Integrating geographical and genetic mapping of salmonella disease in an endemic

描述(由申请人提供)：对居住在撒哈拉以南非洲城市的人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类型，这些基因类型会导致儿童患侵袭性和腹泻疾病，并由特定的宿主和环境因素持续存在。我们提出了一项为期5年的研究，对穆库鲁16岁以下人群中侵袭性非伤寒沙门氏菌病(NTS IBD)、伤寒(TF)和NTS腹泻(NTS D)的人群进行监测。穆库鲁是内罗毕的一个城市贫民窟，有15万人。将在为人口服务的两个卫生保健设施进行监测。血液和粪便培养将分别从出现发烧和腹泻的符合年龄的患者身上获得。每一株沙门氏菌临床分离株都将接受完整的基因测序和药敏测试，并将根据患者的居住地绘制地理地图。侵袭性和腹泻性疾病的病例将纳入三项病例对照研究(TF、侵袭性NTS和NTS腹泻各一项)，以评估个人(包括艾滋病毒和疟疾混合感染、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的年龄和性别匹配的对照(每个TF病例1例；NTS IBD 4例；NTS D 4例)。我们预计将登记93例NTS IBD，422例TF，109例NTS D。通过这些数据和活动，我们将1)评估侵袭性NTS、NTS腹泻和TF的发生率，以及这些感染及其组成基因的空间和时空聚集；2)通过评估这些感染及其基因类型的时空聚集以及个人、家庭和环境危险因素，确定NTS和TF在这种环境中的传播；3)评估NTS和ST中抗生素耐药性的发生率和流行率，抗生素耐药菌株的时空聚集，以及抗生素耐药性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中的候选基因组区域，以更好地了解侵袭性NTS的发病机制，并为未来疫苗的抗原靶标确定抗原靶点；以及5)通过确定发病率，识别可能导致干预措施设计的潜在可改变的危险因素，并描述有助于干预目标的风险因素和时空聚集，为未来疫苗和非疫苗预防性干预措施的使用做好准备。

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.