Cigarette Smoke Deteriorates SARS-CoV-2 Infection-Induced Lung Injury

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic with over 778 million confirmed cases and over 7 million deaths. Chronic obstructive pulmonary disease (COPD) mainly developed by cigarette smoke (CS), is considered as a risk factor for COVID-19 severe symptoms. However, there is a gap in our knowledge of host-viral interactions for susceptibility to SARS-CoV-2 infection and disease severity. Equal numbers (n = 14) of K18-h (angiotensin-converting enzyme) ACE2 transgenic mice were randomized for sham air (SA) exposure as control group or CS group (2-h CS exposure per day) for 7 days. On Day 8, mice were randomly subdivided into mock infection (n = 6) and SARS-CoV-2 infection (n = 8) for 3 days. Lung tissues were harvested after sacrifice for analysis of viral susceptibility, morphological changes, host immune response, and endoplasmic reticulum (ER) stress. CS exposure increased viral susceptibility by upregulating virus binding receptors ACE2 and binding immunoglobulin protein (BiP), subsequently causing ER stress via activation of activating transcription factor (ATF)6 pathway and protein kinase R (PKR) pathway, resulting in greater immune response and apoptosis. Prior CS exposure caused further deterioration of SARS-CoV-2-induced epithelial damage via the loss of epithelial junctions, ciliary dysfunction, mucus hypersecretion, and lung fibrosis. The current findings suggest that ER stress is likely to play a role in the deterioration of SARS-CoV-2-induced lung injury prior CS exposure. This study provides a better understanding of the pathogenesis of SARS-CoV-2 infection in smokers and possible therapeutic targets for treatment.