Glycan-Lectin Receptor Regulation of Macrophage Maturation and Lung InnateDefenses in the Fetus and Newborn Infant

胎儿和新生儿巨噬细胞成熟和肺先天防御的聚糖-凝集素受体调节

• 批准号: 10360375
• 负责人: Victor Nizet
• 金额: $ 34.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-17 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360375
• 关键词: Adult; Alveolar Macrophages; Amniotic Fluid; Area; Aspirate substance; Autoantigens; Bacteria; Binding; Birth; Carbon; Cell Ontogeny; Cells; Characteristics; Childhood; Collaborations; Communicable Diseases; Competence; Data; Defect; Detection; Development; Disease; Elements; Environment; Epithelial; Equation; Exposure to; FDA approved; Fetal Lung; Fetus; Genetic; Genetic Models; Glycobiology; Glycoproteins; Granulocyte-Macrophage Colony-Stimulating Factor; Hemolysin; Human; ITIM; Immune; Immune Evasion; Immune Tolerance; Immune response; Immune signaling; Immune system; Immunity; Immunocompetence; Immunoglobulins; Immunosuppression; In Vitro; Infant; Infection; Infectious Agent; Inflammation; Inflammatory; Inhalation; Injury; Knockout Mice; Laboratories; Lectin Receptors; Leukocytes; Light; Lung; Lung Inflammation; Macrophage Activation; Mammalian Cell; Measures; Microbe; Molecular; Molecular Mimicry; Mothers; Mouse Protein; Mus; Natural Immunity; Neonatal; Neutrophil Activation; Neutrophil Infiltration; Newborn Infant; Organ; Pathogenesis; Pattern; Perinatal; Phagocytes; Pharmaceutical Preparations; Pharmacology; Physicians; Pneumonia; Polysaccharides; Predisposition; Pregnancy; Premature Infant; Prevention; Principal Investigator; Proteins; Pulmonary Inflammation; Race; Regulation; Regulatory Pathway; Research Personnel; Risk; Role; Scientist; Sepsis; Sialic Acids; Side; Signal Pathway; Signal Transduction; Specialist; Streptococcal Infections; Streptococcus Group B; Streptococcus pneumoniae; Surface; Testing; Time; Urine; Virulence; alveolar epithelium; arm; capsule; chronic infection; early onset; fetal; host-microbe interactions; immune activation; immune function; immunoregulation; improved; in utero; in vivo; innovation; insight; leukocyte activation; lung development; lung injury; lung maturation; macrophage; mature animal; mimicry; mortality; mutant; neonatal immune system; neonatal immunity; neonatal mice; neonatal pneumonia; neonatal sepsis; neonate; novel; pathogen; pathogenic microbe; patient population; perinatal period; pneumonia model; pneumonia treatment; prevent; receptor; response; screening; sialic acid binding Ig-like lectin; sialic acid receptor; sialoadhesin; sugar; targeted treatment; therapeutic evaluation; tool; translational approach; treatment group; uptake

Summary The fetal and neonatal immune systems maintain a state of tolerance during pregnancy. However the moment that infants are born, their immature immune system must defend against the sudden onslaught of microbial pathogens present in the environment. Unfortunately for many, the transition from tolerance to protection is slow, providing windows of opportunity for specific infectious organisms. This susceptibility is best illustrated by group B Streptococcus (GBS), which is the most common pathogen in neonates but rarely leads to disease in healthy adults. Neonates are first exposed to GBS around delivery, as GBS frequently colonizes the birth canal. Despite efforts around screening and maternal treatment, GBS continues to be the major cause of neonatal pneumonia and early onset sepsis. To discover the mechanisms of GBS infection and immunity in the immature lung, we developed a novel mouse GBS pneumonia model. Adult mice clear GBS within 24 h, quickly resolve the initial lung inflammation, and universally survive GBS infection. However, neonatal mice fail to efficiently kill GBS, develop persistent lung inflammation and injury, and can die from GBS infection. Macrophages, the first line of defense in adult lungs, are immature in neonates making them vulnerable to inhaled and aspirated bacteria including GBS. Our preliminary studies show that immature neonatal lung macrophages fail to mount a normal immune response against GBS or kill phagocytosed bacteria. GBS avoids detection in the neonatal lung by expressing a capsule coated with sialic acid, mimicking “self” antigens in the host. Neonatal lung macrophages express very low levels of sialoadhesin, which facilitates recognition of sialic acid in the GBS capsule and bacterial killing in adults. However neonatal lung macrophages do express Siglec-E, which suppresses inflammatory signaling upon sialic acid binding. This appears to represent a fetal tolerance mechanism, as the amniotic fluid is rich in the sialic acid modified Tamm-Horsfall Protein (THP). We hypothesize that THP and sialic acid maintain immune tolerance in the fetal lung through interactions with macrophage inhibitory Siglecs. For maturation of lung macrophages, THP-sialic acid-Siglec interactions must give way to the ability to detect and kill pathogens. GBS uses its sialic acid rich capsule to mimic the effects of THP, suppressing immune activation in newborn lungs. This proposal will use novel, state of the art approaches to further investigate the molecular mechanisms regulating both immune tolerance in fetal lungs and neonatal immunity against GBS. By bringing together outstanding expertise in the Principal Investigators’ laboratories, state of the art approaches investigating development of lung immunity and mechanisms of host-microbe interactions will shed important new light on the ongoing battle between immunity and microbes around the time of birth. Collectively the aims in this proposal will identify unique molecular mechanisms that make newborns particularly susceptible to GBS pneumonia and explore new translational approaches for protecting newborns. The results will lead to development of new strategies for preventing and treating disease.

