[WCB-12] The mechanism of pertussis cough revealed by the mouse-coughing model
Pertussis (whooping cough), a contagious respiratory disease caused by Bordetella pertussis, is characterized by paroxysmal coughing, but the mechanism of pertussis cough has not been studied because of a lack of versatile animal models that reproduce the cough. Here we present a mouse model that reproduces coughing, which was checked by characteristic sound waveforms and the postures of mice, after intranasal inoculation with the bacteria or its components. We found that lipooligosaccharide (LOS), pertussis toxin (PTx), and Vag8 of the bacteria cooperatively function to cause the coughing. The analyses for cough-evoking pathway revealed the mechanism of pertussis cough as follows. (1) LOS stimulates bradykinin (Bdk) generation by the kallikrein-kinin system through interaction with toll-like receptor 4. (2) Vag8 accelerates the Bdk generation by inhibiting C1 esterase inhibitor, which is the major negative regulator of the kallikrein-kinin system. (3) Bdk sensitizes a transient receptor potential ion channel, TRPV1, which acts as a sensor to evoke the cough reflex. (4) PTx inhibits intrinsic negative regulation systems for TRPV1 through the inactivation of Gi GTPases. Consequently, TRPV1 is left in the sensitized state to readily the nervous excitation to evoke coughing. Our findings provide a basis to answer long-standing questions on the pathophysiology of pertussis cough.