Multidrug resistant invasive non-typhoidal Salmonella disease in children: The role of carriage in humans and environmental contamination in an endemic setting in Kenya

虽然教科书上的知识区分了侵袭性伤寒和非侵袭性肠道非伤寒沙门氏菌病（NTS），但在撒哈拉以南非洲，迄今为止被忽视和具有威胁性的传染病已经成为血液感染的一个突出原因。这种疾病是由NTS （iNTS）侵袭性菌株引起的。每年病例最多的是5岁以下儿童，相关病死率为20-25%。此外，iNTS中抗菌素耐药性（AMR）的增加引起了全球的极大关注，低收入和中等收入国家主要受到影响，因为用于有效治疗危及生命的侵袭性疾病的替代药物正在迅速减少。令人担忧的是，在德国也发现了iNTS感染，而且流行率越来越高。病原体的携带通常有助于疾病传播，但与有充分记录的伤寒沙门氏菌在人类中的长期携带相比，对非伤寒沙门氏菌的携带的研究要少得多。因此，我们在此旨在确定在地方病环境中，家庭层面的NTS携带和环境污染是否在社区易感儿童中发生的NTS感染中发挥了主要作用，以及是什么导致了抗菌素耐药性问题的不断升级。此外，将对来自侵袭性感染的非洲iNTS菌株与德国iNTS菌株进行全面的基因组分析。拟建项目的具体目标是：1)确定表面健康个体中与NTS菌株持续携带相关的流行、宿主、环境和病原体因素。2)了解来自患者、携带者和环境的多重耐药iNTS菌株的流行病学和基因组学特征，以及它们与iNTS菌株持续携带的关系。3)确定宅基地和环境（露天下水道和水源）中的AMR基因作为iNTS耐药性决定因素的潜在供体。4)开发简单的PCR工具，便于改进检测，并使当地社区参与进来，最大限度地减少iNTS和AMR携带和传播的风险因素。5)建立沙门氏菌分类、分型、基因组测序、基因组和宏基因组分析的综合研究培训计划，使非洲科学家能够对项目样本进行分子检测和表征。

While textbook knowledge divides between invasive typhoidal and non-invasive enteric non-typhoidal Salmonellosis (NTS), in Sub-Saharan Africa so far neglected and threatening infectious disease has emerged as a prominent cause of bloodstream infection. This disease is caused by invasive strains of NTS (iNTS). The largest number of cases annually is found in children less than 5 years of age with an associated case fatality of 20–25%. Further, increasing antimicrobial resistance (AMR) in iNTS is of great global concern, with low and middle-income countries suffering mostly as alternative drugs for effective treatment of life-threatening invasive disease are eroding rapidly. Worryingly, iNTS infections are also found in Germany with increasing prevalence. Carriage of pathogens often contributes to disease transmission, but in contrast to the well-documented prolonged carriage of typhoidal Salmonella in humans, carriage of non-typhoidal Salmonellae is far less studied. Therefore, we here aim to establish in an endemic disease setting if carriage of NTS at the household level and environmental contamination play a major role in iNTS infection occurring in vulnerable children in the community and what drives this escalating problem of antimicrobial resistance. Further, a comprehensive genome analysis of African iNTS strains in comparison to German strains from invasive infections will be performed. Specific objectives of the proposed project are: 1) To determine the prevalence, host, environmental and pathogen factors associated with persistent carriage of NTS strains in apparently healthy individuals. 2) To describe the epidemiology and genomics of multi-drug resistant iNTS strains from patients, carriers and environment and their association with persistent carriage of iNTS strains. To further compare strain genomes to those isolated from infections in Germany. 3) To determine AMR genes in homestead and environment (open sewers and water sources) as potential donors of resistance determinants to iNTS. 4) To develop simple PCR tools which can be easily adapted to improve detection and engage local community to minimize risk factors for carriage and transmission of iNTS and AMR. 5) To establish a comprehensive research training program on Salmonella classification, subtyping, genome sequencing, genome and metagenome analysis with the goal to enable African scientists to perform molecular detection and characterization of project samples.