Dissecting the Role of DDR2 in the Modulation of Antibacterial Host Defense Post Fibrotic Lung Injury

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Project Abstract Idiopathic pulmonary fibrosis (IPF) is a disease characterized by the progression of collagen deposition in the lung and eventual loss of lung function. IPF is fatal and treatments for the disease are limited and lacking efficacy. Much of the mortality associated with IPF can be attributed to acute exacerbation (AE), or a rapid deterioration in lung function, often leading to death within a few months of diagnosis. However, studies within the last decade have also recognized a role for bacteria within the lung in exacerbating IPF disease course. One study found that respiratory infections were the cause of similar mortality rates in hospitalized IPF patient populations compared to AE. Other studies have identified the presence of bacterial genera Staphylococcus and Streptococcus within the lung as being associated with poor IPF patient outcomes. Our lab has preliminary data indicating that mice with bleomycin-induced fibrotic lung injury that were subsequently infected with Staphylococcus aureus or Streptococcus pneumoniae had decreased survival compared to mice with fibrotic lung injury alone. We have also determined that fibrotic mice have impaired ability to clear a bacterial infection compared to non-fibrotic mice. Therefore, in this proposal, we seek to identify the effect of fibrosis on the immune response to bacterial infection. We have identified the collagen receptor discoidin domain receptor 2 (DDR2) as a possible mediator of immune cell function following fibrotic lung injury. We have determined that DDR2 is downregulated in macrophages isolated from fibrotic mice and that DDR2-/- bone marrow-derived macrophages show decreased levels of bacterial phagocytosis and neutrophil chemokine production, two critical functions in the clearance of bacterial infections. This proposal will test the hypothesis that fibrotic lung injury impairs antibacterial host defense via the downregulation of DDR2. This hypothesis will be tested through two specific aims: 1) determine the role of collagen receptor DDR2 in regulating macrophage antibacterial responses following pulmonary fibrosis and 2) characterize the role of DDR2 in mediating decreased neutrophil recruitment in post-fibrosis bacterial pneumonia. Experiments for these aims will be completed with the use of genetically engineered mouse models, cells derived from such mice, and in vitro assays studying the role of DDR2 in various immune cell functions. The results from these innovative studies may inform treatments that help improve IPF patient outcomes following respiratory infection. Completion of this proposal will also allow for the applicant to receive rigorous training in experimental design, implementation, and interpretation that will help her become a successful, independent scientist.