Integrating geographical and genetic mapping of salmonella disease in an endemic

描述（由申请人提供）：对于居住在撒哈拉以南非洲城市人群中沙门氏菌病的分子流行病学知之甚少。我们假设在热点地区存在独特的沙门氏菌基因型，可引起儿童侵袭性和腹泻疾病，并由特定宿主和环境因素持续存在。我们提出了一项为期5年的基于人群的侵袭性非伤寒沙门氏菌病（NTS IBD）、伤寒（TF）和NTS腹泻（NTS D）监测研究，研究对象是内罗毕城市贫民窟穆库鲁（Mukuru）的16岁以下人群，人口为15万。将在为人口服务的两个保健设施进行监测。血液和粪便培养将分别从符合年龄的发热和腹泻患者中获得。每个临床分离的沙门氏菌都将进行完整的基因测序和抗生素敏感性测试，并根据患者的居住地绘制地理图。侵袭性和腹泻性疾病病例将被纳入三个病例对照研究（TF、侵袭性NTS和NTS腹泻各一个），以评估个人（包括HIV和疟疾合并感染、镰状细胞特征/疾病的存在和营养状况）、家庭和环境风险因素。对于每个病例，将选择年龄和性别匹配的对照组，他们因发烧、腹泻或其他肠道症状以外的原因到同一医疗机构就诊（每个TF病例1人；NTS IBD病例4人；NTS D病例4人）。我们预计将纳入93例NTS IBD， 422例TF， 109例NTS d。根据这些数据和活动，我们将1)评估侵袭性NTS， NTS腹泻和TF的发病率，以及这些感染及其组成基因型的空间和时空聚类；2)通过评估NTS和TF的时空聚类以及感染的个人、家庭和环境风险因素及其基因型，确定NTS和TF在该地区的传播；3)评估NTS和ST的抗生素耐药发生率和流行情况、耐药菌株的时空聚类，以及抗生素耐药与特定基因型和个人、家庭和环境风险因素的关系；4)探索NTS的候选基因组区域，以更好地了解侵袭性NTS的发病机制，并确定未来疫苗的抗原靶点；5)通过确定疾病发病率，识别可能导致干预措施设计的潜在可改变的风险因素，以及描述风险因素和促进干预措施目标的时空聚类，为未来使用疫苗和非疫苗预防性干预措施做好准备。

DESCRIPTION (provided by applicant): Little is known about the molecular epidemiology of Salmonella disease in persons residing in urban Sub-Saharan Africa. We hypothesize that there are unique genotypes of Salmonella in hotspots that cause invasive and diarrheal illnesses in children, perpetuated by specific host and environmental factors. We propose a 5-year study of population-based surveillance for invasive non-typhoidal Salmonella disease (NTS IBD) typhoid fever (TF), and NTS diarrhea (NTS D), in persons under 16 years of age in Mukuru, an urban Nairobi slum with 150,000 people. Surveillance will be undertaken at the two health care facilities serving the population. Blood and stool cultures will be obtained from age-eligible patients presenting with fever and diarrhea, respectively. Each Salmonella spp clinical isolate will undergo complete genetic sequencing and antibiotic susceptibility testing, and will be geographically mapped according to the residence of the patient. Cases of invasive and diarrheal illness will be enrolled into three case-control studies (one each for TF, invasive NTS and NTS diarrhea) to evaluate personal (including HIV and malaria co- infection, presence of sickle cell trait/disease, and nutritional status), household, and environmental risk factors. For each case age and sex-matched controls who present to the same medical facility for reasons other than fever, diarrhoea, or other enteric symptoms will be selected (1 for each TF case; 4 for NTS IBD; 4 for NTS D). We expect to enroll 93 cases of NTS IBD, 422 cases of TF, 109 cases of NTS D. With these data and activities we will 1) evaluate the incidence of invasive NTS, NTS diarrhea, and TF, as well as spatial and spatio-temporal clustering of these infections and their constituent genotypes; 2) define the transmission of NTS and TF in this setting by assessment of spatial and spatio-temporal clustering and of personal, household, and environmental risk factors for these infections and their genotypes; 3) assess the incidence and prevalence of antibiotic resistance among NTS and ST, spatial and spatio-temporal clustering of antibiotic-resistant isolates, and the association of antibiotic resistance with specific genotypes and personal, household, and environmental risk factors; 4) explore candidate genomic regions in NTS to better understand invasive NTS pathogenesis and to identify antigenic targets for future vaccines; and 5) prepare the site for future use of vaccines and non-vaccine preventive interventions by determining disease incidence, identifying potentially modifiable risk factors tha could lead to the design of interventions, and delineating risk factors and spatial-temporal clustering that facilitate targeting of interventions.