Epithelial Anion Transporter Pendrin Contributes to Inflammatory Lung Pathology in Mouse Models of Bordetella pertussis Infection

Abstract

c 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.

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

“…More recently, Button and colleagues (52) showed that tethered mucins in the PCL form a mesh to prevent entry of gel-forming mucins and support ciliary beating, and they proposed a gel-onbrush model to describe the ASL. Photobleaching studies support this concept and have established that the fluid phase viscosity of the mucus layer and PCL are similar in non-CF subjects (7-10 times more viscous than saline), but significantly elevated in both regions in CF cultures (25)(26)(27)(28)(29)(30) times more viscous than saline) (51). In addition to forming a permeability barrier, tethered mucins in the PCL generate an osmotic pressure to regulate PCL hydration (52).…”

“…Cl 2 /HCO 3 2 exchange is the relevant pendrin function in the airways during inflammatory responses (10,11,26,35). Pendrin-mediated Cl 2 /HCO 3 2 exchange was measured in pendrin-expressing FRT cells using BCECF to report cytoplasmic pH (pH i ) (Fig.…”

“…Pendrin up-regulation is seen in: 1) airway epithelial cultures chronically exposed to cytokines, including IL-4, IL-13, and IL-17A; 2) rodent models of inflammatory lung disease, including allergen (ovalbumin)-induced asthma, chronic obstructive pulmonary disease, infection, and industrial toxin exposure; and 3) humans with rhinovirus infection, asthma, cystic fibrosis (CF), rhinitis, and chronic rhinosinusitis (10,11,(17)(18)(19)(20)(21)(22)(23)(24)(25). Pendrin knockout is also associated with reduced lung inflammation in a murine model of Bordetella pertussis lung infection (26). IL-13, the cytokine used commonly in in vitro and animal models of airway inflammation, is elevated in CF, asthma, chronic rhinosinusitis, viral and certain bacterial infections, and chronic obstructive pulmonary disease, and in response to cigarette smoke (27)(28)(29)(30)(31)(32)(33)(34).…”

Investigating Pertussis Toxin and its Impact on Vaccination

“…One of the most recently studied novel host proteins involved in the PTX-dependent pathology induced by B. pertussis infection in mice is the epithelial anion transporter protein pendrin, indeed first identified by transcriptomic analyses. This protein was recently shown to contribute to the inflammatory lung pathology in infected mice [112]. It is likely that similar approaches will contribute in the near future to a more comprehensive view on the pathological involvement of PTX during B. pertussis infection in mice.…”

Bordetella protein toxins

“…One of the genes that are most strongly upregulated in a PTX-dependent manner in the lungs of B. pertussis-infected mice codes for the epithelial anion transporter pendrin. Mice deficient for this transporter develop higher bacterial burdens, but reduced lung inflammation upon infection than pendrin-producing mice [73], suggesting that PTX triggers lung pathology via the upregulation of pendrin, which induces inflammatory responses.…”