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

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 severe acute respiratory syndrome coronavirus 2 (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 with non-AUD cells. Bronchial epithelial cells from patients with AUD showed a significant decrease in barrier function 72 h postinfection, 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 (ZO-1), indicative of disorganized tight junctions. However, both AUD and non-AUD cells showed decreased ß-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 proinflammatory cytokines including TNFα, IL-1ß, and IFNγ as opposed to non-AUD cells. In contrast, secretion of the barrier-protective cytokines epidermal growth factor (EGF) and granulocyte macrophage-colony stimulating factor (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 increased barrier dysfunction and increased inflammation in response to infection by SARS-CoV-2.NEW & NOTEWORTHY Alcohol use disorder (AUD) is a significant risk factor for severe acute respiratory distress syndrome. We found that AUD causes a phenotypic shift in gene expression in human bronchial epithelial cells, enhancing expression of epidermal genes. AUD cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had higher levels of proinflammatory cytokine secretion and barrier dysfunction not present in infected non-AUD cells, consistent with increased early COVID-19 severity due to AUD.

Inheritance of paternal lifestyles and exposures through sperm DNA methylation.

Many different lifestyle factors and chemicals present in the environment are a threat to the reproductive tracts of humans. The potential for parental preconception exposure to alter gametes and for these alterations to be passed on to offspring and negatively affect embryo growth and development is of concern. The connection between maternal exposures and offspring health is a frequent focus in epidemiological studies, but paternal preconception exposures are much less frequently considered and are also very important determinants of offspring health. Several environmental and lifestyle factors in men have been found to alter sperm epigenetics, which can regulate gene expression during early embryonic development. Epigenetic information is thought to be a mechanism that evolved for organisms to pass on information about their lived experiences to offspring. DNA methylation is a well-studied epigenetic regulator that is sensitive to environmental exposures in somatic cells and sperm. The continuous production of sperm from spermatogonial stem cells throughout a man's adult life and the presence of spermatogonial stem cells outside of the blood-testis barrier makes them susceptible to environmental insults. Furthermore, altered sperm DNA methylation patterns can be maintained throughout development and ultimately result in impairments, which could predispose offspring to disease. Innovations in human stem cell-based spermatogenic models can be used to elucidate the paternal origins of health and disease.

Implications of testicular ACE2 and the renin-angiotensin system for SARS-CoV-2 on testis function.

Although many studies have focused on SARS-CoV-2 infection in the lungs, comparatively little is known about the potential effects of the virus on male fertility. SARS-CoV-2 infection of target cells requires the presence of furin, angiotensin-converting enzyme 2 (ACE2) receptors, and transmembrane protease serine 2 (TMPRSS2). Thus, cells in the body that express these proteins might be highly susceptible to viral entry and downstream effects. Currently, reports regarding the expression of the viral entry proteins in the testes are conflicting; however, other members of the SARS-CoV family of viruses - such as SARS-CoV - have been suspected to cause testicular dysfunction and/or orchitis. SARS-CoV-2, which displays many similarities to SARS-CoV, could potentially cause similar adverse effects. Commonalities between SARS family members, taken in combination with sparse reports of testicular discomfort and altered hormone levels in patients with SARS-CoV-2, might indicate possible testicular dysfunction. Thus, SARS-CoV-2 infection has the potential for effects on testis somatic and germline cells and experimental approaches might be required to help identify potential short-term and long-term effects of SARS-CoV-2 on male fertility.