Prevention of Neonatal Sepsis by Therapeutic Targeting of MDSCs

通过 MDSC 治疗靶向预防新生儿败血症

基本信息

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
项目类别：
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

项目摘要

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.

抽象的新生儿败血症每年导致全球超过 300 万人死亡，是死亡率最高的疾病发生在早产儿（≤ 37 周）中，这种脆弱性的增加是由于骨髓生成的改变和内在因素造成的。对病原体反应低下，伴随着维持免疫抑制机制的激活母体-胎儿耐受性出生后，新生儿免疫系统经历了从半免疫状态的转变。同种异体无菌条件与富含微生物的产后环境，部分由新生儿调节骨髓源性抑制细胞 (MDSC) 和先天免疫效应细胞反应在新生儿中的作用。 MDSC 备受争议，因为它们不仅可以控制早期微生物定植期间的炎症，还可以还通过诱导先天免疫效应子导致新生儿对感染的易感性。早产儿的细胞功能也出现异常。我们的首要假设是，对和的敏感性增加。早产儿脓毒症死亡率的部分原因可以解释为存在未成熟的、免疫抑制性骨髓细胞群（MDSC）和先天免疫的异常终末分化此外，我们建议预防性施用效应细胞（例如单核细胞、PMN）。生命早期的免疫调节剂可以通过改变 MDSC 数量来刺激宿主的保护性免疫功能，导致先天免疫效应细胞数量和功能（尤其是 PMN）的增强。该策略将减少这个脆弱的“早产儿”人群中微生物感染的发生率和严重程度。两个具体目标如下：（1）检验新生儿早产和生命早期败血症的假设诱导 MDSC 扩增，这与先天免疫细胞功能呈负相关。 (CD33+CD11b+HLADRlow/-) 将在 120 名早产儿和 40 名足月婴儿出生时和产后进行量化我们将确定人类 MDSC 和 PMN 表型。受胎龄和脓毒症以及 MDSC 扩张和 PMN 功能障碍是否存在影响 (2) 无法进行的补充研究在人类中，我们发现骨髓生成和骨髓功能（尤其是 MDSC）会受到影响通过施用免疫调节剂分化成功能性终末先天免疫效应细胞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和中的作用。总而言之，通过诱导非特异性效应（NSE）或“训练有素的免疫力”而导致败血症。拟议的研究将重点关注调节新生儿免疫反应的关键机制。使用-omics技术，我们期望提供：1）骨髓细胞群经历的变化的全局视图在住院期间和败血症期间的早产新生儿中，2）深入了解如何通过使用佐剂（BCG 和 TLR4 激动剂）进行免疫调节会影响骨髓细胞并预防这个高度脆弱的人群患有败血症。