Enhancing neutrophil function in neutropenia-related pneumonia

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DESCRIPTION (provided by applicant): Chemo- and radiotherapy are extensively used to treat various hematological malignancies and solid tumors. Neutropenia and related infection are the most important dose limiting toxicities of these anti-cancer treatments, impacting on quality of life and clinical outcomes, with the potential to cause death. Neutropenia- related pneumonias are involved in 40% infection at a site other than blood alone, and usually treated with broad-spectrum antibiotic therapy and granulocyte colony-stimulating factor (G-CSF) therapy. However, not all patients respond to antibiotic treatment and G-CSF therapy is often associated with side-effects such as bone pain, headache, fatigue, nausea, and higher risk of getting leukemia. The long-term goal of this project is to explore another strategy for treating/preventing neutropenia-related pneumonia - via enhancing neutrophil functions (e.g. recruitment, survival, and bacteria killing) in neutropenic patients. We will try to achieve this by elevating intracellular PtdIns(3,4,5)P3 signaling pathway which has been implicated in a variety of neutrophil functions. Recently, we have shown that the responsiveness of neutrophil to chemoattractant stimulation is much enhanced in PTEN knockout mice in which the PtdIns(3,4,5)P3 signaling is hyperactivated. The recruitment of neutrophils to the inflamed peritoneal cavity was significantly enhanced in these mice. In addition, augmenting PtdIns(3,4,5)P3 signal via depleting PTEN prevents neutrophil spontaneous death. Our preliminary data also demonstrated that the PTEN null neutrophils possess an enhanced bacteria killing capability and their recruitment to the inflamed lungs was also augmented. Based on these intriguing results, we hypothesize that augmentation of PtdIns(3,4,5)P3 signaling pathway should be a legitimate therapeutic strategy for the treatment of neutropenia-related pneumonia. In this proposed research, we will directly examine whether disruption of PTEN can augment neutrophil recruitment and survival in neutropenia-related pneumonia (Aim I), enhance neutrophil bacterial killing capability, and alleviate the severity of neutropenia- related pneumonia (Aim II). In addition, since alveolar macrophages also play a critical role in host defense against respiratory tract infections, whether disruption of PTEN can also enhance the function of alveolar macrophages will be investigated (Aim III). Lastly, PtdIns(3,4,5)P3 signaling can also be augmented by disrupting InsP3KB; and thus we will explore whether disruption of InsP3KB can also reduce the severity of neutropenia-related pneumonia (Aim IV). PUBLIC HEALTH RELEVANCE: Experiments proposed in this study will provide insight into the mechanism of action of PtdIns(3,4,5)P3 pathway in elevating neutrophil and macrophage function in lung infection and inflammation, with the ultimate goal of solidifying PtdIns(3,4,5)P3-related pathways as novel therapeutic targets for treatment of neutropenia- related pneumonia. This will be an important and necessary complementation to the current antibiotic and G- CSF therapies. In addition, although we focus on neutropenia-related pneumonia in this application, the same strategy can be readily applied to other neutropenia-related infectious diseases.