A1 Refereed original research article in a scientific journal
Alpha-1 antitrypsin inhibits pertussis toxin
Authors: Lietz, Stefanie; Sommer, Anja; Sokolowski, Lena-Marie; Kling, Carolin; Rodriguez, Alfonso Armando A.; Preising, Nico; Alpízar-Pedraza, Daniel; King, Jaylyn; Streit, Lisa; Schröppel, Bernd; van Erp, Rene; Barth, Eberhard; Schneider, Marion; Münch, Jan; Michaelis, Jens; Ständker, Ludger; Wiese, Sebastian; Barth, Holger; Pulliainen, Arto T.; Scanlon, Karen; Ernst, Katharina
Publisher: Elsevier BV
Publication year: 2024
Journal: Journal of Biological Chemistry
Journal name in source: Journal of Biological Chemistry
Article number: 107950
Volume: 300
Issue: 12
ISSN: 0021-9258
eISSN: 1083-351X
DOI: https://doi.org/10.1016/j.jbc.2024.107950
Web address : https://doi.org/10.1016/j.jbc.2024.107950
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/459076366
Pertussis (whooping cough) is a vaccine-preventable but re-emerging, highly infectious respiratory disease caused by Bordetella pertussis. There are currently no effective treatments for pertussis, complicating care for non-vaccinated individuals, especially newborns. Disease manifestations are predominantly caused by pertussis toxin (PT), a pivotal virulence factor classified as an ADP-ribosylating AB-type protein toxin. In this work, an unbiased approach using peptide libraries, bioassay-guided fractionation and mass spectrometry revealed α1-antitrypsin (α1AT) as a potent PT inhibitor. Biochemistry-, cell culture- and molecular modeling-based in vitro experimentation demonstrated that the α1AT mode of action is based on blocking PT-binding to the host target cell surface. In the infant mouse model of severe pertussis, α1AT expression was reduced upon infection. Further, systemic administration of α1AT significantly reduced B. pertussis-induced leukocytosis, which is a hallmark of infant infection and major risk factor for fatal pertussis. Taken together our data demonstrates that α1AT is a novel PT inhibitor and that further evaluation and development of α1AT as a therapeutic agent for pertussis is warranted. Importantly, purified α1AT is already in use clinically as an intravenous augmentation therapy for those with genetic α1AT deficiency and could be repurposed to clinical management of pertussis.
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Funding information in the publication:
This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Re-search Foundation)—project number 316249678-SFB1279 (A02, funding to J.Mü.; A07, funding to K.E.; C02, funding to H.B. and J.Mi.; Z01, funding to L.S., S.W.). K.E. is a fellow of the Margarete von Wrangell Habilitation program supported by the European Social Fund and Ministry of Science, Research and Art Baden-Württemberg. S.L. is a fellow of the International Graduate School in Molecular Medicine Ulm (IGradU). D.A.P. and L.S. acknowledge funding by the DAAD/German Ministry for Foreign Affairs via the program Global Health and Pandemic Prevention Centers (project 57592717-GLACIER). K.S. is supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant number AI163595).
