MUCOSAL DEFENSE MECHANISMS IN SUBSTANCE ABUSE

Summary

Principal Investigator: D R Brown
Affiliation: University of Minnesota
Country: USA
Abstract: In the intestinal tract, the first line of defense against pathogenic microorganisms is the layer of epithelial cells that line its extensive mucosal surface. These cells provide a physical barrier to infection and play critical roles at mucosal immune sites by detecting and eliminating enteric pathogens, including the human immunodeficiency virus (HIV) and Salmonella enterica. The intestinal mucosa contains, in addition to epithelial cells, an extensive nervous system capable of pre-programmed behavior, and it houses the largest lymphocyte population in the body; these three cell types communicate with each other through molecular signals which modulate inflammation and coordinate mucosal defense responses to infection. Opioid abuse is an important co-factor in host susceptibility to HIV and other mucosal pathogens, but its impact on mucosal host defense is relatively unknown. Opioid drugs may impair neuro-immuno-epithelial interactions at immune inductive and effector sites in the intestine. The proposed experiments will test the general hypotheses that opioids impair the immune responses of epithelial cells and lymphoid cells in the intestinal mucosa through actions mediated by neuronal and extraneuronal opioid receptors, and that opioid neuroimmune signaling is enhanced by mucosal inflammation. In Specific Aim 1, we will determine and compare the effects of opioids on proinflammatory cytokine release and changes in opioid receptor expression before and after inflammation in porcine intestinal epithelial cells in culture and from explants of Peyer's patch and absorptive mucosae through measurements of secreted cytokines and their mRNA expression. We will also assess opioid actions on intestinal epithelial cell wound healing by electric cell-substrate impedance sensing. In Specific Aim 2, we will compare the morphological interrelationships between opioid receptors and opioid peptides in epithelial cells, neurons and leukocytes of Peyer's patch and absorptive mucosae by immunocytochemical and in situ hybridization methods. We will also examine opioid effects on an epithelial-neuronal co-culture from porcine intestine through measurements of cytokine release and changes in neuronal excitability evoked by Salmonella infection. Finally, we will characterize changes in the ligand affinity and G protein coupling coupling of specific opioid binding sites in neural membranes from inflamed and uninflamed Peyer's patches by radioligand binding techniques. In Specific Aim 3, we will characterize delta-opioid receptors mediating chemokine-induced chemotaxis of intestinal T lymphocytes, and determine the effects of opioids on neurally-mediated secretory immunoglobulin-A release from intestinal mucosa explants. The results from this multi-faceted transdisciplinary project will provide a fundamental understanding of how opioid drugs act to alter mucosal defense function. Moreover, they will unveil new drug targets for the modulation of mucosal immune responses to HIV and other gut pathogens as well as oral vaccines offering protection from these microbes. PUBLIC HEALTH RELEVANCE The goal of the proposed transdisciplinary investigation is to elucidate the mechanisms by which opioid drugs of abuse disrupt the interplay between enteric neurons, epithelial cells and immunocytes at sites of mucosal immunity, which are key targets for infection by enteropathogens like S. typhimurium and the human immunodeficiency virus (HIV). Our experiments will provide new and significant information on the ability of opioids to influence mucosal responses evoked by Salmonella typhimurium, an enteroinvasive zoonotic pathogen and potential HIV vaccine vector. The results that we obtain in this multi-faceted project will advance our understanding of how opioid drugs act to alter mucosal defense function. In addition, they will reveal new drug targets for the modulation of mucosal immune responses to enteric pathogens including HIV, and provide new information contributing to the development of oral vaccines based on bacterial vectors that are designed to confer protection against HIV infection in gut-associated lymphoid tissue, the major body reservoir for this virus.
Funding Period: 1996-09-29 - 2011-07-31
more information: NIH RePORT

