Alcohol-induced metabolic changes enhance interferon-α production and mortality of Mycobacterium tuberculosis infected mice 4617

Description Chronic alcoholism is associated with worse outcomes in individuals infected with Mycobacterium tuberculosis (Mtb). Previously, we found that chronic alcohol consumption increases the mortality of Mtb-infected mice due to an increase in IFN-α- production by CD11b+Ly6G+ cells. In the current study, using single-cell transcriptomics and multi color flow cytometry, we identified CD11b+Ly6G+ cells expressing CD74+CD69+ as the major cellular source of IFN-α in alcohol diet-fed Mtb-infected mice. Metabolomic analyses revealed that dehydroascorbic acid levels were high while caffeic acid levels decreased in the gut, plasma and lungs of alcohol diet-fed Mtb-infected mice. In the gut, we found an association between reduced caffeic acid levels and microbiota, which may play a key role in metabolizing primary metabolites into caffeic acid. Caffeic acid supplementation significantly reduced the mortality of alcohol-diet-fed Mtb-infected mice. This reduction in mortality was associated with a significant decrease in the number of CD11b+Ly6G+ cells expressing CD74+CD69+ and production of IFN-α in the lung. Our study demonstrates that metabolite supplementation may be an effective therapeutic strategy to reduce IFN-α mediated inflammation in the lung and mitigate mortality of alcoholic hosts infected with Mtb. Funding Sources Start up grant from Tulane University and CRDF Global. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)