Mechanisms of Recovery from Viral Pneumonia

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: KAREN M RIDGE
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $2,662,883
Funding agency: National Heart Lung and Blood Institute

PROJECT SUMMARY_OVERALL
Recovery from viral pneumonia is a clinically important yet understudied process. Severe influenza A virus and
severe acute respiratory syndrome coronavirus 2 cause severe viral pneumonia, which damages the lower
respiratory tract to induce acute respiratory distress syndrome (ARDS). 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 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 where 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. The PPG investigators
will test this central hypothesis through a highly integrated and innovative set of experiments by focusing on four
Specific Aims:
Specific Aim 1. To 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.
Specific Aim 2. To 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.
Specific Aim 3. To determine whether persistent activation of LUBAC-mediated NF-kB signaling in the lung
epithelium drives macrophage activation and inhibits lung repair following viral pneumonia.
Specific Aim 4. To determine whether DNA methyltransferase activity and UHRF1 induce DNA
hypermethylation in Treg cells during aging to impair Treg cell reparative function following severe viral
pneumonia in older hosts.

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