Alpha-1 antitrypsin inhibits pertussis toxin

作者：Stefanie Lietz, Anja Sommer, Lena-Marie Sokolowski, Carolin Kling, Armando Rodríguez, Nico Preising, Daniel Alpízar-Pedraza, Jaylyn King, Lisa Streit, Bernd Schröppel, R. van Erp, Eberhard Barth, Marion Schneider, Jan Münch, Jens Michaelis, Ludger Ständker, Sebastian Wiese, Holger Barth, Arto T. Pulliainen, Karen M. Scanlon, Katharina Ernst · 发表于：Journal of Biological Chemistry · 年份：2024 · DOI：10.1016/j.jbc.2024.107950 · 被引用次数：9 · 研究领域：Bacterial Infections and Vaccines、S100 Proteins and Annexins、Protease and Inhibitor Mechanisms

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 nonvaccinated 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 α 1 -antitrypsin (α 1 AT) as a potent PT inhibitor. Biochemistry-, cell culture-, and molecular modeling-based in vitro experimentation demonstrated that the α 1 AT mode of action is based on blocking PT-binding to the host target cell surface. In the infant mouse model of severe pertussis, α 1 AT expression was reduced upon infection. Further, systemic administration of α 1 AT 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 α 1 AT is a novel PT inhibitor and that further evaluation and development of α 1 AT as a therapeutic agent for pertussis is warranted. Importantly, purified α 1 AT is already in use clinically as an intravenous augmentation therapy for those with genetic α 1 AT deficiency and could be repurposed to clinical management of pertussis.