Lipooligosaccharide, Vag8, and pertussis toxin of<i>Bordetella pertussis</i>cooperatively cause coughing in mice

Summary Whooping cough, a contagious respiratory disease caused by Bordetella pertussis , is characterized by paroxysmal coughing; however, the mechanism has not been studied because of the lack of versatile animal models that reproduce the cough. Here, we present a mouse model that reproduces coughing after intranasal inoculation with the bacteria or its components and demonstrate that lipooligosaccharide (LOS), pertussis toxin (PTx), and Vag8 of the bacteria cooperatively function to cause coughing. LOS-induced bradykinin sensitized a transient receptor potential ion channel, TRPV1, which acts as a sensor to evoke the cough reflex. Vag8 further increased bradykinin levels by inhibiting the C1 esterase inhibitor, the major downregulator of the contact system, which generates bradykinin. PTx inhibits intrinsic negative regulation systems for TRPV1 through inactivation of G i GTPases. Our findings provide a basis for answering long-standing questions on the pathophysiology of the pertussis cough.