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Nutrients ; 13(5)2021 May 10.
Article in English | MEDLINE | ID: covidwho-1224082


BACKGROUND: Acute and chronic alcohol abuse has adverse impacts on both the innate and adaptive immune response, which may result in reduced resistance to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and promote the progression of coronavirus disease 2019 (COVID-19). However, there are no large population-based data evaluating potential causal associations between alcohol consumption and COVID-19. METHODS: We conducted a Mendelian randomization study using data from UK Biobank to explore the association between alcohol consumption and risk of SARS-CoV-2 infection and serious clinical outcomes in patients with COVID-19. A total of 12,937 participants aged 50-83 who tested for SARS-CoV-2 between 16 March to 27 July 2020 (12.1% tested positive) were included in the analysis. The exposure factor was alcohol consumption. Main outcomes were SARS-CoV-2 positivity and death in COVID-19 patients. We generated allele scores using three genetic variants (rs1229984 (Alcohol Dehydrogenase 1B, ADH1B), rs1260326 (Glucokinase Regulator, GCKR), and rs13107325 (Solute Carrier Family 39 Member 8, SLC39A8)) and applied the allele scores as the instrumental variables to assess the effect of alcohol consumption on outcomes. Analyses were conducted separately for white participants with and without obesity. RESULTS: Of the 12,937 participants, 4496 were never or infrequent drinkers and 8441 were frequent drinkers. Both logistic regression and Mendelian randomization analyses found no evidence that alcohol consumption was associated with risk of SARS-CoV-2 infection in participants either with or without obesity (All q > 0.10). However, frequent drinking, especially heavy drinking (HR = 2.07, 95%CI 1.24-3.47; q = 0.054), was associated with higher risk of death in patients with obesity and COVID-19, but not in patients without obesity. Notably, the risk of death in frequent drinkers with obesity increased slightly with the average amount of alcohol consumed weekly (All q < 0.10). CONCLUSIONS: Our findings suggest that alcohol consumption has adverse effects on the progression of COVID-19 in white participants with obesity, but was not associated with susceptibility to SARS-CoV-2 infection.

Adaptor Proteins, Signal Transducing/genetics , Alcohol Dehydrogenase/genetics , Alcohol Drinking , Biological Specimen Banks , COVID-19 , Cation Transport Proteins/genetics , Obesity , Polymorphism, Single Nucleotide , SARS Virus , Aged , Alcohol Drinking/genetics , Alcohol Drinking/mortality , COVID-19/genetics , COVID-19/mortality , Disease-Free Survival , Female , Humans , Male , Mendelian Randomization Analysis , Middle Aged , Obesity/genetics , Obesity/mortality , Survival Rate , United Kingdom/epidemiology
mSphere ; 5(3)2020 05 27.
Article in English | MEDLINE | ID: covidwho-774837


Zinc supplementation in cell culture has been shown to inhibit various viruses, like herpes simplex virus, rotavirus, severe acute respiratory syndrome (SARS) coronavirus, rhinovirus, and respiratory syncytial virus (RSV). However, whether zinc plays a direct antiviral role in viral infections and whether viruses have adopted strategies to modulate zinc homeostasis have not been investigated. Results from clinical trials of zinc supplementation in infections indicate that zinc supplementation may be beneficial in a pathogen- or disease-specific manner, further underscoring the importance of understanding the interaction between zinc homeostasis and virus infections at the molecular level. We investigated the effect of RSV infection on zinc homeostasis and show that RSV infection in lung epithelial cells leads to modulation of zinc homeostasis. The intracellular labile zinc pool increases upon RSV infection in a multiplicity of infection (MOI)-dependent fashion. Small interfering RNA (siRNA)-mediated knockdown of the ubiquitous zinc uptake transporter ZIP1 suggests that labile zinc levels are increased due to the increased uptake by RSV-infected cells as an antiviral response. Adding zinc to culture medium after RSV infection led to significant inhibition of RSV titers, whereas depletion of zinc by a zinc chelator, N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) led to an increase in RSV titers. The inhibitory effect of zinc was specific, as other divalent cations had no effect on RSV titers. Both RSV infection and zinc chelation by TPEN led to reactive oxygen species (ROS) induction, whereas addition of zinc blocked ROS induction. These results suggest a molecular link between RSV infection, zinc homeostasis, and oxidative-stress pathways and provide new insights for developing strategies to counter RSV infection.IMPORTANCE Zinc deficiency rates in developing countries range from 20 to 30%, and zinc supplementation trials have been shown to correct clinical manifestations attributed to zinc deficiency, but the outcomes in the case of respiratory infections have been inconsistent. We aimed at understanding the role of zinc homeostasis in respiratory syncytial virus (RSV) infection. Infection of lung epithelial cell lines or primary small-airway epithelial cells led to an increase in labile zinc pools, which was due to increased uptake of zinc. Zinc supplementation inhibited RSV replication, whereas zinc chelation had an opposing effect, leading to increases in RSV titers. Increases in labile zinc in RSV-infected cells coincided with induction of reactive oxygen species (ROS). Both zinc depletion and addition of exogenous ROS led to enhanced RSV infection, whereas addition of the antioxidant inhibited RSV, suggesting that zinc is part of an interplay between RSV-induced oxidative stress and the host response to maintain redox balance.

Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus, Human/metabolism , Virus Replication/drug effects , Zinc/metabolism , Zinc/pharmacology , A549 Cells , Adolescent , Cation Transport Proteins/genetics , Cell Line , Child , Child, Preschool , Epithelial Cells/metabolism , Ethylenediamines/pharmacology , Female , Host-Pathogen Interactions , Humans , Lung/cytology , Lung/metabolism , Male , Oxidative Stress/physiology , RNA Interference , RNA, Small Interfering/genetics , Reactive Oxygen Species/metabolism , Respiratory Mucosa/metabolism , Respiratory Mucosa/virology