Crosslink between SARS-CoV-2 replication and cystic fibrosis hallmarks

Abstract

SARS-CoV-2, the etiological cause of the COVID-19 pandemic, can cause severe illness in certain at-risk populations, including people with cystic fibrosis (pwCF). Nevertheless, several studies indicated that pwCF do not have higher risks of SARS-CoV-2 infection nor do they demonstrate worse clinical outcomes than those of the general population. Recent in vitro studies indicate cellular and molecular processes to be significant drivers in pwCF lower infection rates and milder symptoms than expected in cases of SARS-CoV-2 infection. These range from cytokine releases to biochemical alterations leading to morphological rearrangements inside the cells associated with CFTR impairment. Based on available data, the reported low incidence of SARS-CoV-2 infection among pwCF is likely a result of several variables linked to CFTR dysfunction, such as thick mucus, IL-6 reduction, altered ACE2 and TMPRSS2 processing and/or functioning, defective anions exchange, and autophagosome formation. An extensive analysis of the relation between SARS-CoV-2 infection and pwCF is essential to elucidate the mechanisms involved in this lower-than-expected infection impact and to possibly suggest potential new antiviral strategies.

Beyond Borders of the Cell: How Extracellular Vesicles Shape COVID-19 for People with Cystic Fibrosis

“…These EVs, secreted during EMT, target endothelial cells and contribute to immune suppression and fibrogenesis. Inflammation is a significant component of CF pathogenesis and SARS-CoV-2 infection [110]. The content of EVs in PwCF and SARS-CoV-2 infection is summarized in Figure 1.…”

Loss of CFTR Reverses Senescence Hallmarks in SARS-CoV-2 Infected Bronchial Epithelial Cells

“…Moreover, CFTR has been implicated in cellular processes, such as apoptosis [ 46 ], carcinogenesis [ 47 ], and inflammation [ 48 ]. Research indicates its involvement in host defense against viral infections, such as SARS-CoV-2, where CFTR deficiency correlates with decreased susceptibility [ 31 , 49 , 50 , 51 ]. In this study, we compared senescence markers in WT and CFTR-knockout (KO) human bronchial 16HBE14o-cells.…”

“…Notably, CF cell lines and CFTR knockout animal studies indicate that the loss of CFTR is sufficient to generate a proinflammatory environment [ 62 ], which can lead to the ROS-mediated activation of transglutaminase-2 (TGM-2) and the inactivation of the Beclin-1 complex, resulting in autophagy impairment [ 55 , 63 , 64 ]. Since the results in mock-infected cells suggested the activation of a senescence-like pathway in CFTR-modified cells, and previously published data highlighted a low impact of SARS-CoV-2 on these cells [ 31 , 32 , 49 , 50 , 65 ], we aimed to analyze a possible interaction between senescence pathways, CFTR expression/function, and SARS-CoV-2 infection. Viral infections can trigger premature cellular senescence, known as virus-induced senescence (VIS).…”