Alpha-1 antitrypsin inhibits pertussis toxin

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 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.