Members of the genus Salmonella cause a diverse variety of diseases, including typhoid fever, food-poisoning, gastroenteritis, and septicemia. Salmonellosis, which represents one of the single largest communicable bacterial diseases in this country, is usually acquired by ingestion of contaminated food or water.

Research in the Nickerson laboratory is focused on understanding the molecular mechanisms used by Salmonella typhimurium to modulate expression of its genes in response to the eukaryotic host and to survive within unique environments. We are also interested in the molecular aspects of the host's response to Salmonella infection. An understanding of these processes may lead to novel strategies for prevention and treatment of disease caused by Salmonella. In our studies, we use a powerful combination of molecular, genetic, biochemical, cell biological, microscopic, animal model, and bioinformatic approaches to investigate fundamental questions regarding the interaction between the host, the environment, and the facultative intracellular pathogen, S. typhimurium.

Research emphasis is on understanding the molecular mechanisms used by S. typhimurium to modulate expression of its genes in response to infection, especially in terms of defining genetic loci which may contribute to the pathogenicity of this organism during the early stages of infection. We are also investigating the ability of Salmonella to survive within unique environments, such as those encountered during spaceflight, and we work closely with the National Aeronautics and Space Administration (NASA). We are the first laboratory to show that the environment created by modeled microgravity represents a novel environmental regulatory factor of Salmonella virulence. We are using a powerful positive cDNA selection methodology in combination with high density microarray-mediated expression profiling to identify Salmonella genomic sequences transcribed in response to the unique environment of modeled microgravity. We are also are investigating a novel approach to improve cultured cell technology to bridge the gap between the inherent limitations of traditional tissue culture methodology and animal models which are currently used for investigation of infectivity by microbial pathogens. Specifically, we have used NASA-designed bioreactor technology to develop novel three-dimensional (3-D) cultures of human intestinal epithelial cells as a model system to study the bacterial infectivity of S. typhimurium. This novel tissue culture approach permits the generation of three-dimensional differentiated tissue-like assemblies which model many aspects of in vivo human tissues, and thus offers an innovative approach for studying microbial infectivity from the perspective of the host-pathogen interaction. We have shown that Salmonella establishes infection of the 3-D intestinal cells in a different manner as compared to monolayer cultures of the same cells, with differences in bacterial adherence and invasion, apoptosis, cytokine profiles, and tissue pathology. Many of these differences appear to be more reflective of an in vivo infection. By more accurately modeling many aspects of human in vivo tissues, the 3-D intestinal model may help bridge the gap between the inherent limitations of traditional tissue culture and animal models which are currently used for investigation of Salmonella infectivity. We are investigating the molecular basis of Salmonella enteropathogenesis by defining genetic loci that are differentially expressed by both Salmonella and the 3-D human intestinal cells following infection. We are also investigating the use of the NASA-designed bioreactors to generate 3-D aggregates from a variety of cell types with wide applications in the modeling of infectious diseases. We anticipate that insight gained from these studies will ultimately contribute to the design of strategies to control Salmonella infection and disease.

Carterson, A. J., K. Höner zu Bentrup, C. M. Ott, M. S. Clarke, D. L. Pierson, C. R. Vanderburg, K. L. Buchanan, C. A. Nickerson, and M. J. Schurr. 2005. A549 Lung Epithelial Cells Grown as Three-Dimensional Aggregates: Alternative Tissue Culture Model for Pseudomonas aeruginosa Pathogenesis. Infect Immun. 73(2):1129-1140. Abstract

Wilson, James W., D. H. Figurski, C. A. Nickerson. 2004. VEX-capture: a new technique that allows in vivo excision, cloning, and broad-host-range transfer of large bacterial genomic DNA segments. Journal of Microbiological Methods. 57:297-308. Abstract

Nickerson, Cheryl A., C. M. Ott, J. W. Wilson, R. Ramamurthy, C. L. LeBlanc, K. Höner zu Bentrup, T. Hammond, D. L. Pierson. 2003. Low-shear modeled microgravity: a global environmental regulatory signal affecting bacterial gene expression, physiology, and pathogenesis. Journal of Microbiological Methods 54:1–11. Abstract

Wilson, J., R. Ramamurthy, S. Porwollik, M. McClelland, T. Hammond, P. Allen, C. M. Ott, D. Pierson, and C. A. Nickerson. 2002. Microarray Analysis Identifies Salmonella Genes Belonging to Low-Shear Modeled Microgravity Regulon. Proc. Natl. Acad. Sci. USA. 99(21):13807-13812. Abstract

Wilson, J., C. M. Ott, R. Ramamurthy, S. Porwollik, M. McClelland, D. Pierson, and C. A. Nickerson. 2002. Low-Shear Modeled Microgravity Alters the Salmonella enterica Serovar Typhimurium Stress Response in an RpoS-Independent Manner. Applied and Environmental Microbiology. 68(11):5408-5416. Abstract

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