Mechanisms of Salmonella Bacteremia in Pediatric Malaria

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，免疫受损个体黏膜屏障功能的破坏可能导致威胁生命的菌血症的发生。目前在撒哈拉以南非洲有一种播散性NTS感染的流行，与菌血症、脑膜炎和败血症有关，通常会造成致命后果。流行病学协会认为，幼儿中的严重疟疾是导致NTS菌血症的一种重要的免疫损害条件。特别是，在患有恶性疟疾的儿童中，播散性NTS感染的流行率令人震惊。然而，严重疟疾造成的确切免疫缺陷尚未确定，这种缺陷使患者患上NTS菌血症的风险增加。这项应用的目的是使用最近开发的疟疾和NTS的联合感染模型来确定疟疾对随后的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，潜在的疟疾感染导致肠道屏障功能的破坏，以及通过干扰中性粒细胞募集和杀菌活性来抑制全身部位生长的能力降低。确定对播散性感染易感性增加的基础将有助于更好地理解有助于将NTS限制在健康宿主的胃肠道的免疫机制。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。我们期望所提出的研究将为特定的免疫机制提供重要的新见解，这些机制对于NTS感染的粘膜屏障功能是重要的。拟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。 公共卫生相关性：非伤寒沙门氏菌血清型(NTS)通常会在免疫能力强的人中引起腹泻疾病，是撒哈拉以南非洲免疫功能低下者菌血症的主要原因。严重的疟疾贫血是非洲儿童NTS从肠道传播到血液的主要危险因素。我们期望我们拟议的研究能够确定儿童疟疾患者易患NTS菌血症的免疫缺陷，这将为特定的免疫机制提供重要的新见解，这些机制对于维持肠道对细菌的屏障功能非常重要，并拓宽了我们对多种病原体同时感染如何影响疾病结局的理解。

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, a breach of mucosal barrier functions in immunocompromised individuals can result in the development of a life threatening bacteremia. There is currently an epidemic of disseminated NTS infections in sub-Saharan Africa, which are associated with bacteremia, meningitis and sepsis, and often have a fatal outcome. Epidemiological associations suggest that severe malaria in young children is an important immunocompromising condition predisposing to NTS bacteremia. In particular, the prevalence of disseminated NTS infections in children with Plasmodium falciparum malaria is striking. However the precise immune defect caused by severe malaria, which puts patients at an increased risk of developing NTS bacteremia, has not been identified. The objective of this application is to use a recently developed 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 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. Defining the basis for increased susceptibility to disseminated infection will lead to a better understanding of the immune mechanisms that help to confine NTS to the GI tract of the healthy host. 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. It is our expectation that the proposed research will provide important new insights into specific immune mechanisms that are important for mucosal barrier function to NTS infection. The outcome of the proposed research is likely to provide novel paradigms of how polymicrobial infections affect disease outcome. PUBLIC HEALTH RELEVANCE: Nontyphoidal Salmonella serotypes (NTS), which usually cause diarrheal disease in immunocompetent individuals, are a leading cause of bacteremia in immunocompromised individuals in Sub-Saharan Africa. Severe malarial anemia is a major risk factor in African children for dissemination of NTS from the intestine to the bloodstream. We expect our proposed research to identify the immune defects in pediatric malaria patients predisposing them to NTS bacteremia will provide important new insights into specific immune mechanisms that are important for maintaining the intestinal barrier function to bacteria and broaden our understanding of how simultaneous infection with multiple pathogens affect disease outcome.