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的人群中沙门氏菌病的分子流行病学知之甚少。我们假设热点地区存在独特的沙门氏菌基因型，这些沙门氏菌会在特定的宿主和环境因素的作用下导致儿童侵袭性和腹泻性疾病。我们提出一项为期 5 年的研究，对内罗毕市区贫民窟 Mukuru 16 岁以下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) 进行为期 5 年的监测。将为民众提供服务的两个医疗机构将进行监测。将分别从出现发烧和腹泻的符合年龄条件的患者中获得血液和粪便培养物。每个沙门氏菌临床分离株都将接受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进行地理定位。侵袭性和腹泻性疾病病例将被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 HIV 和疟疾合并感染、是否存在镰状细胞性状/疾病以及营养状况）、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 名；NTS IBD 4 名；NTS D 4 名）。我们预计将招募 93 例 NTS IBD、422 例 TF 和 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) 通过评估空间和时空聚类以及这些感染及其基因型的个人、家庭和环境风险因素，确定 NTS 和 TF 在这种情况下的传播； 3）评估NTS和ST中抗生素耐药性的发生率和患病率、抗生素耐药菌株的空间和时空聚类，以及抗生素耐药性与特定基因型以及个人、家庭和环境风险因素的关联； 4）探索NTS中的候选基因组区域，以更好地了解侵袭性NTS发病机制并确定未来疫苗的抗原靶标； 5) 通过确定疾病发病率、识别可能导致设计干预措施的潜在可改变风险因素、以及描述有助于确定干预措施目标的风险因素和时空聚类，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.