Alpha-1-antitrypsin (AAT) anomalies are associated with lung disease due to rapidly growing mycobacteria and AAT inhibits Mycobacterium abscessus infection of macrophages.
Rapidly growing mycobacteria (RGM) are ubiquitous in the environment but cause lung disease in only a fraction of exposed individuals. This variable susceptibility to disease implies vulnerability to RGM infection due to weakness in host defense. Since most persons who contract RGM lung disease have no known host defense defect, it is likely that uncharacterized host deficiencies exist that predispose to RGM infection. Alpha-1-antitrypsin (AAT) is a host factor that may protect individuals from respiratory infections. Therefore, we assessed AAT protein anomalies as a risk factor for RGM lung disease. In a cohort of 100 patients with RGM lung disease, Mycobacterium (M.) abscessus was the most prevalent organism, isolated in 64 (64%) subjects. Anomalous AAT proteins were present in 27% of the cohort, which is 1.6 times the estimated prevalence of anomalous AAT proteins in the United States population (p=0.008). In in vitro studies, both AAT and a synthetic inhibitor of serine proteases suppressed M. abscessus infection of monocyte-derived macrophages by up to 65% (p<0.01). AAT may be an anti-RGM host-defense factor, and anomalous AAT phenotypes or AAT deficiency may constitute risk factors for pulmonary disease due to RGM.
Chan
Edward D
ED
Department of Medicine, National Jewish Medical and Research Center, Denver, CO, USA.
Kaminska
Aleksandra M
AM
Gill
Wendy
W
Chmura
Kathryn
K
Feldman
Nicole E
NE
Bai
Xiyuan
X
Floyd
Corinne M
CM
Fulton
Kayte E
KE
Huitt
Gwen A
GA
Strand
Matthew J
MJ
Iseman
Michael D
MD
Shapiro
Leland
L
D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008264:Macrophages / Q000382:microbiology*; D008297:Male; D008875:Middle Aged; D009159:Mycobacteriaceae / Q000254:growth & development / Q000472:pathogenicity*; D009165:Mycobacterium Infections, Nontuberculous / Q000201:enzymology*; D010641:Phenotype; D012189:Retrospective Studies; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014397:Tuberculosis, Pulmonary / Q000201:enzymology*; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000235:genetics* / Q000494:pharmacology; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics* / Q000382:microbiology
C043392:SERPINA1 protein, human; D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin