Mucosal Defense Mechanisms in Substance Abuse

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Enteric infections by Salmonella and other enteroinvasive microorganisms are a major contributing factor to morbidity and mortality in individuals with AIDS and other immunosuppressed conditions. The large surface area of the human intestinal mucosa is in direct contact with the external environment, and must coexist with commensal enteric microflora but exclude luminal pathogens. In addition, Peyer's patches (PP) in the small intestine play a key role in mucosal immunity by delivering luminal antigens across the mucosal barrier to submucosal antigen-presenting cells, but PP may also serve as entryways for infection by enteroinvasive microorganisms which can produce enteritis and septicemia. In the previous funding period, we obtained evidence that a novel inhibitory opioid receptor in the porcine ileal submucosa is expressed in an enteric neural circuit through which inflammatory mediators evoke epithelial anion secretion. In the course of these experiments, we made the exciting new discovery that the intracellular uptake of the highly lethal Salmonella serovar choleraesuis into PP and non-PP epithelia of porcine jejunum may be modulated by the enteric nervous system of the host. This application seeks to continue this novel line of investigation by addressing the hypotheses that (1) bacterial uptake into PP and non-PP intestinal epithelia is altered by changes in enteric neural activity and key enteric neuroinhibitory molecules, including opioids and cannabinoids; and (2) that neuroregulation of Salmonella uptake is not specific for this microorganism. These hypotheses will be tested by examining the effects of drugs and other treatments on the internalization of S. choleraesuis into isolated jejunal PP and non-PP mucosa from pigs through the following Specific Aims: (1) to characterize the projections, chemical coding and receptor signatures of enteric neurons innervating PP in porcine jejunal segments; (2) to functionally identify classes of enteric neurotransmitters modulating Salmonella internalization into PP; (3) to define the actions of norepinephrine, opioids and cannabinoids in altering PP and non-PP mucosal uptake of Salmonella; and (4) to examine the actions of norepinephrine and other neuroinhibitory drugs on bacteria-specific and non-specific mucosal uptake processes in PP and non-PP intestinal mucosae. The results of the proposed experiments should enhance our understanding of the deleterious effects of abused drugs in AIDS- related enteric infections and may identify new pharmacological treatments capable of enhancing the efficacy of oral vaccines designed to prevent infections by the human immunodeficiency virus and other enteropathogens.