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：
10597701
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/10597701
关键词：
Adjuvant Adult Agonist 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 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 clinically relevant deviant fetal high risk human old age (65+)immune function immune modulating agents 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导致全球每年300万人死亡，死亡率最高发生在早产儿（≤37周）。这种增加的脆弱性是由于脊髓虫的改变和内在的对病原体的低反应性，与维持免疫抑制机制的激活相关母亲耐受性。出生后，新生儿免疫系统经历了从半适合富含微生物的后产后环境的同种异体无菌状况，该环境部分由新生儿调节髓样衍生的抑制细胞（MDSC）和先天免疫效应细胞反应。在新生儿中， MDSC引起了极大争议，因为它们不仅可以控制早期微生物定植期间的注射，而且还可以控制注射。还通过诱导的免疫抑制导致新生儿对感染的敏感性。先天免疫效应子细胞功能的早产性也异常。我们的总体假设是，对和早产新生儿中败血症的死亡率可以部分通过未成熟的存在来解释免疫抑制髓样细胞群（MDSC）和先天性免疫的异常终末分化效应细胞（例如单核细胞，PMN）。此外，我们提出了预防性给药生命早期免疫调节剂可以通过改变MDSC数量和功能，导致先天免疫效应细胞数量和功能（尤其是PMN）的增强。这策略将减少在这个脆弱的“天生”人群中微生物感染的发病率和严重程度。这两个具体目的如下：（1）测试新生儿早产和早期败血症的假设诱导MDSC扩展，这与先天免疫细胞功能成反比。循环的MDSC （CD33+CD11B+HLADRLOL/ - ）将在出生时和40个早产和40个完整的婴儿中进行量化住院和发生败血症的人。我们将确定人类MDSC和PMN表型如何受妊娠年龄和败血症的影响，以及MDSC和PMN功能障碍的扩展是否在出生是有益的或增加了感染的敏感性。（2）在无法进行的免费研究中在人类中，我们假设骨髓性和髓样功能（尤其是MDSC）可能会影响到通过给予免疫调节，分化为功能性终末免疫调节剂细胞代理商。使用新生儿败血症的模型，我们将测试MDSC在免疫球效应子功能和通过诱导非特异性效应（NSE）或“受过训练的免疫力”来败血症的结果。总而言之，拟议的研究将集中于调节新生儿新生儿免疫反应至关重要的机制。和我们希望使用-omics技术的使用：1）髓样人群发生的变化的全球视图在住院期间和败血症期间的早产新生儿中，以及2）洞察有关如何的基本机制通过使用调节器（BCG和TLR4激动剂）的免疫调节会影响髓样细胞并防止在这个高度脆弱的人群中败血症。