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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.

摘要