Top Publications

  1. pmc Salmonella enterica serovar Choleraesuis infection of the porcine jejunal Peyer's patch rapidly induces IL-1beta and IL-8 expression
    Kendra A Hyland
    Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, 1971 Commonwealth Avenue, St Paul, MN 55108, USA
    Vet Immunol Immunopathol 109:1-11. 2006
  2. ncbi Catecholamines and sympathomimetic drugs decrease early Salmonella Typhimurium uptake into porcine Peyer's patches
    David R Brown
    Department of Veterinary and Biomedical Sciences, University of Minnesota, St Paul, MN 55108 6010, USA
    FEMS Immunol Med Microbiol 52:29-35. 2008
  3. ncbi Comparison of growth phase on Salmonella enterica serovar Typhimurium invasion in an epithelial cell line (IPEC J2) and mucosal explants from porcine small intestine
    Lisa D Schmidt
    Department of Veterinary and Biomedical Sciences, University of Minnesota, 1988 Fitch Avenue, St Paul, MN 55108 6010, USA
    Comp Immunol Microbiol Infect Dis 31:63-9. 2008
  4. pmc Anatomical evidence for enteric neuroimmune interactions in Peyer's patches
    Lucy Vulchanova
    Department of Veterinary and Biomedical Sciences, University of Minnesota, 1988 Fitch Avenue, St Paul, Minnesota 55108 6010, USA
    J Neuroimmunol 185:64-74. 2007
  5. pmc Autonomic neurotransmitters modulate immunoglobulin A secretion in porcine colonic mucosa
    Lisa D Schmidt
    Department of Veterinary and Biomedical Sciences, University of Minnesota, 1988 Fitch Avenue, St Paul, Minnesota 55108 6010, USA
    J Neuroimmunol 185:20-8. 2007
  6. pmc Characterization of Salmonella enterica serovar Typhimurium DT104 invasion in an epithelial cell line (IPEC J2) from porcine small intestine
    David R Brown
    Department of Veterinary and Biomedical Sciences, University of Minnesota, St Paul, MN 55108 6010, USA
    Vet Microbiol 120:328-33. 2007
  7. ncbi Mucosally-directed adrenergic nerves and sympathomimetic drugs enhance non-intimate adherence of Escherichia coli O157:H7 to porcine cecum and colon
    Chunsheng Chen
    Department of Veterinary and Biomedical Sciences, University of Minnesota, 1988 Fitch Avenue, St Paul, MN 55108 6010, USA
    Eur J Pharmacol 539:116-24. 2006
  8. ncbi Adrenocorticotrophic hormone modulates Escherichia coli O157:H7 adherence to porcine colonic mucosa
    Kristin L Schreiber
    Graduate Program in Neuroscience, University of Minnesota, Minnesota 55108 6010, USA
    Stress 8:185-90. 2005
  9. pmc Differential effects of clathrin and actin inhibitors on internalization of Escherichia coli and Salmonella choleraesuis in porcine jejunal Peyer's patches
    Benedict T Green
    Department of Veterinary and Biomedical Sciences, University of Minnesota, 1988 Fitch Avenue, St Paul, MN 55108 6010, USA
    Vet Microbiol 113:117-22. 2006
  10. ncbi Mucosal innate immune response to intragastric infection by Salmonella enterica serovar Choleraesuis
    Kendra A Hyland
    Department of Microbiology, University of Minnesota, 1460 Mayo Memorial Building, 420 Delaware Street, S E, Minneapolis, MN 55455, USA
    Mol Immunol 43:1890-9. 2006

Scientific Experts

  • D R Brown
  • Lucy Vulchanova
  • Kendra A Hyland
  • Lisa D Schmidt
  • Kristin L Schreiber
  • Michael P Murtaugh
  • Mark Lyte
  • Benedict T Green
  • Chunsheng Chen
  • Melissa A Casey
  • Juliana G Machado
  • DeWayne Townsend
  • Laura J Kohrt
  • Yonghong Xie
  • William R Kennedy
  • Lisa D Price
  • Gwen W Crabb
  • Mark P Stevens
  • Laura Kohrt
  • Cheryl M T Dvorak

