Investigation of the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in SARS-CoV-2 pathogenesis 2308341

Abstract

Acute lung injury and persistent inflammation caused by SARS-CoV-2 may lead to further complications after the virus gets cleared. People with Cystic fibrosis (pwCF) are highly vulnerable to pulmonary diseases due to mutations in the CFTR gene. However, there is limited research about SARS-CoV-2 severity in pwCF and subjects carrying a single variant of this gene. Middle-aged (4-5 months old) and elderly (>18 months) mice expressing various levels of CFTR (WT, CFTR Knock out (KO), and heterozygous for CFTR (HET)) were infected with the mouse-adapted SARS-CoV-2 virus, MA10. Body weight and body temperature were measured in addition to spike specific antibodies detected by ELISA, flow cytometry on immune cells from blood samples, and lung histology. Middle-aged KO mice significantly lost less weight than WT and HET mice for both male and female mice. However, HET males lost significantly more weight compared to WT and KO male mice (p = 0.0058 and 0.0004, respectively). HET mice body weight recovery took much longer especially in males for both middle-aged and aged mice (∼28 days for middle-aged mice vs 21 days for KO mice, and 51 days for aged mice vs 25 days for KO mice). This study highlights the significance of carrying CFTR mutation in susceptibility and lung pathology to COVID-19. Our data show that the severity of SARS-CoV-2 infection in different mice CFTR genotypes is highly dependent on the age and gender. Internal OSU funding Viral Immunology (VIR)