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