In vivo vaccine-driven evolution in Bordetella pertussis

 描述(申请人提供)：百日咳是一种重要的人类病原体，它是百日咳的病原体，每年导致数十万婴儿和儿童死亡。尽管采取了广泛的疫苗接种方案，但近年来百日咳杆菌感染在整个工业世界的流行率大幅上升，导致美国和其他国家的疫情。重新出现的原因尚不清楚，但已被提出涉及病原体不断适应日益接种疫苗和免疫的人类人口。尽管研究越来越多，但关于细菌病原体在感染过程中演变的研究却很少，这阻碍了开发新疫苗和治疗方法的努力。具体地说，没有对感染期间整个细菌基因组累积的遗传变化进行分析，以评估疫苗接种对百日咳杆菌基因组进化的影响。在这项建议中，我们识别了感染期间百日咳杆菌基因组中出现的序列变化，这使得可以直接测量突变和重组率，并获得前所未有的洞察这种重要的人类病原体的体内进化。我们比较了免疫幼稚和免疫接种的动物宿主中百日咳基因组的进化，这使我们能够阐明最近百日咳疾病的死灰复燃是否与疫苗驱动的这种病原体的进化有关。

 DESCRIPTION (provided by applicant): The important human pathogen Bordetella pertussis is the causative agent of whooping cough, which kills hundreds of thousands of babies and children every year. Despite an extensive vaccination regimen, the prevalence of B. pertussis infection has dramatically increased throughout the industrial world in recent years, leading to epidemics in the U.S. and other countries. The reason for the reemergence is unclear but has been proposed to involve ongoing adaptation of the pathogen to an increasingly vaccinated and immune human population. Despite increasing research, studies on the evolution of the bacterial pathogen during infection are missing, hampering efforts to develop new vaccines and treatments. Specifically, there are no analyses of genetic changes that accumulate across the entire bacterial genome during an infection to evaluate the impact of vaccination on the genomic evolution of B. pertussis. In this proposal, we identify sequence changes that arise in B. pertussis genomes during infection which allows direct measurement of the mutation and recombination rates and to gain unprecedented insight into the in vivo evolution of this important human pathogen. We compare pertussis genome evolution in immunologically naïve and vaccinated animal hosts, which enables us to elucidate whether the recent resurgence of pertussis disease is associated with vaccine driven evolution of this pathogen.