幼儿园儿童肺炎链球菌分子特征及传播机制研究

肺炎链球菌已成为全球儿童细菌性感染和儿童死亡的首位病因，导致全球疾病负担呈明显增长趋势。课题组前期研究提示，肺炎链球菌在学龄前儿童中广泛传播，但传播机制不明；多糖疫苗引入导致非疫苗覆盖菌株流行呈加速上升趋势，给疾病预防带来极大挑战。值得关注的是，预防和控制儿童肺炎链球菌流行和传播的有效策略仍未明确，已成为当前医学研究中迫切需要解决的难题。本项目拟开展幼儿园儿童及所处环境的大样本连续监测研究，利用深度测序技术检测高维基因组学分子特征，①建立实用的“数据降维→判别建模→模型验证和筛选→效应估计和模型预测”高维数据分析策略，运用随机森林法揭示菌株的特异性分子标志物，为追踪溯源提供遗传学证据；②借助遗传背景聚类分析和流行病学溯源分析来揭示传播机制，并构造传播动力学模型来验证传播机制，为有效切断疾病传播提供科学证据；③阐明分子特征间的高维关联性，筛选结合疫苗的最优组合，为研发新型结合疫苗提供新思路。

Streptococcus pneumoniae (S. pneumoniae) has become the leading cause of bacterial infections and death in children worldwide, which causes the global burden of disease is increasing year by year. Previous studies in our study group revealed that S. pneumoniae spread widely among pre-school children, but the transmission mechanism is still unclear. The prevalence of non-vaccine isolates has increased rapidly since the introduction of capsular polysaccharide vaccine, which brings great challenges to disease prevention. It is noteworthy that the effective strategies for preventing S. pneumoniae epidemic and transmission among children are still unclear, which has become a difficult problem to be solved urgently in current medical research. This project intends to conduct a large-sample consecutive surveillance of kindergarten children and their environments and detect high-dimensional genome molecular characteristics by deep sequencing technology. First, this project aims to establish practical strategies for high-dimensional data analysis ("high-dimensional reduction, discriminant modeling, model validation and screening, and effect estimation and model prediction") and reveal specific molecular markers by using Random-Forest method, providing genetic evidence for tracing the sources of infection. Second, both cluster analysis of genetic background and traceability analysis of epidemiological data are used to reveal potential transmission mechanisms, and dynamics models of disease transmission are constructed to verify transmission mechanisms, providing scientific evidence for effectively cutting off the spread of diseases. Finally, the study aims to clarify the high-dimensional relations between molecular characteristics and screen the optimal combination of conjugated vaccines, providing new ideas for the development of new conjugated vaccines.