Mechanisms of group B streptococcal interactions with extraplacental membranes

描述（由申请人提供）：妊娠子宫的细菌感染是早产、死产、孕产妇死亡和儿童残疾的主要原因。B族链球菌（GBS）是一个主要的罪魁祸首，但由于我们对感染的宿主-微生物相互作用的理解存在差距，因此预防和治疗策略的进展缓慢。我们的长期愿景是通过确定疾病发病机制的分子机制来减少围产期感染的负担。该项目的目标是新确定侵入性GBS感染的宿主和细菌决定因素。遗传学上不同的GBS菌株在新生儿和孕妇中引起疾病的能力存在相当大的差异，范围从无症状定植到严重感染。这些差异的基础尚不清楚。GBS和母体妊娠组织之间相互作用的早期阶段可能决定感染的结果。新的数据表明，宿主和细菌对初始接触的反应根据菌株的不同而有很大差异，但这在母胎感染方面几乎没有受到关注。基于我们小组和其他人的初步数据，我们假设（1）GBS独特的多位点序列类型（ST）中不同的毒力基因表达谱是由与人类妊娠组织接触触发的，以及（2）宿主对GBS的免疫反应是由感染性ST的毒力决定的。我们建议通过三个利用专家合作的特定目标来验证这些新的假设在微生物发病机理、生殖生物学、传染病和先天免疫方面。目标是：（1）鉴定在人胎盘巨噬细胞和完整的胎盘外妊娠膜的感染期间不同GBS ST的整体转录组重构的差异;（2）定义对不同GBS序列类型的宿主免疫应答，所述不同GBS序列类型介导人胎盘外妊娠膜中的侵袭性与定殖GBS表型;和（3）确定胎盘巨噬细胞行为受GBS ST变异影响的程度。这些研究将揭示围产期GBS感染的发病机制，揭示可用于改善全球母亲和儿童健康的新靶点。

DESCRIPTION (provided by applicant): Bacterial infections of the pregnant uterus are major causes of preterm birth, stillbirth, maternal death, and childhood disability. Group B Streptococcus (GBS) is a major culprit, but advancing preventive and therapeutic strategies has been slowed by gaps in our understanding of the host-microbial interactions responsible for infection. Our long term vision is to reduce the burden of perinatal infections by defining molecular mechanisms of disease pathogenesis. The goal of this project is to newly identify host and bacterial determinants of invasive GBS infection. There is considerable variation in the ability of phylogenetically distinct GBS strains to cause disease in neonates and pregnant women, ranging from asymptomatic colonization to severe infection. The basis of these differences is unclear. Early stages in the interaction between GBS and maternal gestational tissues potentially determine the outcome of infection. New data suggest that both host and bacterial responses to initial contact vary significantly depending on the strain, yet this has received almost no attention in regards to maternal-fetal infection. Based on preliminary data from our groups and others, we hypothesize that (1) distinct virulence gene expression profiles in unique multilocus sequence types (STs) of GBS are triggered by contact with human gestational tissues, and (2) host immune responses to GBS are shaped by the virulence of the infecting ST. We propose to test these novel hypotheses through three Specific Aims that take advantage of collaborations among experts in microbial pathogenesis, reproductive biology, infectious diseases, and innate immunity. The Aims are: (1) identify differences in global transcriptome remodeling of diverse GBS STs during infection of human placental macrophages and intact extraplacental gestational membranes; (2) define host immune responses to diverse GBS sequence types that mediate invasive vs. colonizing GBS phenotypes in human extraplacental gestational membranes; and (3) determine the extent to which placental macrophage behavior is influenced by GBS ST variation. These studies will shed new light on the pathogenesis of perinatal GBS infections, revealing novel targets that could be used to improve the health of mothers and children worldwide.