Obesity is a major public health issue and the obese population is steadily increasing. One consequence of obesity is increased susceptibility to bacterial pneumonia. While altered immune function in the lung is an important driver of this susceptibility, the contribution of the bacterial response to the obese lung environment has not been examined. Klebsiella pneumoniae (Kp) is one of the bacteria to which obese individuals are susceptible and is an important drug-resistant pathogen. The goal of this proposal is to examine the bacterial response to the obese lung and use this to better understand host biology and bacterial pathogenesis during infection. Our published preliminary data show increased susceptibility of obese mice to Kp using four different mouse models, three genetic (db/db, ob/ob, and CPEfat/fat) and one high-fat diet-induced (DIO). While all four obese models are more susceptible to Kp than lean littermates, each shows different bacterial growth/survival kinetics in the lung. Each model manifests different degrees of diabetes and other elements of the metabolic syndrome meaning that interaction of the bacteria with each of these models happens in an environment that is likely chemically and immunologically different. Our preliminary data of Kp transcriptome response to db/db bronchoalveolar lavage fluid combined with our published data on host cellular immune defects suggests that host defects are combined with pro-pathogenic bacterial responses to the obese lung environment to promote infection in the lung. The bacterial response in these four obese models will be used to identify Kp genes important for infection of obese mice as well as provide a means to probe altered host physiology, via two Specific Aims: (1) Use the Kp transcriptome response to identify genes contributing to infection in obesity models and (2) Use Kp transcriptomes to identify altered host parameters in the lung. Complete Kp transcriptomes from the four obese models will allow specific dissection of the host-pathogen interface related to obesity, and using Kp as a living probe will uncover altered airspace lining fluid composition in obesity that will vary with the elements and degree of metabolic syndrome expression in each model. The bulk of bacterial-host interaction studies in obesity have focused on deficiencies in the host cellular immune response. Here we will use the transcriptome response of Kp to understand changes to the lung airspace during obesity that alter bacterial gene expression. The ability to compare and test mutant phenotypes in relation to four different models of obesity will allow discovery of new aspects of host-bacterial interactions, and provide a foundation for mechanistic understanding of these interactions.

Public Health Relevance

The research proposed here is relevant to human health because obese humans are at higher risk for bacterial pneumonia and Klebsiella pneumoniae is an important cause of bacterial pneumonia in this population. This proposal is relevant to the NIH mission in terms of using animal models of human disease to help identify bacterial and host pathways that are strong candidates for therapeutic intervention.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Research Grants (R03)
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Special Emphasis Panel (ZRG1)
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Ernst, Nancy L
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University of Vermont & St Agric College
Schools of Medicine
United States
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