Dual Oxidase 2 Bidirectional Promoter Polymorphisms Confer Differential Immune Responses in Airway Epithelia

Abstract

The dual oxidase enzymes, DUOX, localized to the respiratory tract epithelium, are important components of innate host defense against bacteria and virus. However, little is known regarding the regulation of DUOX transcription. To better understand DUOX2-mediated mechanisms of antiviral host defense in the airway epithelium, we designed a bidirectional promoter luciferase reporter system to identify important cis-regulatory regions in the human DUOX2/DUOXA2 promoter. In this report, we demonstrate that the genomic region between the translation start sites of DUOX2 and DUOXA2 functions as a bidirectional promoter in human airway tissue. We also identified key regulatory regions on the DUOX2/DUOXA2 promoter that were necessary for both bidirectional and unidirectional transcriptional activity. Importantly, we discovered two functionally important single-nucleotide polymorphisms (SNPs) within the promoter that differentially regulated DUOX2/DUOXA2 transcription in response to exogenous double-stranded DNA. One of these SNPs, rs269855 (enriched in people of African descent), conferred the highest level of DUOX2 promoter activity. The clinical sequelae for individuals who carry this polymorphism remain to be determined.