This administrative supplement (under NIH PA-18-591 Administrative Supplements to Existing NIH Grants and Cooperative Agreements) seeks funding for research responsive to the SARS-CoV-2/COVID-19 outbreak that falls within the scope of the ongoing grant 5R01AI124121-05. The original grant (5R01AI124121-05) is focused on understanding the role of the ion channel Cystic Fibrosis Transmembrane conductance Regulator (CFTR) on exacerbated inflammation in the airways. Patients with mutations in this ion channel leading to its malfunction develop Cystic Fibrosis (CF), a disease associated with impaired bacterial clearance and increased lung inflammation, which ultimately results in lung failure. As an ion channel, CFTR regulates fluid homeostasis in the lung. In addition, our published studies demonstrated for the first time that macrophages lacking functional CFTR had impaired autophagy resulting in excessive inflammatory profile. In addition to inflammation, the CFTR ion channel plays also a role in fluid homeostasis in the lung such as edema. Relevant to this Supplement, findings from our group show that mice with reduced CFTR (heterozygous) have increased expression of the severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 receptor ACE2. The novel emergent pathogen responsible for COVID-19, SARS-CoV-2, is a global threat responsible for over 420,000 deaths worldwide as of today and is projected to cause >130,000 deaths in the US alone by the end of June 2020.
In Aim 1, we will identify mutations and polymorphisms in the CFTR gene in SARS-CoV-2 positive patients.
Aim 2 will determine whether there is a genetic association between CFTR mutations and polymorphisms and severity of respiratory disease. Findings from this study will reveal whether CFTR is a modifier gene to COVID-19. This study will help in the identification of patients prone to respiratory failure or death upon SARS-CoV-2 infection and manage them before they succumb to respiratory failure. Future studies will establish pharmacological compounds that increase CFTR function as new therapeutics for COVID-19.
Lay Summary SARS-CoV-2, responsible for COVID-19 has already caused over 420,000 deaths worldwide and a second wave is expected to cause additional deaths since there is currently no vaccine or cure. We hypothesize that the ion channel CFTR contributes to SARS-CoV-2 infection and decline of pulmonary function, and here we will identify mutations and polymorphisms present in the CFTR gene to determine whether they correlate with severity of lung disease. This will help in the identification and management of patients that have the tendency to succumb to infection before they go into respiratory failure.
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| Krause, Kathrin; Kopp, Benjamin T; Tazi, Mia F et al. (2018) The expression of Mirc1/Mir17-92 cluster in sputum samples correlates with pulmonary exacerbations in cystic fibrosis patients. J Cyst Fibros 17:454-461 |
| Shrestha, Chandra L; Assani, Kaivon D; Rinehardt, Hannah et al. (2017) Cysteamine-mediated clearance of antibiotic-resistant pathogens in human cystic fibrosis macrophages. PLoS One 12:e0186169 |
