Respiratory tract colonization with Ureaplasma urealyticum (Uu) in preterm infants is a highly significant risk factor for Bronchopulmonary Dysplasia (BPD). In a prospective cohort of infants less than 32 wk gestation, 50 percent mod-severe BPD, 29 percent mild BPD, and 19 percent non-BPD subjects were Uu tracheal aspirate (TA) positive. Five of six (83 percent) infants who were TA Uu positive and serum or CSF PCR positive had BPD, suggesting invasiveness of the organism may be associated with increased pulmonary pathogenicity. However, invasive disease alone was not significantly associated with BPD, suggesting local immunomodulatory effects of Uu in the lung are required to develop BPD. We previously observed that Uu respiratory tract colonization in preterm infants was associated with greater levels of the pro-inflammatory cytokines tumor necrosis factor (TNF) and interleukin (IL)-1B in TA during the first week of life. In vitro studies of cultured preterm monocytes, Uu serovar 3 alone stimulated TNF and IL-8, and, in combination with bacterial endotoxin (LPS) augmented LPS-induced TNF release, but blocked LPS-induced IL-6 release. We used a clinical Uu isolate (biovar 2) to develop the first non-neonatal mouse model of Uu pneumonia. While these mice develop little detectable illness and minimal signs of lung injury, Uu infection caused a biphasic influx of neutrophils peaking 24h and again 14d after inoculation, and of macrophages peaking 48h and 14-28d after inoculation. Our long-term objective is to determine how Uu modulates the pulmonary immune response alone and in the presence of co-inflammatory stimuli.
The specific aims of this proposal focus on the central hypothesis that the Uu serovars; differ in their ability to promote the development of BPD due to differences in capacity to augment the pulmonary inflammatory response.
The specific aims are: 1) determine whether the risk for BPD is Uu biovar or serovar specific by PCR typing of archived TA isolates, blood and CSF samples from preterm infants with and without BPD, and 2) characterize pathologic properties of TA Uu isolates from BPD and nort-BPD infants using our cell culture and murine Uu pneumonia models. These studies will provide new insights into how certain serovars contribute to the prolonged inflammatory process in BPD.
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