Epithelial anion transporter pendrin contributes to inflammatory lung pathology in mouse models of Bordetella pertussis infection.

Pertussis disease, characterized by severe and prolonged coughing episodes, can progress to a critical stage with pulmonary inflammation and death in young infants. However, there are currently no effective treatments for pertussis. We previously studied the role of pertussis toxin (PT), an important Bordetella pertussis virulence factor, in lung transcriptional responses to B. pertussis infection in mouse models. One of the genes most highly upregulated in a PT-dependent manner encodes an epithelial transporter of bicarbonate, chloride, and thiocyanate, named pendrin, that contributes to asthma pathology. In this study, we found that pendrin expression is upregulated at both gene and protein levels in the lungs of B. pertussis-infected mice. Pendrin upregulation is associated with PT production by the bacteria and with interleukin-17A (IL-17A) production by the host. B. pertussis-infected pendrin knockout (KO) mice had higher lung bacterial loads than infected pendrin-expressing mice but had significantly reduced levels of lung inflammatory pathology. However, reduced pathology did not correlate with reduced inflammatory cytokine expression. Infected pendrin KO mice had higher levels of inflammatory cytokines and chemokines than infected pendrin-expressing mice, suggesting that these inflammatory mediators are less active in the airways in the absence of pendrin. In addition, treatment of B. pertussis-infected mice with the carbonic anhydrase inhibitor acetazolamide reduced lung inflammatory pathology without affecting pendrin synthesis or bacterial loads. Together these data suggest that PT contributes to pertussis pathology through the upregulation of pendrin, which promotes conditions favoring inflammatory pathology. Therefore, pendrin may represent a novel therapeutic target for treatment of pertussis disease.