UMMS Affiliation

Horae Gene Therapy Center

Publication Date

2021-02-08

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Bacterial Infections and Mycoses | Immunology and Infectious Disease | Molecular Biology | Pulmonology | Respiratory Tract Diseases

Abstract

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.

Keywords

Bacterial infections, Neutrophils, Proteases, Pulmonology

Rights and Permissions

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

10.1172/jci.insight.140816

Source

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

Journal/Book/Conference Title

JCI insight

Related Resources

Link to Article in PubMed

PubMed ID

33554955

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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