SUBSTANCE P AND THE PATHOGENESIS OF CRYPTOSPORIDIOSIS IN AIDS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cryptosporidiosis, caused by the protozoan parasite Cryptosporidium parvum causes self-limited diarrhea in AIDS patients. There is no specific prevention or therapy available for cryptosporidiosis. Therefore, there is an urgent need for innovative drugs to treat this disease. Cryptosporidium infection results in intestinal path physiologic changes such as glucose-malabsorption, increased chloride-ion (CI^-) secretion and epithelial barrier disruption leading to disease pathogenesis. In order to develop tools to combat this opportunistic pathogen, it is vital to understand mediators involved in disease pathogenesis. Substance P (SP), a neuropeptide and pain-transmitter, is located in the gastrointestinal-tract. SP can cause CI^- secretion in human gastrointestinal-explants. However, its role in cryptosporidiosis has not been fully studied. Jejunal samples from macaques before and after C. parvum infection were assayed for SP and SP receptor, NK1 (neurokinin 1) mRNA and protein levels by RT-PCR and by immunohistochemistry and ELISA, respectively. Path physiologic alterations, such as CI^- secretion and glucose-malabsorption and the role of SP in these alterations was also studied using tissues derived from macaques infected with C. parvum by the Ussing chamber technique. SP and NK1 mRNA and protein expression were increased in jejunal samples following C. parvum infection and were accompanied by increased CI^- secretion and glucose-malabsorption. In vitro treatment of samples obtained from infected macaques with SP receptor antagonist, Emend completely reversed the increase in CI^- secretion and corrected the glucose-malabsorption. Our findings raise the possibility of using SP receptor antagonists for treatment of syptoms associated with this disease.