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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 非伤寒沙门氏菌血清型（NTS）是全球食源性感染的主要原因，最常见的分离血清型是S。鼠伤寒沙门氏菌（S.肠道。在免疫功能正常的个体中，NTS引起自限性胃肠炎，仅有罕见的死亡。然而，在患有疟疾的儿童中，NTS会引起菌血症。疟疾在撒哈拉以南非洲的高流行率促使NTS成为该地区菌血症的主要原因，导致相当大的死亡率（21%至38%）。感染NTS的儿童疟疾患者通常表现为菌血症，而胃肠炎则不常见。目前没有关于疟疾和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童疟疾患者感染NTS的发病机制。该项目的目标是使用疟原虫脆弱/NTS恒河猴模型，以确定如何改变疟疾患者的先天免疫反应NTS。我们的中心假设是疟原虫感染减弱了肠道中导致炎症的先天免疫反应，从而防止大量中性粒细胞流入和腹泻，这两者都是NTS感染的特征，并有助于防止NTS的全身传播。 拟议的工作的理由是，更好地了解疟疾损害先天免疫反应NTS感染的机制将是相关的治疗或预防其他机会性感染粘膜表面。 为了验证我们的假设，我们将调查NTS感染的结扎回肠环在未感染的恒河猴和猕猴感染猴疟疾寄生虫疟原虫脆弱的发展过程中的细胞因子和炎症反应。我们将使用结扎回肠袢模型，该模型非常适合研究先天性免疫反应，例如NTS感染期间触发快速中性粒细胞募集的事件。我们将监测主机的反应和测试的工作假设，即中性粒细胞浸润的严重程度是负相关的NTS的能力，在主机组织内传播。