Mechanisms of group B streptococcal interactions with extraplacental membranes

B 族链球菌与胎盘外膜相互作用的机制

• 批准号: 8507835
• 负责人: David M Aronoff
• 金额: $ 59.61万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507835
• 关键词: Attention; Bacterial Infections; Behavior; Cells; Cessation of life; Child; Childhood; Collaborations; Communicable Diseases; Data; Development; Disease; Female; Future; Gene Expression; Gene Expression Profile; Genome; Genotype; Global Change; Goals; Health; Human; Immune; Immune response; Immunology; Infection; Infection of amniotic sac and membranes; Inflammatory Response; Invaded; Investigation; Light; Maternal Mortality; Mediating; Membrane; Modeling; Molecular; Molecular Profiling; Mothers; Natural Immunity; Neonatal Mortality; Outcome; Pathogenesis; Patient currently pregnant; Perinatal; Perinatal Infection; Phenotype; Pregnancy; Pregnant Uterus; Pregnant Women; Premature Birth; Prevention strategy; Preventive; Publishing; Reporting; Reproductive Biology; Research Personnel; Science; Sepsis; Shapes; Staging; Streptococcal Infections; Streptococcus; Streptococcus Group B; System; Testing; Therapeutic; Tissues; Variant; Virulence; Vision; Women' s Health; base; disability; fetal infection; improved; macrophage; microbial; microbial host; microorganism interaction; neonatal morbidity; neonate; novel; placental membrane; prevent; reproductive; response; stillbirth; transcriptomics

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.

描述（由申请人提供）：怀孕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) 是罪魁祸首，但由于我们对导致感染的宿主-微生物相互作用的理解存在差距，预防和治疗策略的进展已经放缓。我们的长期愿景是通过明确疾病发病机制的分子机制来减轻围产期感染的负担。该项目的目标是新确定侵袭性 GBS 感染的宿主和细菌决定因素。系统发育上不同的 GBS 菌株引起新生儿和孕妇疾病的能力存在很大差异，从无症状定植到严重感染。这些差异的基础尚不清楚。 GBS 与母体妊娠组织相互作用的早期阶段可能决定感染的结果。新数据表明，宿主和细菌对初次接触的反应根据菌株的不同而有很大差异，但这在母婴感染方面几乎没有受到关注。根据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通过与人类妊娠组织接触而触发的，(2) 宿主对 GBS 的免疫反应是由感染 ST 的毒力决定。我们建议通过三个具体目标来检验这些新假设，这些目标利用微生物发病机制、生殖生物学、传染病和先天免疫方面的专家之间的合作。目标是：（1）确定不同 GBS ST 在感染人胎盘巨噬细胞和完整胎盘外妊娠膜期间的整体转录组重塑的差异； (2) 定义宿主对多种 GBS 序列类型的免疫反应，这些序列类型介导人胎盘外妊娠膜中的侵袭性和定植性 GBS 表型； (3) 确定胎盘巨噬细胞行为受 GBS ST 变异影响的程度。这些研究将为围产期 GBS 感染的发病机制提供新的线索，揭示可用于改善全世界母亲和儿童健康的新靶点。