The central goal of this project is to gain a better understanding of the pathogenesis of and immunity to infections caused by LPS-smooth strains P. aeruginosa strains in immunocompromised patients. Based on previous studies by the sponsor's laboratory and collaborators, we have established a reproducible mouse model of P. aeruginosa gastrointestinal-colonization and systemic spread during neutropenia. Preliminary studies using this model have identified several factors that are necessary for gastrointestinal colonization and dissemination. Of note, virulence factors expected to play an important role in colonization, namely pill and flagella, were not needed whereas LPS-outer core polysaccharide and O-side chains were. The duration and intensity of neutropenia, related to cyclophosphamide dose, was important in identifying virulence factors needed for dissemination. These preliminary experiments have led to the following testable hypothesis: Surface factors of P. aeruginosa needed to colonize the gastrointestinal mucosa and to translocate and cause bacteremia are not fully known. Identification of such factors can be accomplished in a murine model that will define both pathogen virulence factors (colonization and translocation factors) and host immune responses (cellular and humoral immune effectors). The findings could lead to means to effectively disrupt mucosal colonization and dissemination and diminish the impact of P. aeruginosa infection in immunocompromised hosts.
In Aim 1, virulence factors needed by P. aeruginosa to establish gastrointestinal colonization, translocation, and dissemination will be identified by use of microarray and TraSH (transposon site hybridization) technology, and mutants will be created for testing in the colonization/dissemination model.
In Aim 2, the role of host immune effectors (cellular and humoral innate immunity) that are necessary for preventing P. aeruginosa colonization and dissemination will be further delineated. The candidate seeks an intensive, formal, and mentored training to provide the necessary intellectual and technical tools to achieve independence as a scientist. As a specialist in pediatric hematology/oncology and infectious diseases, his long-term goal is to develop strategies and potential therapies to prevent or ameliorate the consequences of P. aeruginosa infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Investigator Award (CIA) (K08)
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Microbiology and Infectious Diseases B Subcommittee (MID)
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Korpela, Jukka K
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Brigham and Women's Hospital
United States
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Lopez-Medina, Eduardo; Neubauer, Megan M; Pier, Gerald B et al. (2011) RNA isolation of Pseudomonas aeruginosa colonizing the murine gastrointestinal tract. J Vis Exp :
Kamei, Akinobu; Koh, Andrew Y; Gadjeva, Mihaela et al. (2010) Analysis of acquisition of Pseudomonas aeruginosa gastrointestinal mucosal colonization and horizontal transmission in a murine model. J Infect Dis 201:71-80
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Koh, Andrew Y; Priebe, Gregory P; Ray, Christopher et al. (2009) Inescapable need for neutrophils as mediators of cellular innate immunity to acute Pseudomonas aeruginosa pneumonia. Infect Immun 77:5300-10
Van Gennip, Maria; Christensen, Louise Dahl; Alhede, Morten et al. (2009) Inactivation of the rhlA gene in Pseudomonas aeruginosa prevents rhamnolipid production, disabling the protection against polymorphonuclear leukocytes. APMIS 117:537-46
Koh, Andrew Y; Kohler, Julia R; Coggshall, Kathleen T et al. (2008) Mucosal damage and neutropenia are required for Candida albicans dissemination. PLoS Pathog 4:e35