Abnormal nasal nitric oxide production, ciliary beat frequency, and toll-like receptor response in pulmonary nontuberculous mycobacterial disease epithelium

Abstract

Rationale: Pulmonary nontuberculous mycobacterial (PNTM) disease has increased over the past several decades, especially in older women. Despite extensive investigation, no consistent immunological abnormalities have been found. Using evidence from diseases such as cystic fibrosis and primary ciliary dyskinesia, in which mucociliary dysfunction predisposes subjects to high rates of nontuberculous mycobacterial disease that increase with age, we investigated correlates of mucociliary function in subjects with PNTM infections and healthy control subjects. Objectives: To define ex vivo characteristics of PNTM disease. Methods: From 2009 to 2012, 58 subjects with PNTM infections and 40 control subjectswere recruited.Nasal nitric oxide (nNO)was determined at the time of respiratory epithelial collection. Ciliary beat frequency at rest and in response to Toll-like receptor (TLR) and other agonists was determined using high-speed videomicroscopy. Measurements and Main Results: We found decreased nNO production, abnormally low resting ciliary beat frequency, and abnormal responses to agonists of TLR2, -3, -5, -7/8, and -9 in subjects with PNTM compared with healthy control subjects. The low ciliary beat frequency in subjects withPNTMwas normalized ex vivo by augmentation of the NO-cyclic guanosinemonophosphate pathwaywithout normalization of their TLR agonist responses. Conclusions: Impaired nNO, ciliary beat frequency, and TLR responses in PNTM disease epithelium identify possible underlying susceptibility mechanisms as well as possible avenues for directed investigation and therapy. Show more