Dr. Guoshun Wang Presents Work on Cystic Fibrosis at February Dean’s Seminar
Dr. Guoshun Wang presented his work on Cystic fibrosis (CF) at the Dean’s seminar in February. The title of the seminar was “Cystic Fibrosis – An Immunodeficiency Disease.”
CF is one of the most common and deadly genetic disorders and it is caused by
mutations in the CF transmembrane conductance regulator gene that encodes CFTR, a
cAMP-activated chloride channel. Even though CF affects multiple organ systems, including
the respiratory, gastrointestinal and reproductive systems, it is the lung complications
that claim the most morbidity and mortality of the disease.
The cardinal lung pathology is marked by chronic bacterial infection, persistent neutrophilic inflammation and mucopurulent small airway obstruction. Since the discovery of the disease-associated gene over 30 years ago, the field has been struggling to establish a causative link between the chloride channel defect and the host defense failure. As a result, all current therapies, including the Highly Effective Modulator Therapy (HEMT), can mitigate the disease but are not curative.
Thus, understanding the underlying mechanism responsible for the disease pathogenesis is critical to the search for a cure. Ground-breaking work from the Wang lab has uncovered a novel defect in CF, which resides in the neutrophils, a professional bacteria-killer cell. Normal neutrophils transport chloride to their phagosomes to produce hypochlorous acid (HOCl or chlorine bleach) for bacterial killing. Due to the CFTR chloride channel dysfunction, chloride transport is impaired in CF neutrophils and they have a compromised microbial killing capacity. This impairment is further enhanced by the CF epithelial defect, which cuts off the chloride supply from the circulation to the lung-recruited neutrophils. This finding provides a mechanistic explanation to why CF patients have a host defense defect and succumb to lung bacterial infection.
This work asserts that CF is virtually an immunodeficiency disease, and any effective therapy needs to correct the immune defect.
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