Novel Mechanisms and Approaches to Treat Neonatal Sepsis

治疗新生儿败血症的新机制和新方法

• 批准号: 9308983
• 负责人: Shawn David Larson
• 金额: $ 29.93万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308983
• 关键词: Adjuvant; Adjuvant Therapy; Adult; Africa South of the Sahara; Agonist; Aluminum Magnesium; Antibiotic Therapy; Antibodies; Award; Birth; Blood Cells; CASP1 gene; Cells; Cessation of life; Chemotaxis; Clinical; Clinical Trials; Complex; Defect; Development; Endotoxins; Escherichia coli; FDA approved; Failure; Funding; Goals; Heel; Human; Hydroxides; Immune; Immune response; Immunity; Immunologic Adjuvants; Incidence; Infant; Infection; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Laboratories; Left; Leukocyte Chemotaxis; Low Birth Weight Infant; Lymphoid; Maternal antibody; Microfluidics; Mus; Natural Immunity; Neonatal; Neonatal Intensive Care; Neonatal Mortality; Organ; Outcome; Pathway interactions; Pattern recognition receptor; Peripheral; Phenotype; Population; Predisposition; Pregnancy; Production; Property; Prophylactic treatment; Publishing; Receptor Signaling; Recruitment Activity; Reporting; Risk; Sepsis; Severities; Shock; Signal Transduction; TLR4 gene; Techniques; Testing; Toll-like receptors; Umbilical Cord Blood; Vaccination; Vaccine Adjuvant; Very Low Birth Weight Infant; adaptive immunity; aluminum sulfate; base; chemokine; high risk; improved; improved outcome; innate immune function; killings; mortality; mouse model; neonatal immune system; neonatal sepsis; neonate; neutrophil; novel; peripheral blood; prophylactic; protective effect; public health relevance; receptor

 DESCRIPTION (provided by applicant): Despite significant advances in neonatal intensive care, including directed antibiotic therapy, mortality from neonatal sepsis remains significant with more than three million deaths worldwide. The highest risk of mortality occurs in preterm, low birth weight (LBW) and very low birth weight (VLBW) neonates. During the initial funding period of this award, we made three novel observations: 1) the neonate relies predominantly on its innate immune system to recognize infections and to provide early protective immunity, 2) host innate immunity is also defective due in part to a failure of innate immune cells to recognize and respond to chemokines essential for recruitment and activation, and 3) adjuvant treatment of mice with TLR and NLR agonists can stimulate PMN function, improve protective immunity, and increase survival to sepsis through MyD88- and inflammasome-independent pathways. Based on these findings, our ultimate goal is to develop adjuvant- therapies based on TLR signaling that can reduce the incidence and severity of both early and late sepsis in LBW/VLBW infants. To accomplish this, there are three specific aims: 1) To delineate the mechanism by which pretreatment of neonates with TRIF-specific pattern recognition receptor (PRRs) agonists improves survival in neonatal sepsis; 2) To determine the mechanisms by which immune adjuvants improve protective immunity and outcomes to neonatal sepsis; and, 3) To determine whether LBW and VLBW infants express comparable defects in PMN chemotaxis, ROS production and bacterial killing seen in PMNs from murine models of neonatal sepsis, and whether treatment of these human cells with TLR4 agonists restores innate immune function. The first two specific aims will determine the mechanisms by which pretreatment of neonatal mice with TRIF-specific TLR4 agonists with and without alum adjuvants improves outcome from E.coli and polymicrobial sepsis. The final specific aim will validate whether the protective effect of TLR agonists and alum seen in neonatal mice are recapitulated in cord and peripheral blood from full-term and LBW/VLBW infants. The ultimate goal of these studies is the reduction of early and late sepsis with improved survival in the highly vulnerable LBW/VLBW infant population by augmenting their immature innate immune system. Ultimately, it is our goal (at the end of this proposed funding period) to move novel or FDA-approved adjuvants and unique TRIF agonists into preliminary clinical trials in LBW/VLBW infants at risk of developing sepsis.

 描述（由申请人提供）：尽管新生儿重症监护取得了重大进展，包括定向抗生素治疗，但新生儿败血症的死亡率仍然很高，全世界有300多万例死亡。早产儿、低出生体重儿和极低出生体重儿的死亡风险最高。在该奖项的最初资助期间，我们提出了三个新的观察结果：1）新生儿主要依靠其先天免疫系统来识别感染并提供早期保护性免疫，2）宿主先天免疫也有缺陷，部分原因是先天免疫细胞无法识别 并且对募集和活化所必需的趋化因子应答，以及3）用TLR和NLR激动剂辅助治疗小鼠可以刺激PMN功能，改善保护性免疫，并且通过MyD 88和炎性体非依赖性途径增加脓毒症的存活率。基于这些发现，我们的最终目标是开发基于TLR信号传导的辅助疗法，其可以降低LBW/VLBW婴儿中早期和晚期脓毒症的发生率和严重程度。为了实现这一点，有三个具体的目标：1）描述用TRIF特异性模式识别受体（PRRs）激动剂预处理新生儿提高新生儿败血症存活率的机制; 2）确定免疫佐剂提高新生儿败血症保护性免疫和结局的机制;和，3）为了确定LBW和VLBW婴儿是否在来自新生儿败血症的鼠模型的PMN中观察到的PMN趋化性、ROS产生和细菌杀伤方面表达可比较的缺陷，以及用TLR 4激动剂处理这些人类细胞是否恢复先天免疫功能。前两个具体目标将确定用TRIF特异性TLR 4激动剂预处理新生小鼠（有或无明矾佐剂）改善大肠杆菌和多微生物败血症结果的机制。最终的具体目标将验证在新生小鼠中观察到的TLR激动剂和明矾的保护作用是否在足月和LBW/VLBW婴儿的脐带血和外周血中重现。这些研究的最终目标是通过增强不成熟的先天免疫系统，减少早期和晚期脓毒症，提高高度脆弱的LBW/VLBW婴儿群体的生存率。最终，我们的目标是（在本拟议资助期结束时）将新型或FDA批准的佐剂和独特的TRIF激动剂用于有败血症风险的LBW/VLBW婴儿的初步临床试验。