Mechanisms of Salmonella Bacteremia in Pediatric Malaria

小儿疟疾沙门氏菌菌血症的机制

• 批准号: 8033247
• 负责人: Renee M Tsolis
• 金额: $ 18.21万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033247
• 关键词: Adult; Affect; Africa South of the Sahara; African; Anemia; Animal Model; Bacteremia; Bacteria; Bacterial Infections; Biology; Blood Circulation; Child; Childhood; Communicable Diseases; Comparative Pathology; Data; Defect; Development; Diarrhea; Disease; Disease Outcome; Employee Strikes; Environment; Epidemic; Epidemiology; Falciparum Malaria; Fatal Outcome; Focal Infection; Funding; Gastroenteritis; Gastrointestinal tract structure; Goals; Grant; Growth; HIV Infections; Health; Human; Immune; Immune response; Immunocompetent; Immunocompromised Host; Immunology; Individual; Infection; Inflammatory disease of the intestine; Insect Vectors; Intestines; Lead; Life; Malaria; Malnutrition; Medical Microbiology; Meningitis; Modeling; Mucosal Immunity; Mus; Muscle Cramp; Natural Immunity; Neutrophil Infiltration; Outcome; Parasites; Pathogenesis; Patients; Predisposition; Prevalence; Research; Research Personnel; Risk; Risk Factors; Salmonella; Salmonella infections; Salmonella typhimurium; Scientist; Sepsis; Serotyping; Site; Testing; Training; United States National Institutes of Health; Virus Diseases; Vomiting; Work; animal model development; base; expectation; innovation; insight; mortality; neutrophil; novel; pathogen; public health relevance

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.

描述（由申请人提供）：在免疫功能正常的个体中，非伤寒沙门氏菌血清型（NTS）与胃肠炎有关，胃肠炎是一种低死亡率的局部感染，表现为腹泻、呕吐和肠痉挛。然而，免疫功能低下个体的粘膜屏障功能的破坏可能导致危及生命的菌血症的发生。目前，撒哈拉以南非洲地区流行着播散性 NTS 感染，这种感染与菌血症、脑膜炎和败血症有关，通常会造成致命的后果。流行病学协会表明，幼儿中的严重疟疾是一种重要的免疫功能低下疾病，易诱发 NTS 菌血症。特别是，患有恶性疟原虫疟疾的儿童中传播性 NTS 感染的流行率令人震惊。然而，严重疟疾导致的确切免疫缺陷导致患者患 NTS 菌血症的风险增加，这一点尚未确定。该应用的目的是使用最近开发的疟疾和 NTS 混合感染模型来确定疟疾对随后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，潜在的疟疾感染会导致肠道屏障功能破坏，并通过干扰中性粒细胞募集和杀菌活性来降低控制全身部位生长的能力。确定播散性感染易感性增加的基础将有助于更好地了解有助于将 NTS 限制在健康宿主胃肠道的免疫机制。尽管 NTS/疟疾混合感染是撒哈拉以南非洲地区死亡的主要原因，但对它们的研究还不够充分，这一事实使得拟议的工作非常重要。我们期望所提出的研究将为特定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非常重要。拟议研究的结果可能为多种微生物感染如何影响疾病结果提供新的范例。 公共卫生相关性：非伤寒沙门氏菌血清型 (NTS) 通常会在免疫功能正常的个体中引起腹泻病，是撒哈拉以南非洲地区免疫功能低下个体发生菌血症的主要原因。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。我们希望我们提出的研究能够确定儿科疟疾患者中易患 NTS 菌血症的免疫缺陷，这将为特定免疫机制提供重要的新见解，这些机制对于维持细菌的肠道屏障功能非常重要，并拓宽我们对多种病原体同时感染如何影响疾病结果的理解。