Pathogenesis of Salmonella bacteremia

说明(申请人提供)：在具有免疫能力的个人中，非伤寒沙门氏菌血清型(NTS)与胃肠炎有关，胃肠炎是一种死亡率较低的局部感染，表现为腹泻、呕吐和肠道痉挛。然而，在免疫受损的个体中，黏膜屏障功能的破坏可能导致威胁生命的菌血症的发生。在撒哈拉以南非洲，播散性NTS感染的发病率已达到流行状态，在那里，这些感染与菌血症、脑膜炎和败血症有关，往往会造成致命后果。在幼儿中，流行病学研究已经确定，严重疟疾是一种重要的免疫损害疾病，容易导致NTS菌血症。在患有严重恶性疟疾的儿童中，播散性NTS感染的流行率尤其惊人。然而，严重疟疾引起的免疫缺陷增加了发生NTS菌血症的风险，目前尚不清楚。这项应用的目的是使用我们最近开发的疟疾和NTS的小鼠混合感染模型来确定疟疾对后续细菌感染的免疫反应的影响。我们的中心假设是，在儿科患者中，潜在的疟疾寄生虫感染导致肠道屏障功能的破坏，并通过干扰中性粒细胞募集和杀菌活性来降低抑制全身部位生长的能力。我们将通过(I)确定潜在的疟疾寄生虫感染损害粘膜炎症的机制，以及(Ii)确定疟疾寄生虫感染对控制细菌器官负荷的免疫机制的影响来验证我们的假设。尽管NTS/疟疾混合感染是撒哈拉以南非洲地区死亡的一个主要原因，但对它们的研究还很少，这使得拟议的工作具有非常重要的意义。我们期望这项拟议的研究将为特定的免疫机制提供重要的和新的见解，这些机制对于NTS感染的粘膜屏障功能非常重要。此外，我们建议的研究结果可能为多菌感染如何影响疾病结局提供新的范例。

DESCRIPTION (provided by applicant): In immunocompetent individuals, non-typhoidal Salmonella serotypes (NTS) are associated with gastroenteritis, a localized infection with low mortality manifesting as diarrhea, vomiting and intestinal cramping. However, in immunocompromised individuals, a breach of mucosal barrier functions can result in the development of a life threatening bacteremia. The incidence of disseminated NTS infections has reached epidemic status in sub-Saharan Africa, where these infections are associated with bacteremia, meningitis and sepsis, and often have a fatal outcome. In young children, epidemiologic studies have determined that severe malaria is an important immunocompromising condition predisposing to NTS bacteremia. In children with severe Plasmodium falciparum malaria the prevalence of disseminated NTS infections is particularly striking. However, the immune defects caused by severe malaria that increase the risk of developing NTS bacteremia, are not known. The objective of this application is to use our recently developed murine co-infection model of malaria and NTS to identify effects of malaria on the immune response to a subsequent bacterial infection. Our central hypothesis is that in pediatric patients, underlying malaria parasite infection leads to both a breach in intestinal barrier function and a reduced ability to check growth at systemic sites by interfering with neutrophil recruitment and bacteriocidal activity. We will test our hypothesis by (i) identifying mechanisms by which underlying malaria parasite infection compromises mucosal inflammation, and (ii) determining effects of malaria parasite infection on immunologic mechanisms that control bacterial organ loads. The fact that NTS/malaria co-infections are understudied, even though they represent a major cause of mortality in sub-Saharan Africa, makes the proposed work highly significant. We expect that the proposed research will provide important and novel insights into specific immune mechanisms that are important for mucosal barrier function to NTS infection. Further, the results of our proposed studies are likely to provide novel paradigms of how polymicrobial infections affect disease outcome.