概括 胎儿和新生儿的免疫系统在怀孕期间保持耐受状态。然而此刻 婴儿出生后，他们不成熟的免疫系统必须抵御微生物的突然袭击 环境中存在的病原体。不幸的是，对许多人来说，从宽容到保护的转变是缓慢的， 为特定传染性生物体提供机会之窗。这种敏感性最好通过群体来说明 B 型链球菌 (GBS)，是新生儿最常见的病原体，但很少导致健康人患病 成年人。新生儿在分娩时首先接触 GBS，因为 GBS 经常在产道中定植。尽管 围绕筛查和孕产妇治疗所做的努力，GBS仍然是新生儿肺炎的主要原因 和早发性败血症。为了发现未成熟肺中 GBS 感染和免疫的机制，我们 开发了一种新型小鼠 GBS 肺炎模型。成年小鼠24小时内清除GBS，快速解决最初的问题 肺部炎症，并且普遍能在 GBS 感染中存活下来。然而，新生小鼠无法有效杀死GBS， 出现持续性肺部炎症和损伤，并可能死于 GBS 感染。巨噬细胞，第一线 成人肺部的防御能力在新生儿中尚不成熟，因此容易受到吸入和吸入细菌的影响 包括GBS。我们的初步研究表明，未成熟的新生儿肺巨噬细胞无法形成正常的 针对 GBS 的免疫反应或杀死吞噬细菌。 GBS 通过以下方式避免在新生儿肺部检测到： 表达一种涂有唾液酸的胶囊，模仿宿主体内的“自身”抗原。新生儿肺巨噬细胞 表达非常低水平的唾液酸粘附素，这有助于识别 GBS 胶囊中的唾液酸 杀死成人的细菌。然而，新生儿肺巨噬细胞确实表达 Siglec-E，它会抑制 唾液酸结合后的炎症信号传导。这似乎代表了胎儿的耐受机制，因为 羊水中富含唾液酸修饰的 Tamm-Horsfall 蛋白 (THP)。我们假设 THP 和唾液酸 酸通过与巨噬细胞抑制性 Siglecs 相互作用维持胎儿肺部的免疫耐受性。为了 随着肺巨噬细胞的成熟，THP-唾液酸-Siglec 相互作用必须让位于检测和处理的能力。 杀死病原体。 GBS 使用富含唾液酸的胶囊来模拟 THP 的作用，抑制免疫激活 在新生儿的肺部。该提案将使用新颖、最先进的方法来进一步研究分子 调节胎儿肺部免疫耐受和新生儿对 GBS 免疫力的机制。通过带来 汇集了首席研究员实验室的杰出专业知识和最先进的方法 研究肺免疫的发展和宿主-微生物相互作用的机制将具有重要意义 对出生前后免疫与微生物之间持续斗争的新认识。总体目标 该提案将确定使新生儿特别容易感染 GBS 的独特分子机制 肺炎并探索保护新生儿的新转化方法。结果将导致 制定预防和治疗疾病的新策略。