Unraveling the role of the CFTR ion channel in susceptibility to SARS-CoV-2 infection and inflammation

SummaryThis administrative supplement (under NIH PA-18-591 Administrative Supplements to Existing NIH Grants andCooperative Agreements) seeks funding for research responsive to the SARS-CoV-2/COVID-19 outbreak thatfalls 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 FibrosisTransmembrane 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 withimpaired bacterial clearance and increased lung inflammation, which ultimately results in lung failure. As an ionchannel, CFTR regulates fluid homeostasis in the lung. In addition, our published studies demonstrated for thefirst time that macrophages lacking functional CFTR had impaired autophagy resulting in excessive inflammatoryprofile. 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 aglobal 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 theCFTR 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 willreveal 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 newtherapeutics for COVID-19.