Alpha-1 antitrypsin deficiency impairs lung antibacterial immunity in mice
Maus, Ulrich A.
UMass Chan AffiliationsHorae Gene Therapy Center
Document TypeJournal Article
Amino Acids, Peptides, and Proteins
Bacterial Infections and Mycoses
Immunology and Infectious Disease
Respiratory Tract Diseases
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AbstractAlpha-1 antitrypsin (AAT) is a major inhibitor of serine proteases in mammals. Therefore, its deficiency leads to protease-antiprotease imbalance and a risk for developing lung emphysema. Although therapy with human plasma-purified AAT attenuates AAT deficiency-related emphysema, its impact on lung antibacterial immunity is poorly defined. Here, we examined the effect of AAT therapy on lung protective immunity in AAT-deficient (KO) mice challenged with Streptococcus pneumoniae. AAT-KO mice were highly susceptible to S. pneumoniae, as determined by severe lobar pneumonia and early mortality. Mechanistically, we found that neutrophil-derived elastase (NE) degraded the opsonophagocytically important collectins, surfactant protein A (SP-A) and D (SP-D), which was accompanied by significantly impaired lung bacterial clearance in S. pneumoniae-infected AAT-KO mice. Treatment of S. pneumoniae-infected AAT-KO mice with human AAT protected SP-A and SP-D from NE-mediated degradation and corrected the pulmonary pathology observed in these mice. Likewise, treatment with Sivelestat, a specific inhibitor of NE, also protected collectins from degradation and significantly decreased bacterial loads in S. pneumoniae-infected AAT-KO mice. Our findings show that NE is responsible for the degradation of lung SP-A and SP-D in AAT-KO mice affecting lung protective immunity in AAT deficiency.
Ostermann L, Maus R, Stolper J, Schütte L, Katsarou K, Tumpara S, Pich A, Mueller C, Janciauskiene S, Welte T, Maus UA. Alpha-1 antitrypsin deficiency impairs lung antibacterial immunity in mice. JCI Insight. 2021 Feb 8;6(3):e140816. doi: 10.1172/jci.insight.140816. PMID: 33554955; PMCID: PMC7934856. Link to article on publisher's site