Areas of Research
Innate immune responses to airway pathogens
Our laboratory studies the interaction of host-adapted pathogens and the airway mucosa, asking how bacteria change gene expression to maintain infection in the human lung; and how the host responds to these organisms. We use a variety of model systems; classic bacterial genetics, constructing and studying mutants to identify which gene products are important; murine models of pneumonia using a variety of mouse models as well as in vitro studies using human airway epithelial and immune cells. We are especially interested in the adaptation of clinical isolates and routinely use whole genome sequenced strains, proteomic and RNASeq analyses to query the host response to infection. Ongoing studies focus upon the carbapenem-resistant K. pneumoniae, P. aeruginosa and S. aureus.
Pathogenesis of infection in cystic fibrosis
P. aeruginosa is the most prevalent pathogen in CF, uniquely associated with the progressive decline in lung function that characterizes this disease. Exactly why P. aeruginosa and not other pathogens is so closely associated with CF has been a topic of great interest to us. Using a collection of sequenced CF isolates, we are examining how the metabolic activity of P. aeruginosa, particularly their response to succinate and itaconate, drives their adaptation to the CF airway. We are exploring how the tumor suppressor PTEN is directly associated with CFTR at the cell membrane, and how this effects succinate metabolism, which in turn promotes P. aeruginosa adaptation to the lung.
S. aureus is a frequent cause of severe pneumonia. Using metabolomic studies, we have identified how changes in staphylococcal metabolism, specifically utilization of the TCA cycle are associated with infection. Our ongoing studies seek to identify the metabolic and cytokine signals in the airway that promote S. aureus biofilm formation and persistent pulmonary infection both in normal hosts and in cystic fibrosis patients.