Obesity is a major public health issue and the obese population is steadily increasing. Obese individuals are more susceptible to bacterial pneumonia, in part due to altered immune function in the lung. Obese mouse models exist for Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae, however, pneumonia caused by the important Gram negative pathogen Pseudomonas aeruginosa has not been evaluated in obese mouse models. The goal of this R03 proposal is to develop two obese mouse models of P. aeruginosa pneumonia. While current acute lung infection models are informative, none accurately captures the disease pathology and progression seen for P. aeruginosa pneumonia, where there are no physical obstructions and neutrophils play both protective and pathologic roles in disease. Our preliminary data show that the obese db/db mice are permissive to P. aeruginosa infection and show net bacterial growth in the lung, unlike lean heterozygote controls and other models of P. aeruginosa infection where bacteria are rapidly cleared. Therefore, we propose the obese mouse as a physiologically relevant model of infection by which to understand human P. aeruginosa pneumonia. In this proposal we will expand our preliminary data by characterizing the infection progression from both the host and bacterial side in the db/db model and extending this work in a diet-induced model of obesity, via two Specific Aims: (1) Determine optimal infective dose and infection kinetics for P. aeruginosa in db/db mice, and (2) Determine if diet-induced obese mice are hyper- susceptible to P. aeruginosa pneumonia. For both of these Aims, we will measure bacterial load in lung and spleen and assess both host cellular infiltration and cytokine production. Completion of the work described in this proposal will generate an important model for the general study of P. aeruginosa lung infections. Specifically, having an infection model that shows robust bacterial growth at a physiologically relevant inoculum will allow us to better decipher the importance of P. aeruginosa metabolism of host-derived compounds during infection and study host factors contributing to P. aeruginosa susceptibility.
The research proposed here is relevant to human health because obese humans are at higher risk for bacterial pneumonia and Pseudomonas aeruginosa is an important cause of bacterial pneumonia. This proposal is relevant to the NIH mission in terms of establishing a physiologically relevant infection model to help identify bacterial and host pathways that are strong candidates for therapeutic intervention.
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