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. Non-typhoidal Salmonella serotypes (NTS) are a leading cause of food-borne infections worldwide, with S. Typhimurium and S. Enteritidis being isolated most frequently. In immunocompetent individuals, NTS cause a localized gastroenteritis with low mortality rates. However, NTS cause bacteremia in patients with acquired immunodeficiency syndrome (AIDS). The high prevalence of HIV in sub-Saharan Africa has made NTS a leading cause of bacteremia in this region, resulting in considerable mortality (21 to 38%). AIDS patients acquiring an infection with NTS usually present with bacteremia while gastroenteritis is not observed. There is currently no information available on how human immunodeficiency virus (HIV) and NTS synergize to cause this atypical clinical picture. Our long-range goal is to understand the pathogenesis of infections with NTS in HIV patients. The objectives of this project are to use a simian immunodeficiency virus (SIV)/NTS rhesus macaque model to determine how the innate immune response to NTS is altered in HIV patients. Our central hypothesis is that SIV infection reduces innate immune responses in the gut leading to inflammation, thus preventing the massive neutrophil influx, which prevents systemic dissemination of NTS and contributes to diarrhea. The rationale for the proposed research is that a better understanding of the mechanisms by which HIV impairs innate immune response to NTS infection will be relevant for the treatment or prevention of other opportunistic infections at mucosal surfaces. We plan to test our hypothesis and fulfill the objectives of this application by pursuing the following specific aim: 1. Investigate the development of cytokine and inflammatory responses during NTS infection of ligated ileal loops in SIV negative and SIV positive rhesus macaques. We will use the a ligated ileal loop model, which is ideally suited to study innate immune responses, such as the events resulting in 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. Most importantly, we will test several models by which SIV-infection reduces innate immune responses leading to IL17 and/or CXC chemokine production.
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