The Role of Tuft Cells During Virus-Mediated Acute Lung Injury

Our proposed study is highly relevant to the following Fiscal Year 2020 Peer Reviewed Medical Research Program Topic Area(s): Respiratory Health and Emerging Viral Diseases, in terms of the roles of tuft cells in virus-mediated lung injury. Respiratory infections continue to threaten global health security and economics, with a higher risk in military trainees and newly mobilized troops, including coronaviruses (e.g., SARS-CoV, MERSCoV), influenza viruses (e.g., avian influenza H5N1, H7N9 and H10N8; variant influenza A H1N1 and H3N2), adenovirus (e.g., human adenovirus-14). Coronavirus disease 2019 (COVID-19), an emerging, rapidly evolving situation, is caused by a newly identified betacoronavirus (SARS-COV-2). As of May 17, 2020, the COVID-19 pandemic has affected almost 4.5 million people in 214 countries on five continents, carrying a mortality of approximately 6.8%. With more than 1.4 million confirmed cases and close to 86,000 deaths, the USA has become the current center of the global COVID-19 pandemic. The COVID-19 pandemic is not the first of its kind and it won't be the last. The pandemic potential of newly emerging viruses heightens the importance of understanding disease pathogenesis, which may lead to new therapeutic strategies.

Viral infections in the lung are thought to induce acute respiratory distress syndrome (ARDS), which displays a rapid onset of pneumonia, diffuse alveolar damage and hypercytokinemia and associated hypoxia. Additionally, severe virus-infected lungs (including patients with ARDS), and idiopathic pulmonary fibrotic (IPF) lungs, display the characteristics of honeycombed cysts, which are a massive expansion of a rear subpopulation of cells characterized by cytokeratin 5 (Krt5) expression. They form dysplastic 'epithelial scars' that persist throughout the lifespan of mice and likely humans and seemingly do not contribute to pulmonary gas exchange functions. In addition, in terms of viral infection, mucus plays a critical role in fighting against pathogens and in protecting the lung. However, impaired mucus clearance after chronic mucus hyperproduction causes airway obstruction and infection, as seen in IPF, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis (CF), primary ciliary dyskinesia (PCD), and bronchiectasis. The increased production and secretion of mucus by goblet cells contribute to morbidity and mortality in the above common pulmonary disorders.

Within the disorganized peripheral lung (Krt5+ pods), tuft cells have been recently observed. Regarding the roles of tuft cells, it's reported that tuft cells initiate a type 2 immune response in the trachea and in the small intestine, and result in goblet cell hyperplasia in the small intestine. However, the roles of newly emerging tuft cells in Krt5+ pod areas during virus-meditated injury remain unknown, which we propose to study utilizing H1N1 influenza mouse model. We hypothesize that tuft cells impede lung injury-repair (Aim 1) and promote excessive mucus production in lung parenchyma (Aim 2), by which tuft cells at least in part regulate the cell fate of Krt5+ pod cells towards alveolar cells versus goblet cells through activating Notch pathway. Notably, immunofluorescence staining of COVID-19/IPF tissues showed the presence of Krt5+ pod cells/tuft cells, which implies the general role of tuft cells in common pulmonary diseases. The proposed study would provide new knowledge in the area of lung epithelial remodeling, particularly for the role of tuft cells in virus-meditated injury-repair and mucous metaplasia in lung parenchyma. The characterization of tuft cells' role would provide a new therapeutic target for virus-mediated fatal acute lung injury. If successful, this study would also pave a new road for the treatment of patients with other common pulmonary disorders.