Prevention of Neonatal Sepsis by Therapeutic Targeting of MDSCs

通过 MDSC 治疗靶向预防新生儿败血症

• 批准号: 10443320
• 负责人: Shawn David Larson
• 金额: $ 37.36万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443320
• 关键词: 2019-nCoV; Adjuvant; Adult; Age; Agonist; Allogenic; Anti-Bacterial Agents; Attenuated Vaccines; Birth; Cause of Death; Cell Count; Cell Maturation; Cell physiology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cessation of life; Cytometry; Effector Cell; Environment; Exhibits; Flow Cytometry; Functional disorder; Genomics; Gestational Age; Hospitalization; Human; ITGAM gene; Immune; Immune response; Immunity; Immunologic Adjuvants; Immunomodulators; Immunosuppression; Incidence; Infant; Infection; Inflammation; Intra-abdominal; Knowledge; Life; Measles; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Myelopoiesis; Natural Immunity; Neonatal; Newborn Infant; Outcome; Phenotype; Population; Predisposition; Premature Birth; Premature Infant; Prevention; Prophylactic treatment; Proteins; Risk; Role; SARS-CoV-2 infection; Sepsis; Severities; Signal Pathway; Sterility; Systemic infection; TLR4 gene; Technology; Term Birth; Testing; Tissues; Training; Transgenic Organisms; Viral; Vulnerable Populations; Work; base; clinically relevant; deviant; fetal; high risk; immune function; immunomodulatory strategy; immunoregulation; improved; in vivo; infection risk; innate immune function; insight; microbial; microbial colonization; monocyte; mortality; mortality risk; multiple omics; neonatal immune system; neonatal mice; neonatal sepsis; neonate; neutrophil; novel; organ injury; pathogen; pathogen exposure; polymicrobial sepsis; postnatal; premature; prenatal exposure; preterm newborn; prevent; prophylactic; protective effect; response; septic; single-cell RNA sequencing; subcutaneous; therapeutic target

ABSTRACT Neonatal sepsis results in more than 3 million deaths per annum worldwide and the highest risk of mortality occurs in preterm infants (≤37 weeks). This increased vulnerability is due to altered myelopoiesis and an intrinsic hypo-responsiveness to pathogens, concomitant with activation of immunosuppressive mechanisms that sustain maternal-fetal tolerance. Following birth, the neonatal immune system undergoes transition from a semi- allogeneic sterile condition to a microbial-rich postnatal environment, which is modulated in part by neonatal myeloid-derived suppressor cell (MDSC) and innate immune effector cell responses. In newborns, the role of MDSCs is highly controversial, as they may not only control inflammation during early microbial colonization, but also contribute to neonatal susceptibility to infection by inducing immunosuppression. Innate immune effector cell function is also aberrant in prematurity. Our overarching hypothesis is that the increased susceptibility to and mortality from sepsis in preterm neonates can be explained in part by the presence of immature, immunosuppressive myeloid cell populations (MDSCs) and deviant terminal differentiation of innate immune effector cells (e.g. monocytes, PMNs). Furthermore, we propose that the prophylactic administration of immunomodulatory agents early in life can stimulate host protective immunity by altering MDSC numbers and function, leading to augmentation of innate immune effector cell numbers and function (especially PMNs). This strategy will reduce the incidence and severity of microbial infections in this fragile ‘born-too-soon’ population. The two specific aims are as follows: (1) to test the hypothesis that neonatal prematurity and sepsis in early life induce MDSC expansion, which is inversely correlated with innate immune cell function. Circulating MDSCs (CD33+CD11b+HLADRlow/-) will be quantified in 120 preterm and 40 full-term infants at birth and during hospitalization and in those who develop sepsis. We will determine how human MDSC and PMN phenotypes are influenced by gestational age and sepsis, as well as whether expansion of MDSCs and PMN dysfunction at birth is beneficial or increases susceptibility to infections. (2) In complimentary studies that cannot be performed in humans, we hypothesize that myelopoiesis and myeloid function (especially MDSCs) can be influenced to differentiate into functional terminal innate immune effector cells by the administration of immunomodulatory agents. Using a model of neonatal sepsis, we will test the role of MDSCs in immune cell effector functions and outcomes to sepsis through the induction of non-specific effects (NSEs) or ‘trained immunity’. In summary, the proposed studies will focus on mechanisms critical to regulate neonatal immune responses in neonates. With the use of -omics technology, we expect to provide: 1) a global view of changes that myeloid populations undergo in preterm neonates during hospitalization and sepsis, and 2) insights into underlying mechanisms of how immunomodulation through the use of adjuvants (BCG and TLR4 agonists) influences myeloid cells and prevents sepsis in this highly vulnerable population.

摘要 新生儿败血症每年导致全球超过300万人死亡，是死亡风险最高的疾病。 发生于早产儿（≤37周）。这种增加的脆弱性是由于改变骨髓和内在的 对病原体的低反应性，伴随着免疫抑制机制的激活， 母胎耐受性出生后，新生儿免疫系统经历了从半免疫系统到免疫系统的转变。 同种异体不育条件下的微生物丰富的出生后环境，这是部分调制新生儿 骨髓源性抑制细胞（MDSC）和先天性免疫效应细胞应答。在新生儿中， MDSC是非常有争议的，因为它们不仅可以在早期微生物定植期间控制炎症， 还通过诱导免疫抑制而导致新生儿对感染的易感性。先天性免疫效应 细胞功能在早产儿中也是异常的。我们的总体假设是， 早产新生儿败血症的死亡率可以部分解释为存在未成熟的， 免疫抑制性髓样细胞群（MDSC）和先天免疫的异常终末分化 效应细胞（例如单核细胞、PMN）。此外，我们建议预防性给予 生命早期的免疫调节剂可以通过改变MDSC数量来刺激宿主保护性免疫， 功能，导致先天免疫效应细胞数量和功能（特别是PMN）的增加。这 该战略将减少这一脆弱的“过早死亡”人群中微生物感染的发生率和严重程度。 本研究的两个具体目的如下：（1）检验新生儿早产与早期败血症的关系 诱导MDSC扩增，其与先天免疫细胞功能负相关。循环MDSC (CD33将在120名早产儿和40名足月儿出生时和出生期间定量检测（+CD 11b + HLADR低/-） 住院和发生败血症的患者。我们将确定人类MDSC和PMN表型 受胎龄和脓毒症的影响，以及MDSC的扩张和PMN功能障碍是否受胎龄的影响。 出生是有益的或增加感染的易感性。(2)在无法进行的免费研究中 在人类中，我们假设骨髓生成和骨髓功能（特别是MDSC）可以受到影响， 通过施用免疫调节剂， 剂.使用新生儿败血症模型，我们将测试MDSC在免疫细胞效应功能中的作用， 通过诱导非特异性效应（NSE）或“训练免疫”导致脓毒症。总而言之， 拟议的研究将侧重于调节新生儿免疫应答的关键机制。与 利用组学技术，我们期望提供：1）髓系细胞群体经历的变化的全局视图 在早产儿住院期间和败血症，和2）洞察的潜在机制，如何 通过使用佐剂（BCG和TLR 4激动剂）的免疫调节影响骨髓细胞并防止 感染败血症