Pathogenesis of Salmonella bacteremia

沙门氏菌菌血症的发病机制

基本信息

批准号：
8231073
负责人：
Renee M Tsolis
金额：
$ 36.52万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231073
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 Data Defect Development Diarrhea Disease Disease Outcome Employee Strikes Environment Epidemic Epidemiologic Studies Epidemiology Exploratory/Developmental Grant for Diagnostic Cancer Imaging Falciparum Malaria Fatal Outcome Focal Infection Funding Gastroenteritis Gastrointestinal tract structure Goals Grant Growth HIV Infections Immune Immune response Immunocompetent Immunocompromised Host Immunologics Immunology Incidence Individual Infection Inflammatory disease of the intestine Insect Vectors Intestines Lead Life Malaria Malnutrition Medical Microbiology Meningitis Modeling Mucosal Immunity Mucositis Mus Muscle Cramp Natural Immunity Neutrophil Infiltration Organ Outcome Parasites Pathogenesis Patients Predisposition Prevalence Research Research Personnel Risk Risk Factors Salmonella Salmonella infections Scientist Sepsis Serotyping Site Testing Training United States National Institutes of Health Virus Diseases Vomiting Work base expectation innovation insight mortality neutrophil novel pathogen

项目摘要

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. 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 that 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）：在免疫能力的个体中，非细类沙门氏菌血清型（NTS）与胃肠炎有关，胃肠炎是一种局部感染，死亡率低，表现为腹泻，呕吐和肠痉挛。但是，在免疫受损的个体中，违反粘膜屏障功能会导致威胁生命的菌血症的发展。在撒哈拉以南非洲，传播NTS感染的发生率已达到流行病，这些感染与菌血症，脑膜炎和败血症有关，并且常常有致命的结果。在幼儿中，流行病学研究确定严重的疟疾是易受NTS菌血症的重要免疫促进性疾病。在严重的恶性疟原虫疟疾的儿童中，传播NTS感染的流行尤其引人注目。然而，尚不清楚由严重疟疾引起的免疫缺陷，从而增加患NTS菌血症的风险。该应用的目的是使用我们最近开发的疟疾和NTS的鼠共感染模型来鉴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，在小儿患者中，潜在的疟疾寄生虫感染既导致肠道屏障功能的违反，又导致通过干扰中性粒细胞募集和拟肽活性来检查全身性部位的生长能力。我们将通过（i）确定基本疟疾寄生虫感染损害粘膜炎症的机制来检验我们的假设，以及（ii）确定疟原虫感染对控制细菌器官负荷的免疫机制的影响。 NTS/疟疾共感染被研究了，即使它们代表了撒哈拉以南非洲死亡的主要原因，这一事实使该提议的工作变得非常重要。我们预计拟议的研究将为特定的免疫机制提供重要和新颖的见解，这对于对NTS感染的粘膜屏障功能很重要。此外，我们提出的研究的结果可能会提供有关多数菌感染如何影响疾病预后的新型范式。公共卫生相关性：通常在免疫能力的个体中引起腹泻病的非类型沙门氏菌血清型（NTS）是撒哈拉以南非洲免疫功能低下个体菌血症的主要原因。严重的疟疾贫血是非洲儿童从肠道传播到血液的主要危险因素。我们预计，我们提出的研究将确定儿科疟疾患者的免疫缺陷，使他们易于接受NTS菌血症，将为特定的免疫机制提供重要的新见解，这些新见解对于维持肠道屏障功能至关重要，以维持肠道屏障功能，并扩大我们对多种病原体同时感染的理解。