Hypothesis: The overall hypothesis to be tested in this proposal is that SP-A plays an important protective role in pulmonary host defense against M. pneumoniae (MP) infections and airway reactivity by modulating the transition from innate to adaptive immunity.
Specific Aims : (1) to investigate the role of SP-A in regulating DC maturation and cytokine modulation in response to M. pneumoniae infection in vitro;(2) to determine if SP-A acts as an opsonin and aids in the uptake of M. pneumoniae by immature DCs and alveolar macrophages, thereby increasing clearance while decreasing epithelial binding and insult to the host;(3) to examine the effects of SP-A on M. pneumoniae induced airway hyperactivity using mice deficient in SP-A to better understand the role of SP-A in an experimental asthma setting. Study Design: The role of SP-A in regulating MP-induced DC maturation and cytokine modulation will first be examined by studying bone marrow derived dendritic cells cultured from wild type and SP-A null mice. These parameters will then be assessed using mice deficient in SP-A infected with M. pneumoniae. I will perform more comprehensive experiments examining MP clearance, uptake and epithelial damage and determine if SP-A mediates these activities. Experiments using SP-A null mice with experimental allergic asthma will be used to study the role of SP-A in MP induced asthma exacerbations. Relevance: The relationship between allergen, infection and asthma comprises a spectrum ranging from exacerbation of established disease to development and persistence of disease. The interactions between the innate and adaptive immune systems may be pivotal in ultimately determining the phenotypic presentation of asthma. Surfactant proteins have not been widely studied in asthma but are known to play important roles in host defense and modulation of inflammation which may contribute to the development and persistence of asthma. The research proposed in this project will aid in elucidating the role of Surfactant Protein-A in M. pneumoniae pulmonary infections specifically associated with asthma related symptoms.
|Hsia, Bethany J; Ledford, Julie G; Potts-Kant, Erin N et al. (2012) Mast cell TNF receptors regulate responses to Mycoplasma pneumoniae in surfactant protein A (SP-A)-/- mice. J Allergy Clin Immunol 130:205-14.e2|
|Ledford, Julie G; Mukherjee, Sambuddho; Kislan, Michele M et al. (2012) Surfactant protein-A suppresses eosinophil-mediated killing of Mycoplasma pneumoniae in allergic lungs. PLoS One 7:e32436|
|Ledford, Julie G; Lo, Bernice; Kislan, Michele M et al. (2010) Surfactant protein-A inhibits mycoplasma-induced dendritic cell maturation through regulation of HMGB-1 cytokine activity. J Immunol 185:3884-94|
|Ledford, Julie G; Pastva, Amy M; Wright, Jo Rae (2010) Review: Collectins link innate and adaptive immunity in allergic airway disease. Innate Immun 16:183-90|
|Ledford, Julie G; Goto, Hisatsugu; Potts, Erin N et al. (2009) SP-A preserves airway homeostasis during Mycoplasma pneumoniae infection in mice. J Immunol 182:7818-27|