Mycoplasma pneumoniae can exacerbate asthma and recent clinical evidence links the presence of the organism with chronic asthma. The focus of this proposal is to examine the interactions between M. pneumoniae and the pulmonary surfactant proteins, SP-A and SP-D. Preliminary evidence demonstrates that SP-A and SP-D bind to the bacteria with high affinity and that the principal ligands are membrane lipids. We plan to examine the basis of the physical interaction between mycoplasma, SP-A and SP-D by elucidating the structures of the lipid ligands. These studies will also utilize a large collection of SP-A and SP-D structural variants to identify the protein domains that are required for interaction with specific lipid ligands. The interaction of SP-A with mycoplasma markedly attenuates the growth of the bacteria and we will also define which protein domains are essential for this process. SP-A amplifies the host response to mycoplasma by stimulating the production of TNFalpha and nitric oxide from macrophages several fold. The SP-A mutant proteins will also be used to identify the domains of the protein that are required for this amplification of the inflammatory response. Both alveolar and bronchial epithelial cells are exposed to mycoplasma during infection. We will determine the cytokine response of these epithelia to mycoplasma and elucidate how this response is modulated by SP-A and SP-D. In conjunction with the proposed in vitro studies we plan to examine the in vivo response of mice challenged with mycoplasma and the modulation of this response by SP-A and SP-D. Both normal and SP-A null mice will be challenged with the bacteria and its derivative components under conditions of supplementation with exogenous SP-A and SP-D. From the experiments described in this proposal we will identify specific lipid and protein components of M. pneumoniae that interact with the surfactant proteins and regulate the host inflammatory response. This information will provide important new details about the events that follow mycoplasma infection and how they can contribute to asthma.
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