EFFECTS OF MALARIA ON PARASITE INFECTION ON INTESTINAL RESPONSE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Non-typhoidal Salmonella serotypes (NTS) are a leading cause of food-borne infections worldwide, with the most frequently isolated serotypes being S. Typhimurium and S. Enteritidis. In immunocompetent individuals, NTS cause aself-limiting gastroenteritis with only infrequent fatalities. However, in children with malaria, NTS cause bacteremia. The high prevalence of malaria in sub-Saharan Africa has contributed to the emergence of NTS as a leading cause of bacteremia in this region, with results in considerable mortality (21 to 38%). Pediatric malaria patients infected with NTS usually present with bacteremia, while gastroenteritis is uncommon. No information is currently available on how malaria and NTS synergize to cause this atypical clinical presentation. Our long-term goal is to understand the pathogenesis of infections with NTS in pediatric malaria patients. The objectives of this project are to use a Plasmodium fragile/NTS rhesus macaque model to determine how the innate immune response to NTS is altered in malaria patients. Our central hypothesis is that malaria parasite infection blunts innate immune responses in the gut that result in inflammation, thereby preventing the massive neutrophil influx and diarrhea that are both characteristic of NTS infections and serve to prevent systemic dissemination of NTS. The rationale for the proposed work is that a better understanding of the mechanisms by which malaria impairs innate immune response to NTS infection will be relevant for the treatment or prevention of other opportunistic infections at mucosal surfaces. To test our hypothesis we will investigate the development of cytokine and inflammatory responses during NTS infection of ligated ileal loops in uninfected rhesus macaques and in macaques infected with the simian malaria parasite Plasmodium fragile. We will use the a ligated ileal loop model, which is ideally suited to study innate immune responses, such as the events triggering rapid neutrophil recruitment during NTS infection. We will monitor host responses and test the working hypothesis that the severity of neutrophil infiltration is inversely correlated to the ability of NTS to disseminate within host tissue.