Chronic alcohol use primes bronchial cells for altered inflammatory response and barrier dysfunction during SARS-CoV-2 infection.

Abstract

Alcohol Use Disorder (AUD) is a significant public health concern and people with AUD are more likely to develop severe acute respiratory distress syndrome (ARDS) in response to respiratory infections. To examine whether AUD was a risk factor for more severe outcome in response to SARS-CoV-2 infection, we examined early responses to infection using cultured differentiated bronchial epithelial cells derived from brushings obtained from people with AUD or without AUD. RNA-seq analysis of uninfected cells determined that AUD cells were enriched for expression of epidermal genes as compared to non-AUD cells. Bronchial epithelial cells from AUD patients showed a significant decrease in barrier function 72 h post infection, as determined by transepithelial electrical resistance. In contrast, barrier function of non-AUD cells was enhanced 72 h after SARS-CoV-2 infection. AUD cells showed claudin-7 that did not colocalize with zonula occludens-1, indicative of disorganized tight junctions. However, both AUD and non-AUD cells showed decreased β-catenin expression following SARS-CoV-2 infection. To determine the impact of AUD on the inflammatory response to SARS-CoV-2 infection, cytokine secretion was measured by multiplex analysis. SARS-CoV-2-infected AUD bronchial cells had enhanced secretion of multiple pro-inflammatory cytokines including TNFα, IL-1β, and IFNγ as opposed to non-AUD cells. In contrast, secretion of the barrier-protective cytokines EGF and GM-CSF was enhanced for non-AUD bronchial cells. Taken together, these data support the hypothesis that AUD is a risk factor for COVID-19, where alcohol primes airway epithelial cells for increased inflammation and barrier dysfunction in response to infection by SARS-CoV-2.