MEchanisms of LOng-lasting neonatal ImmunomoDulation following Placental Malaria (Myeloid-PM)

Newborns born to mothers with Plasmodium falciparum (Pf) placental malaria (PM) have a greater susceptibility to all infections in infancy. Recent studies showed that immune cells of those newborns exhibited a dysregulated innate immune response at birth and at 18 months of age. Of note, in those studies, neonatal immune cell responses varied from attenuated to enhanced depending on the timing of in utero Pf-infection. The underlying mechanisms of PM-induced immunomodulation of neonates and the effect of the timing/duration of PM on this modulation remain unknown. Trained innate immunity is defined by epigenetic reprogramming of innate cell precursors that leads to an attenuated or enhanced innate response lasting for months or years in their progeny. The capability of innate cells to respond depends on the nature, the magnitude and the duration of exposure to components responsible for the first stimulation of the precursor. In Myeloid-PM, the hypothesis is that PM induces such modifications in neonatal monocyte precursors, which leads to long-lasting susceptibility to all infections in infancy. Pf-infected erythrocyte sequestration in intervillous causing PM modifies the local environment into a pro-inflammatory state. Molecules from the Pf-infected placental microenvironment are very important to contextualize our findings and identify probable effectors at play from the hosts and the parasite in the modulation of neonatal immunity. State-of-the-art technologies, already implemented in the lab during a previous pilot study, will depict precisely the Pf-infected placental environment and its contribution to neonatal immunomodulation.Benin is an endemic area for malaria. In the project Myeloid-PM, 210 pregnant women and their newborns will be enrolled in a one-year longitudinal study. Timing/duration of PM will be considered in the selection of women and four clinical groups will be constituted based on presence/absence of Pf-parasites and of hemozoin-loaded maternal immune cells (marker for persistent infection) in the placenta: (i) not infected, (ii) recent and active PM, (iii) chronic and active PM and (iv) past PM. Using epigenetic, transcriptomic and functional approaches on mononuclear cells collected at birth (from cord blood) and at 12 months of age from naturally exposed-individuals, we propose to clarify the mechanisms of neonatal and infant innate cell modulations following in-utero priming during PM. Single-cell ATAQseq/RNAseq will be performed on freshly collected cells. The same approach will be implemented on CD34+ cells to determine whether epigenetic modifications on myeloid precursors may explain the long-lasting susceptibility to infections. In parallel, systemic and integrative approach will be deployed, at organ-, cell-, protein- and metabolite-levels to shed light on the modifications in the placental environment. Specifically, 12 placentae (3 per clinical groups) will be selected for spatial transcriptomic and scATAcseq/RNAseq on dissociated placental cells. Plasma from maternal blood and cord blood will be characterized using Somalogic technology (~7000 human proteins), mass spectrometry and metabolomics in order to identify soluble factors that can induce directly or indirectly epigenetic modification in neonatal immune cells. Finally, candidate molecules will be tested in vitro on naturally exposed cells to reverse the modulation through functional experiments. Myeloid-PM will likely uncover new aspects of trained immunity and placental malaria. Because epigenetic modifications are plastic and reversible, this project will provide the proof-of-concept, on naturally exposed individual cells, that PM-induced neonatal immunomodulation can be reverted and will offer new directions for future therapies targeting metabolism and epigenetic reprogramming.

Project details

Vaccines (Immune Correlates)
Vulnerable Populations

Dec 2023 — Dec 2027

$494,340

France