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Wardwell-Scott, Leslie Hansen

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Wardwell-Scott

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Leslie Hansen

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Wardwell-Scott, Leslie Hansen

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    Functional and Genomic Analyses of Klebsiella Pneumoniae Population Dynamics in the Gastrointestinal Tract
    (2015-12-17) Wardwell-Scott, Leslie Hansen; Lesser, Cammie; Comstock, Laurie; Leong, John
    The gastrointestinal tract is home to trillions of bacteria that interact with each other and with the host’s mucosal immune system. Obligate and facultative anaerobes thrive in the small and large intestine. While many of these bacteria have beneficial relationships with their host, opportunistic pathogens can bloom in times of inflammation and prolong disease. Klebsiella pneumoniae is an opportunistic pathogen that is part of the gut microbiota in many healthy individuals. Here we explore the population dynamics of K. pneumoniae in the gastrointestinal tract in mouse models of health and disease. To assess the role of intra-species genomic diversity in interactions with the host, a mouse K. pneumoniae isolate and three human clinical isolates from human stool, sputum, and urine were studied in the T-bet-/- Rag2-/- and dextran sodium sulfate models of ulcerative colitis and in a mouse model of systemic neonatal infection. Regardless of host origin, isolate site source, or genomic differences, all four K. pneumoniae isolates were able to stimulate colonic inflammation. However, only exposure to the murine K. pneumoniae isolate, and not human clinical isolates, led to neonatal death. In addition, this murine isolate correlated with differential shifts in levels of other Enterobacteriaceae species in the colon. Murine K. pneumoniae was found in higher amounts in host mesenteric lymph nodes compared to human isolates, suggesting subtle strain-based differences that affect response to K. pneumoniae in the gastrointestinal tract. A defining feature of K. pneumoniae is its mucoid capsular polysaccharide coat. To begin investigating a role for K. pneumoniae’s capsule in the gastrointestinal tract, K. pneumoniae biogeography was assessed in gnotobiotic mice. Encapsulated K. pneumoniae were outcompeted by naturally arising variants with reduced capsule throughout the gastrointestinal tract of gnotobiotic mice, except in the distal small intestine. This portion of the small intestine was also the region with the highest host Paneth cell antimicrobial peptide expression. Micro-injection of K. pneumoniae into small intestinal organoids revealed increased growth of encapsulated K. pneumoniae in the presence of α-defensins and decreased survival of K. pneumoniae with reduced capsule production. Capsule also conferred an advantage when K. pneumoniae was part of a diverse microbiota. Competition assays between K. pneumoniae and Escherichia coli showed enhanced survival of encapsulated K. pneumoniae compared to isolates with reduced capsule production. These data suggest that host AMPs, in combination with bacterial-bacterial interactions, shape population dynamics of K. pneumoniae and select for encapsulated K. pneumoniae throughout the gastrointestinal tract. Overall, these studies provide a foundation for understanding interactions between K. pneumoniae, the host, and other bacteria in the gastrointestinal tract.