EFFECTS OF MALARIA ON PARASITE INFECTION ON INTESTINAL RESPONSE

疟疾寄生虫感染对肠道反应的影响

• 批准号: 8357364
• 负责人: Shirley Luckhart
• 金额: $ 5.04万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357364
• 关键词: Africa South of the Sahara; Bacteremia; California; Characteristics; Child; Childhood; Clinical; Development; Diarrhea; Event; Funding; Gastroenteritis; Goals; Grant; High Prevalence; Immune response; Immunocompetent; Individual; Infection; Inflammation; Inflammatory Response Pathway; Intestines; Macaca; Macaca mulatta; Malaria; Modeling; Monitor; National Center for Research Resources; Neutrophil Infiltration; Opportunistic Infections; Parasites; Pathogenesis; Patients; Plasmodium; Prevention; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Salmonella; Serotyping; Severities; Source; Surface; Testing; Tissues; United States National Institutes of Health; Work; cost; foodborne infection; mortality; neutrophil; prevent; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Non-typhoidal Salmonella serotypes (NTS) are a leading cause of food-borne infections worldwide, with the most frequently isolated serotypes being S. Typhimurium and S. Enteritidis. In immunocompetent individuals, NTS cause aself-limiting gastroenteritis with only infrequent fatalities. However, in children with malaria, NTS cause bacteremia. The high prevalence of malaria in sub-Saharan Africa has contributed to the emergence of NTS as a leading cause of bacteremia in this region, with results in considerable mortality (21 to 38%). Pediatric malaria patients infected with NTS usually present with bacteremia, while gastroenteritis is uncommon. No information is currently available on how malaria and NTS synergize to cause this atypical clinical presentation. Our long-term goal is to understand the pathogenesis of infections with NTS in pediatric malaria patients. The objectives of this project are to use a Plasmodium fragile/NTS rhesus macaque model to determine how the innate immune response to NTS is altered in malaria patients. Our central hypothesis is that malaria parasite infection blunts innate immune responses in the gut that result in inflammation, thereby preventing the massive neutrophil influx and diarrhea that are both characteristic of NTS infections and serve to prevent systemic dissemination of NTS. The rationale for the proposed work is that a better understanding of the mechanisms by which malaria impairs innate immune response to NTS infection will be relevant for the treatment or prevention of other opportunistic infections at mucosal surfaces. To test our hypothesis we will investigate the development of cytokine and inflammatory responses during NTS infection of ligated ileal loops in uninfected rhesus macaques and in macaques infected with the simian malaria parasite Plasmodium fragile. We will use the a ligated ileal loop model, which is ideally suited to study innate immune responses, such as the events triggering 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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 非伤寒沙门氏菌血清型 (NTS) 是全世界食源性感染的主要原因，最常见的分离血清型是鼠伤寒沙门氏菌和肠炎沙门氏菌。在免疫功能正常的个体中，NTS 会引起自限性胃肠炎，但很少导致死亡。然而，在患有疟疾的儿童中，NTS 会导致菌血症。撒哈拉以南非洲地区疟疾的高流行导致 NTS 成为该地区菌血症的主要原因，并导致相当大的死亡率（21% 至 38%）。感染 NTS 的小儿疟疾患者通常会出现菌血症，但胃肠炎并不常见。目前尚无关于疟疾和 NTS 如何协同作用导致这种非典型临床表现的信息。 我们的长期目标是了解儿科疟疾患者 NTS 感染的发病机制。该项目的目标是使用脆弱疟原虫/NTS 恒河猴模型来确定疟疾患者对 NTS 的先天免疫反应如何改变。我们的中心假设是，疟疾寄生虫感染会削弱肠道内的先天免疫反应，从而导致炎症，从而防止大量中性粒细胞流入和腹泻，这都是 NTS 感染的特征，并有助于防止 NTS 的全身传播。 这项工作的基本原理是，更好地了解疟疾损害对 NTS 感染的先天免疫反应的机制，将有助于治疗或预防粘膜表面的其他机会性感染。 为了检验我们的假设，我们将研究未感染的恒河猴和感染了脆弱疟原虫的猕猴结扎回肠环的 NTS 感染期间细胞因子和炎症反应的发展。我们将使用结扎回肠环模型，该模型非常适合研究先天免疫反应，例如 NTS 感染期间触发中性粒细胞快速募集的事件。我们将监测宿主反应并检验中性粒细胞浸润的严重程度与 NTS 在宿主组织内传播的能力成反比相关的工作假设。