Pathogenesis of Salmonella bacteremia

沙门氏菌菌血症的发病机制

• 批准号: 8968809
• 负责人: Renee M Tsolis
• 金额: $ 36.58万
• 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: 2011-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968809
• 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; co-infection; expectation; innovation; insight; malaria infection; mortality; neutrophil; novel; pathogen; pediatric patients

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.

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，在免疫功能低下的个体中，粘膜屏障功能的破坏可能导致危及生命的菌血症的发生。播散性 NTS 感染的发生率在撒哈拉以南非洲地区已达到流行病水平，这些感染与菌血症、脑膜炎和败血症有关，并且常常导致致命的结果。在幼儿中，流行病学研究已确定，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。在患有严重恶性疟原虫疟疾的儿童中，播散性 NTS 感染的患病率尤其惊人。然而，严重疟疾引起的免疫缺陷是否会增加发生 NTS 菌血症的风险尚不清楚。本应用的目的是利用我们最近开发的疟疾和 NTS 小鼠共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，潜在的疟疾寄生虫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。我们将通过（i）确定潜在的疟疾寄生虫感染损害粘膜炎症的机制，以及（ii）确定疟疾寄生虫感染对控制细菌器官负荷的免疫机制的影响来检验我们的假设。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且新颖的见解，这些机制对于 NTS 感染的粘膜屏障功能非常重要。此外，我们提出的研究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。

项目成果

Mast cells and histamine alter intestinal permeability during malaria parasite infection.

• DOI: 10.1016/j.imbio.2015.11.003
• 发表时间: 2016-03
• 期刊: Immunobiology
• 影响因子: 2.8
• 作者: Potts RA;Tiffany CM;Pakpour N;Lokken KL;Tiffany CR;Cheung K;Tsolis RM;Luckhart S
• 通讯作者: Luckhart S