Novel Mechanisms and Approaches to Treat Neonatal Sepsis

 描述(申请人提供)：尽管新生儿重症监护方面取得了重大进展，包括直接的抗生素治疗，但新生儿败血症的死亡率仍然很高，全球有300多万人死亡。死亡风险最高的是早产、低出生体重(LBW)和极低出生体重(VLBW)新生儿。在该奖项的最初资助期间，我们进行了三个新颖的观察：1)新生儿主要依靠其先天免疫系统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未能识别 3)用TLR和NLR激动剂辅助治疗小鼠可以刺激PMN功能，提高保护性免疫，并通过MyD88和炎症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信号的辅助疗法，以降低LBW/VLBW婴儿早期和晚期脓毒症的发生率和严重程度。为实现这一目标，有三个具体目标：1)描述TRIF特异性模式识别受体(PRRS)激动剂预处理新生儿可提高新生儿败血症存活率的机制；2)确定免疫佐剂改善保护性免疫力和新生儿败血症结局的机制；3)确定低出生体重儿和极低出生体重儿是否在中性粒细胞趋化、ROS产生和细菌杀灭方面表达类似的缺陷，以及TLR4激动剂治疗这些人类细胞是否恢复了固有免疫功能。前两个具体目标将确定用TRIF特异性TLR4激动剂(加和不加明胶佐剂)预治疗新生小鼠改善大肠杆菌和多菌败血症结局的机制。最终的特定目标将验证在新生小鼠中看到的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LBW/VLBW婴儿的未成熟先天免疫系统，减少早期和晚期败血症，并提高高度脆弱的LBW/VLBW婴儿群体的存活率。最终，我们的目标是(在这个拟议的资助期结束时)将新的或FDA批准的佐剂和独特的TRIF激动剂应用于有发生脓毒症风险的LBW/VLBW婴儿的初步临床试验。

 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.