Cigarette smoke increases susceptibility to infection in lung epithelial cells by upregulating caveolin-dependent endocytosis

Abstract

Cigarette smoke exposure is a risk factor for many pulmonary diseases, including Chronic Obstructive Pulmonary Disease (COPD). Cigarette smokers are more prone to respiratory infections with more severe symptoms. In those with COPD, viral infections can lead to acute exacerbations resulting in lung function decline and death. Epithelial cells in the lung are the first line of defense against inhaled insults such as tobacco smoke and are the target for many respiratory pathogens. Endocytosis is an essential cell function involved in nutrient uptake, cell signaling, and sensing of the extracellular environment, yet, the effect of cigarette smoke on epithelial cell endocytosis is not known. Here, we report for the first time that cigarette smoke alters the function of several important endocytic pathways in primary human small airway epithelial cells. Cigarette smoke exposure impairs clathrin-mediated endocytosis and fluid phase macropinocytosis while increasing caveolin mediated endocytosis. We also show that influenza virus uptake is enhanced by cigarette smoke exposure. These results support the concept that cigarette smoke-induced dysregulation of endocytosis contributes to lung infection in smokers. Targeting endocytosis pathways to restore normal epithelial cell function may be a new therapeutic approach to reduce respiratory infections in current and former smokers.

Smoking and COVID-19: What we know so far

“…There are multiple mechanisms through which smoking or exposure to cigarette smoke may increase the risk of viral infections. These include alterations in airway biology, such as activation of the epithelium and hallmark structural changes in the respiratory tract such as impaired mucociliary clearance, mucus hypersecretion, fibrosis and epithelial barrier dysfunction, as well as alterations in the immune response [28,[32][33][34][35].…”

Molecular Mechanisms of Lipid Metabolism Disorders in Infectious Exacerbations of Chronic Obstructive Pulmonary Disease

“…Recent studies demonstrate convincingly the ability of some viruses and bacteria to use the endocytic properties of lipid microdomains to enter cells [ 164 , 165 , 166 , 167 , 168 ]. It is also shown that cigarette smoke alters the function of several important endocytic pathways in the epithelial cells of the respiratory tract, increasing caveolin-mediated endocytosis, which may contribute to lung infection in smokers [ 169 ].…”

Exploring the Mystery of Angiotensin-Converting Enzyme II (ACE2) in the Battle against SARS-CoV-2

“…Furin and TMPRSS2 (transmembrane protease serine 2) are also other host cellular enzymes involved in the priming of coronavirus spike proteins [ 7 , 11 ]. Recent research has shown that ACE2 is differentially regulated in certain circumstances (cigarette smoking) at RNA and protein levels and suggested that its RNA and protein levels are generally correlated [ 16 ].…”

“…These results provide the clue that increased expression of the ACE2 might increase the risk of SARS-CoV-2 infection. ACE2 receptors mediate the entry into the cell of three strains of coronaviruses (SARS-CoV, NL63, and SARS-CoV-2) [ 16 ]. ACE2 downregulation induced by viral invasion may be especially detrimental in people with baseline ACE2 deficiency associated.…”