Detail Information

Publications13

  1. pmc Salmonella enterica serovar Choleraesuis infection of the porcine jejunal Peyer's patch rapidly induces IL-1beta and IL-8 expression
    Kendra A Hyland
    Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, 1971 Commonwealth Avenue, St Paul, MN 55108, USA
    Vet Immunol Immunopathol 109:1-11. 2006
    ....
  2. ncbi Catecholamines and sympathomimetic drugs decrease early Salmonella Typhimurium uptake into porcine Peyer's patches
    David R Brown
    Department of Veterinary and Biomedical Sciences, University of Minnesota, St Paul, MN 55108 6010, USA
    FEMS Immunol Med Microbiol 52:29-35. 2008
    ..These results suggest that enteric catecholaminergic nerves modulate Salmonella colonization of Peyer's patches at the earliest stages of infection, in part by altering epithelial uptake of bacteria...
  3. ncbi Comparison of growth phase on Salmonella enterica serovar Typhimurium invasion in an epithelial cell line (IPEC J2) and mucosal explants from porcine small intestine
    Lisa D Schmidt
    Department of Veterinary and Biomedical Sciences, University of Minnesota, 1988 Fitch Avenue, St Paul, MN 55108 6010, USA
    Comp Immunol Microbiol Infect Dis 31:63-9. 2008
    ..Growth phase-related differences in S. Typhimurium invasion are similar in porcine intestinal epithelial cells and mucosal explants, but may be greater in multidrug-resistant strains...
  4. pmc Anatomical evidence for enteric neuroimmune interactions in Peyer's patches
    Lucy Vulchanova
    Department of Veterinary and Biomedical Sciences, University of Minnesota, 1988 Fitch Avenue, St Paul, Minnesota 55108 6010, USA
    J Neuroimmunol 185:64-74. 2007
    ..The results suggest that nerve fibers in PP may participate in neuroimmune cross-talk within individual antigen-sampling sites as well as integrate information across multiple antigen-sampling sites...
  5. pmc Autonomic neurotransmitters modulate immunoglobulin A secretion in porcine colonic mucosa
    Lisa D Schmidt
    Department of Veterinary and Biomedical Sciences, University of Minnesota, 1988 Fitch Avenue, St Paul, Minnesota 55108 6010, USA
    J Neuroimmunol 185:20-8. 2007
    ..Acetylcholine and norepinephrine, acting respectively through muscarinic cholinergic and alpha-adrenergic receptors in the colonic mucosa, stimulate sIgA secretion and may enhance mucosal defense in vivo...
  6. pmc Characterization of Salmonella enterica serovar Typhimurium DT104 invasion in an epithelial cell line (IPEC J2) from porcine small intestine
    David R Brown
    Department of Veterinary and Biomedical Sciences, University of Minnesota, St Paul, MN 55108 6010, USA
    Vet Microbiol 120:328-33. 2007
    ..Early DT104 invasion of porcine enterocytes appears to be mediated by Rac1 GTPase-independent changes in epithelial actin assembly...
  7. ncbi Mucosally-directed adrenergic nerves and sympathomimetic drugs enhance non-intimate adherence of Escherichia coli O157:H7 to porcine cecum and colon
    Chunsheng Chen
    Department of Veterinary and Biomedical Sciences, University of Minnesota, 1988 Fitch Avenue, St Paul, MN 55108 6010, USA
    Eur J Pharmacol 539:116-24. 2006
    ..This in turn may alter host susceptibility to enteric infections...
  8. ncbi Adrenocorticotrophic hormone modulates Escherichia coli O157:H7 adherence to porcine colonic mucosa
    Kristin L Schreiber
    Graduate Program in Neuroscience, University of Minnesota, Minnesota 55108 6010, USA
    Stress 8:185-90. 2005
    ..Moreover, ACTH7-38 decreased EHEC adherence in the absence of ACTH. These results suggest that ACTH acts via melanocortin receptors located on enteric nerves to enhance mucosal adherence of EHEC...
  9. pmc Differential effects of clathrin and actin inhibitors on internalization of Escherichia coli and Salmonella choleraesuis in porcine jejunal Peyer's patches
    Benedict T Green
    Department of Veterinary and Biomedical Sciences, University of Minnesota, 1988 Fitch Avenue, St Paul, MN 55108 6010, USA
    Vet Microbiol 113:117-22. 2006
    ..coli but not that of rodent-adapted E. coli or SC-54. Internalization of SC-54 and non-pathogenic E. coli in Peyer's patches appears to occur through different cellular routes...
  10. ncbi Mucosal innate immune response to intragastric infection by Salmonella enterica serovar Choleraesuis
    Kendra A Hyland
    Department of Microbiology, University of Minnesota, 1460 Mayo Memorial Building, 420 Delaware Street, S E, Minneapolis, MN 55455, USA
    Mol Immunol 43:1890-9. 2006
    ..These data indicate that IL-1beta and IL-8 expression in the IPP plays a key role early in the interaction between Salmonella serovar Choleraesuis and the small intestine...
  11. ncbi Gene expression profiling of jejunal Peyer's patches in juvenile and adult pigs
    Juliana G Machado
    Department of Veterinary and Biomedical Sciences, University of Minnesota, 1971 Commonwealth Avenue, St Paul, Minnesota, 55108, USA
    Mamm Genome 16:599-612. 2005
    ....
  12. ncbi Mediation of neurogenic ion transport by acetylcholine, prostanoids and 5-hydroxytryptamine in porcine ileum
    DeWayne Townsend
    Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, MN 55108 6010, USA
    Eur J Pharmacol 519:285-9. 2005
    ..Neurogenic secretion in porcine ileum appears to be mediated by tryptaminergic and prostanoid-sensitive cholinergic pathways...
  13. ncbi Evidence for neuromodulation of enteropathogen invasion in the intestinal mucosa
    Kristin L Schreiber
    Graduate Program in Neuroscience, University of Minnesota, 1988 Fitch Avenue, St Paul, MN 55108 6010, USA
    J Neuroimmune Pharmacol 2:329-37. 2007
    ..Based on these findings, enteric neural activity appears to modulate interactions between the intestinal mucosa and pathogenic bacteria...