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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=U01ES029234&format=word)
| Principal Investigator: Chougnet, Claire A | |
|---|---|
| Institute Receiving Award | Cincinnati Childrens Hosp Med Ctr |
| Location | Cincinnati, OH |
| Grant Number | U01ES029234 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 01 Sep 2017 to 31 Aug 2023 |
| DESCRIPTION (provided by applicant): | ABSTRACT The “Developmental Origin of Health and Disease” hypothesis posits that susceptibility to a number of non- communicable diseases can be influenced by in utero exposures (nutritional, environmental, inflammatory). While this hypothesis is increasingly accepted, particularly for diseases with an immune etiology (i.e. allergic, autoimmune), the mechanisms involved remain unresolved. A major knowledge gap that limits progress in this area is the remaining paucity of information regarding the “normal” immune processes that occur during critical pre- and perinatal periods, and how this development may be influenced by fetal exposures. One fetal exposure with a repeated and robust impact on long-term health is inflammation of the placenta – termed chorioamnionitis (chorio), which, in severe cases, leads to inflammation of fetal membranes and increased levels of inflammatory mediators in both the amniotic fluid and the neonates’ cord bloods. Our preliminary data show in human infants that exposure to severe chorio (1) is associated with respiratory morbidity during early infancy, and (2) leads to increased levels of the Th17-associated transcription factor RORC in the circulation in the first month of life. To get deeper insights into the underlying mechanisms, we have developed an experimental model of chorio in the Rhesus macaque, which presents with very high level of similarities with human chorio. Intra-amniotic (IA) injection of LPS into pregnant animals leads to massive neutrophilic infiltration and up-regulation of inflammatory cytokines in the chorio-decidua, and significant changes in the fetal immune system, including (1) severe lung inflammation;; (2) alteration of the regulatory T cell (Treg)/Th17 balance in the spleen, with the increased accrual of “inflammatory Tregs”;; and (3) increased proportion of activated type 3 innate lymphoid cells (ILC3) in the mucosal areas. LPS-induced fetal inflammation was largely driven by IL-1-dependent mechanisms. These data lead us to hypothesize that exposure to chorio induces alterations of the fetal systemic and mucosal immune system, notably through alterations of Tregs and ILCs, that predispose to post-natal diseases, including respiratory problems. We will (1) analyze in depth the accrual of fetal inflammatory Tregs in the context of chorio, using single cell RNAseq, methylation profiling and unique functional assays;; (2) analyze how fetal inflammation directs the ontogeny and functional development of ILC3 through detailed phenotyping of ILC and their progenitors for homing/adhesion molecules, analysis of the transcriptome of fetal NHP ILC by scRNAseq, and the use of unique ILC3 functional assays we have developed;; and 3) determine how fetal inflammation longitudinally impacts accumulation of inflammatory Tregs or ILC3 precursor development, and neonatal immune function, by monitoring control and chorio-exposed neonates from birth to 4 months of age, characterizing 1) the normal course of recruitment of inflammatory Tregs and ILC3 in various compartments, and 2) immune responses to common neonatal vaccines and environmental allergens. |
| Science Code(s)/Area of Science(s) |
Primary: 52 - Immunology/Immunotoxicology Secondary: - |
| Publications | See publications associated with this Grant. |
| Program Officer | Michael Humble |