Scope of Research
Our laboratory studies the interaction of the host and bacterial pathogens in the airway, focusing primarily upon the multiply antibiotic resistant ESKAPE pathogens. As much of the pathology due to organisms such as Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus is due to the host response to infection, we study the host response to bacterial components, especially the activation of immunometabolites and how this response is activated and regulated.
Immunometabolic Responses to Airway Pathogens
Our laboratory studies the host response to bacteria that have become adapted to the airways, host-adapted pathogens. We focus specifically upon Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa. This involves changes in bacterial gene expression that often entail shifts in metabolic activity to optimally support bacterial proliferation within the setting of the inflamed airway. In contrast to an invitro setting, airway pathogens must adapt to metabolites such as itaconate and succinate and to the ROS generated by immune cells and the bacteria themselves. We are especially interested in how Pseudomonas aeruginosa adapts to the inflamed airway and the nature of the immunometabolic response.
The role of itaconate in the pathogenesis of infection
Human pathogens that cause persistent infection trigger an immune response that is tolerant to infection. Itaconate is a major metabolite of myeloid cells that functions primarily to suppress inflammation and protect the host from damage. We are interested in how bacterial pathogens adapt to itaconate; as some such as P. aeruginosa, consume it as a carbon source, whereas others, such as S. aureus and K. pneumoniae, actively change their patterns of gene expression in response to itaconate. This metabolite contributes to the type of immune response that is elicited, as well as the nature of the genetic programs activated by the bacteria. Current topics of research include the mechanisms underlying the selective induction of itaconate production in specific immune cells and their roles in preventing infection.
Type 6 secretion systems in pathogenesis
Both K. pneumoniae and P. aeruginosa express multiple copies of the T6SS, which are activated in specific settings in vivo. We are actively exploring the host signals that stimulate this bacterial system and how they are regulated. In P. aeruginosa, we are focusing on metabolic signals that differentially activate the T3SS important in acute infection and the T6SS, which has an important role in bacterial adaptation to the oxidant stress generated by immune cells and their production of itaconate. In K. pneumoniae, we are examining how the T6SS is selectively activated in vivo specifically in the setting of airway infection.