Julie Ledford

Julie Ledford

Associate Professor, Cellular and Molecular Medicine
Associate Professor, Immunobiology
Associate Professor, Medicine
Associate Professor, Clinical Translational Sciences
Associate Professor, Applied BioSciences - GIDP
Member of the Graduate Faculty
Associate Professor, BIO5 Institute
Primary Department
Contact
(520) 626-0276

Work Summary

Julie Ledford's research focuses on respiratory disease, and genetic and molecular mechanisms of allergic airway diseases in children.

Research Interest

Dr. Ledford’s current work in the area of pulmonary surfactant immunobiology combines her knowledge of mouse genetics, pulmonary disease models and immune function regulation and focuses on understanding the role of Surfactant Protein-A (SP-A) and how it regulates signaling pathways within various immune cell populations. Specifically, she is interested in how SP-A regulates degranulation, either directly or indirectly, of two important cell types in asthma: mast cells and eosinophils. More recently, Dr. Ledford’s research has focused on understanding how genetic variation within human SP-A2 alters functionality of the protein in relation to eosinophil activities and how this translates to characteristics observed in human asthma.

Publications

Li, Z., Tighe, R. M., Feng, F., Ledford, J. G., & Hollingsworth, J. W. (2013). Genes of innate immunity and the biological response to inhaled ozone. Journal of biochemical and molecular toxicology, 27(1), 3-16.

Ambient ozone has a significant impact on human health. We have made considerable progress in understanding the fundamental mechanisms that regulate the biological response to ozone. It is increasingly clear that genes of innate immunity play a central role in both infectious and noninfectious lung disease. The biological response to ambient ozone provides a clinically relevant environmental exposure that allows us to better understand the role of innate immunity in noninfectious airways disease. In this brief review, we focus on (1) specific cell types in the lung modified by ozone, (2) ozone and oxidative stress, (3) the relationship between genes of innate immunity and ozone, (4) the role of extracellular matrix in reactive airways disease, and (5) the effect of ozone on the adaptive immune system. We summarize recent advances in understanding the mechanisms that ozone contributes to environmental airways disease.

Ledford, J. G., Pastva, A. M., & Wright, J. R. (2010). Review: Collectins link innate and adaptive immunity in allergic airway disease. Innate immunity, 16(3), 183-90.

Although the lipoprotein complex of pulmonary surfactant has long been recognized as essential for reducing lung surface tension, its role in lung immune host defense has only relatively recently been elucidated. Surfactant-associated proteins A (SP-A) and D (SP-D) can attenuate bacterial and viral infection and inflammation by acting as opsonins and by regulating innate immune cell functions. Surfactant-associated protein A and D also interact with antigen-presenting cells and T cells, thereby linking the innate and adaptive immune systems. A recent study from our laboratory demonstrated that mice deficient in SP-A have enhanced susceptibility to airway hyper-responsiveness and lung inflammation induced by Mycoplasma pneumonia, an atypical bacterium present in the airways of approximately 50% of asthmatics experiencing their first episode, and further supports an important role for SP-A in the host response to allergic airway disease. Animal and human studies suggest that alterations in the functions or levels of SP-A and SP-D are associated with both infectious and non-infectious chronic lung diseases such as asthma. Future studies are needed to elucidate whether alterations in SP-A and SP-D are a consequence and/or cause of allergic airway disease.

Holmer, S. M., Evans, K. S., Asfaw, Y. G., Saini, D., Schell, W. A., Ledford, J. G., Frothingham, R., Wright, J. R., Sempowski, G. D., & Perfect, J. R. (2014). Impact of surfactant protein D, interleukin-5, and eosinophilia on Cryptococcosis. Infection and immunity, 82(2), 683-93.

Cryptococcus neoformans is an opportunistic fungal pathogen that initiates infection following inhalation. As a result, the pulmonary immune response provides a first line of defense against C. neoformans. Surfactant protein D (SP-D) is an important regulator of pulmonary immune responses and is typically host protective against bacterial and viral respiratory infections. However, SP-D is not protective against C. neoformans. This is evidenced by previous work from our laboratory demonstrating that SP-D-deficient mice infected with C. neoformans have a lower fungal burden and live longer than wild-type (WT) control animals. We hypothesized that SP-D alters susceptibility to C. neoformans by dysregulating the innate pulmonary immune response following infection. Thus, inflammatory cells and cytokines were compared in the bronchoalveolar lavage fluid from WT and SP-D(-/-) mice after C. neoformans infection. Postinfection, mice lacking SP-D have reduced eosinophil infiltration and interleukin-5 (IL-5) in lung lavage fluid. To further explore the interplay of SP-D, eosinophils, and IL-5, mice expressing altered levels of eosinophils and/or IL-5 were infected with C. neoformans to assess the role of these innate immune mediators. IL-5-overexpressing mice have increased pulmonary eosinophilia and are more susceptible to C. neoformans infection than WT mice. Furthermore, susceptibility of SP-D(-/-) mice to C. neoformans infection could be restored to the level of WT mice by increasing IL-5 and eosinophils by crossing the IL-5-overexpressing mice with SP-D(-/-) mice. Together, these studies support the conclusion that SP-D increases susceptibility to C. neoformans infection by promoting C. neoformans-driven pulmonary IL-5 and eosinophil infiltration.

Mitsuhashi, A., Goto, H., Kuramoto, T., Tabata, S., Yukishige, S., Abe, S., Hanibuchi, M., Kakiuchi, S., Saijo, A., Aono, Y., Uehara, H., Yano, S., Ledford, J. G., Sone, S., & Nishioka, Y. (2013). Surfactant protein A suppresses lung cancer progression by regulating the polarization of tumor-associated macrophages. The American journal of pathology, 182(5), 1843-53.

Surfactant protein A (SP-A) is a large multimeric protein found in the lungs. In addition to its immunoregulatory function in infectious respiratory diseases, SP-A is also used as a marker of lung adenocarcinoma. Despite the finding that SP-A expression levels in cancer cells has a relationship with patient prognosis, the function of SP-A in lung cancer progression is unknown. We investigated the role of SP-A in lung cancer progression by introducing the SP-A gene into human lung adenocarcinoma cell lines. SP-A gene transduction suppressed the progression of tumor in subcutaneous xenograft or lung metastasis mouse models. Immunohistochemical analysis showed that the number of M1 antitumor tumor-associated macrophages (TAMs) was increased and the number of M2 tumor-promoting TAMs was not changed in the tumor tissue produced by SP-A-expressing cells. In addition, natural killer (NK) cells were also increased and activated in the SP-A-expressing tumor. Moreover, SP-A did not inhibit tumor progression in mice depleted of NK cells. Taking into account that SP-A did not directly activate NK cells, these results suggest that SP-A inhibited lung cancer progression by recruiting and activating NK cells via controlling the polarization of TAMs.

Takezaki, A., Kitamura, A., Setoguchi, Y., Itoh, Y., Ledford, J., Goto, H., Nishioka, Y., & Yasutomo, K. (2017). Notch-mediated necroptosis due to a mutation in SFTPA1 is a crucial driver for pulmonary fibrosis.. Nature Immunology.