Persistent respiratory tract colonization with Ureaplasma urealyticum (Uu) in preterm infants is a highly significant risk factor for the development of Bronchopulmonary Dysplasia (BPD), a chronic lung disorder that is characterized by arrested alveolarization and angiogenesis, chronic inflammation and variable interstitial fibrosis. Our long-term objective is to determine how Uu modulates the pulmonary immune response and contributes to lung injury. In recent in vitro studies in the Pi's laboratory, live Uu stimulated IL- 8 by toll-like receptor (TLR)2- and TLR9-overexpressing, but not TLR4-overexpressing HEK293 cells. While bone marrow derived macrophages (BMDM) from MyD88 (-/-) and TLR2(-/-) mice were unresponsive to Uu, BMDM from TLR4-/- mice were as responsive to Uu as wild-type BMDM. These observations suggest that Uu exerts agonist activity for multiple MyD88-dependent TLR receptors, including TLR2 and TLR9.
The specific aims of this proposal focus on the central hypothesis that developmental deficiencies and/or specific polymorphisms of the TLRs recognizing Uu increase the susceptibility of the preterm infant to Uu infection, prolonged dysregulated inflammation, and the development of BPD.
The specific aims are 1) to analyze the TLR signaling pathways activated by a BPD-associated UU isolate; 2) to define the roles of MyD88, TLR2, or TLR9 deficiency in Uu clearance, acute lung inflammation/injury and long-term functional outcomes in a murine pneumonia model; and 3) to analyze the effect of polymorphisms in relevant TLR genes on the risk for Uu infection and BPD in preterm infants by determining the frequencies of single nucleotide polymorphisms in TLR1, TLR2, TLR6 and TLR9 genes in a cohort of preterm infants using archived blood, CSF and tracheal aspirates and by determining the function of identified polymorphic TLR proteins in vitro. These studies may lead to the generation of novel therapeutic approaches to counteract the detrimental effects of Uu on the immature lung. Relevance to public health: Babies who are born prematurely with an infection with the bacteria Ureaplasma urealyticum may develop a chronic lung disease called Bronchopulmonary Dysplasia. The proposed study will determine if defects in the babies' immune system (ability to fight infection) increase the risk for this infection and the detrimental effects on lung development and may lead to new therapies to prevent BPD. ? ? ?
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