS onset—a time when patients are recovering from the inciting insult—yet studies in murine models typically focus on the early development of acute lung injury and death from overwhelming infection. Other than avoidance of additional lung injury, via low tidal volume ventilation and a handful of other supportive therapies, there are no specific therapies for patients with viral pneumonia–induced ARDS.

A central hypothesis of this PPG award, led by SQLIFTS Health Education Program Director Karen Ridge, PhD, is that the persistence of respiratory failure and the development of multiple organ dysfunction in patients with ARDS is a consequence of the failure of normal mechanisms of inflammation resolution and lung tissue repair. This hypothesis is clinically supported by a recent analysis of patients enrolled in the ARDSnet in which a “hyperinflammatory” endotype of ARDS patients was associated with worse clinical outcomes, including death. We propose to investigate the process of recovery from viral pneumonia with a focus on mechanisms that promote resolution of lung inflammation and healthy repair of lung damage.

Investigators at SQLIFTS collaborate to test this central hypothesis through a highly integrated and innovative set of experiments. In Project 1, led by Karen Ridge, PhD, we will determine whether vimentin regulates persistent inflammation during recovery from severe influenza A virus–induced pneumonia by promoting a pro-inflammatory phenotype in monocyte-derived alveolar macrophages and by limiting the pro-repair capacity of regulatory T cells. In Project 2, led by led by SQLIFTS Discovery Program Director Navdeep Chandel, PhD, we will determine whether mitochondrial electron transport chain complex I or III, and lactate production, drives persistent NLRP3 inflammasome–dependent inflammation during recovery from severe influenza A virus–induced pneumonia. In Project 3, led by SQLIFTS Director Scott Budinger, MD, we will determine whether persistent activation of LUBAC-mediated NF-kB signaling in the lung epithelium drives macrophage activation and inhibits lung repair following viral pneumonia. In Project 4, led by Benjamin Singer, MD, we will determine whether DNA methyltransferase activity and UHRF1 induce DNA hypermethylation in regulatory T (Treg) cells during aging to impair Treg cell reparative function following severe viral pneumonia in older hosts.

By linking causal mechanistic studies in cell and murine models with bronchoalveolar samples from patients with severe viral pneumonia, we seek to identify mechanisms that promote the successful transition from the initial deleterious phases of acute lung injury to the later phases of resolution and lung repair in the virus-injured lung.