Horae Gene Therapy Center
Amino Acids, Peptides, and Proteins | Bacterial Infections and Mycoses | Immunology and Infectious Disease | Molecular Biology | Pulmonology | Respiratory Tract Diseases
Alpha-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.
Bacterial infections, Neutrophils, Proteases, Pulmonology
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Copyright: © 2021, Ostermann et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
DOI of Published Version
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
Ostermann L, Maus R, Stolper J, Schutte L, Katsarou K, Tumpara S, Pich A, Mueller C, Janciauskiene S, Welte T, Maus UA. (2021). Alpha-1 antitrypsin deficiency impairs lung antibacterial immunity in mice. Open Access Publications by UMMS Authors. https://doi.org/10.1172/jci.insight.140816. Retrieved from https://escholarship.umassmed.edu/oapubs/4609
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Amino Acids, Peptides, and Proteins Commons, Bacterial Infections and Mycoses Commons, Immunology and Infectious Disease Commons, Molecular Biology Commons, Pulmonology Commons, Respiratory Tract Diseases Commons