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Infection and Immunity, November 2001, p. 7106-7120, Vol. 69, No. 11
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.11.7106-7120.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Three-Dimensional Tissue Assemblies: Novel Models for the Study of Salmonella enterica Serovar Typhimurium Pathogenesis

Cheryl A. Nickerson,1,* Thomas J. Goodwin,2 Jacqueline Terlonge,1 C. Mark Ott,3 Kent L. Buchanan,1 William C. Uicker,1 Kamal Emami,3 Carly L. LeBlanc,1 Rajee Ramamurthy,1 Mark S. Clarke,4 Charles R. Vanderburg,5 Timothy Hammond,6 and Duane L. Pierson2

Program in Molecular Pathogenesis and Immunity, Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana 701121; Life Sciences Research Laboratories, NASA-Johnson Space Center,2 EASI/Wyle Laboratories, Johnson Space Center,3 and Universities Space Research Association, Division of Space Life Sciences,4 Houston, Texas 77058; Massachusetts General Hospital, Boston, Massachusetts 021145; and Section of Nephrology, Tulane University Medical Center, New Orleans, Louisiana 70112-26996

Received 13 June 2001/Returned for modification 23 July 2001/Accepted 15 August 2001

The lack of readily available experimental systems has limited knowledge pertaining to the development of Salmonella-induced gastroenteritis and diarrheal disease in humans. We used a novel low-shear stress cell culture system developed at the National Aeronautics and Space Administration in conjunction with cultivation of three-dimensional (3-D) aggregates of human intestinal tissue to study the infectivity of Salmonella enterica serovar Typhimurium for human intestinal epithelium. Immunohistochemical characterization and microscopic analysis of 3-D aggregates of the human intestinal epithelial cell line Int-407 revealed that the 3-D cells more accurately modeled human in vivo differentiated tissues than did conventional monolayer cultures of the same cells. Results from infectivity studies showed that Salmonella established infection of the 3-D cells in a much different manner than that observed for monolayers. Following the same time course of infection with Salmonella, 3-D Int-407 cells displayed minimal loss of structural integrity compared to that of Int-407 monolayers. Furthermore, Salmonella exhibited significantly lower abilities to adhere to, invade, and induce apoptosis of 3-D Int-407 cells than it did for infected Int-407 monolayers. Analysis of cytokine expression profiles of 3-D Int-407 cells and monolayers following infection with Salmonella revealed significant differences in expression of interleukin 1alpha (IL-1alpha ), IL-1beta , IL-6, IL-1Ra, and tumor necrosis factor alpha mRNAs between the two cultures. In addition, uninfected 3-D Int-407 cells constitutively expressed higher levels of transforming growth factor beta 1 mRNA and prostaglandin E2 than did uninfected Int-407 monolayers. By more accurately modeling many aspects of human in vivo tissues, the 3-D intestinal cell model generated in this study offers a novel approach for studying microbial infectivity from the perspective of the host-pathogen interaction.

* Corresponding author. Mailing address: Program in Molecular Pathogenesis and Immunity, Department of Microbiology and Immunology, SL38, Tulane University Medical School, 1430 Tulane Ave., New Orleans, LA 70112. Phone: (504) 988-4609. Fax: (504) 588-5144. E-mail: cnicker{at}tulane.edu.

Infection and Immunity, November 2001, p. 7106-7120, Vol. 69, No. 11
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.11.7106-7120.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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