Acute bacterial pneumonia is a significant source of morbidity and mortality worldwide, but our understanding of the early signaling pathways involved in the pulmonary immune response remains limited. During pneumonia, the innate immune system rapidly detects pathogenic bacteria, leading to a cascade of effector molecules that activate resident cells and recruit effector cells such as neutrophils to promote antimicrobial defense. Cytokines are perhaps the most prominent of these factors. It is our hope that by understanding these early signals in pneumonia, we may be able to develop novel diagnostics based on cytokine patterns or therapeutic immunomodulators that alter their function. Our preliminary results are the first to indicate that the IL-6 family cytokine Oncostatin-M (OSM) fortifies innate immunity during pneumonia. While the mechanisms of this response remain unknown, we have found that OSM shapes the pulmonary transcriptome to guide alveolar neutrophil recruitment. We will focus our initial efforts on dissecting the sources, targets, and consequences of OSM during pneumonia, with particular emphasis on a novel STAT3-CXCL5 axis that we posit as an intermediate of OSM-driven immune responses. To do this, we will pursue the following three aims to test our central hypothesis that myeloid-derived Oncostatin M targets lung epithelium to activate gene programs driving acute pulmonary inflammation during pneumonia.
Aim 1 ? Test the hypothesis that OSM is produced by alveolar macrophages and recruited neutrophils to promote acute inflammation during pneumonia.
Aim 2 ? Test the hypothesis that OSM directly modulates lung epithelial cells through its receptor, OSMR?, to promote innate immunity during pneumonia.
Aim 3 ? Test the hypothesis that Cxcl5 induction and maximal neutrophil recruitment require STAT3-mediated OSM signaling during pneumonia. Dr. Traber will be performing the studies outlined in this proposal as part of a larger training program designed to foster her transition towards a career as an independent physician-scientist. Through a program of formal didactics and one-one on training, she will develop expertise in pulmonary innate immunity and master advanced research methodologies. During this project, she will work closely with her mentors, Drs. Lee Quinton and Joseph Mizgerd, both experts in the field of pulmonary innate immunity. She will also receive scientific and career guidance from several additional faculty members with wide-ranging expertise in pulmonary disease research. With her combined expertise in microbiology (Ph.D. training), pulmonary and critical care medicine (clinical training), and lung immunology (fellowship research training) Dr. Traber is well qualified to undertake this project. The proposed studies will be performed at the Pulmonary Center of Boston University School of Medicine, a department with a reputation for cutting edge pulmonary disease research, collegiality, and superb training of physician scientists.
Lung infections are a major public health concern, accounting for the greatest burden of disease in both poor and wealthy communities. Despite this, the early immune response to bacteria in the lung is not well understood and so, the goal of our laboratory and this proposal is to better understand this immune response. With this increased understanding we may someday be able to develop new medications to treat this important disease.
| Traber, Katrina E; Symer, Elise M; Allen, Eri et al. (2017) Myeloid-epithelial cross talk coordinates synthesis of the tissue-protective cytokine leukemia inhibitory factor during pneumonia. Am J Physiol Lung Cell Mol Physiol 313:L548-L558 |
| Jacob, Anjali; Morley, Michael; Hawkins, Finn et al. (2017) Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. Cell Stem Cell 21:472-488.e10 |
