Maternal nematode infection upregulates expression of Th2/Treg and diapedesis related genes in the neonatal brain

Nawal El Ahdab,Ejimedo Madogwe,Marilyn E Scott,Kristine G Koski,Manjurul Haque

doi:10.1038/s41598-021-01510-0

Abstract

Intestinal nematode infections common during pregnancy have recently been shown to have impacts that extend to their uninfected offspring including altered brain gene expression. If maternal immune signals reach the neonatal brain, they might alter neuroimmune development. We explored expression of genes associated with four distinct types of T cells (Th1, Th2, Th17, Treg) and with leukocyte transendothelial migration and endocytosis transport across the blood–brain barrier (BBB) in the postnatal brain of offspring of nematode-infected mice, through secondary analysis of a whole brain gene expression database. Th1/Th17 expression was lowered by maternal infection as evidenced by down-regulated expression of IL1β, Th1 receptors and related proteins, and of IL22 and several Th17 genes associated with immunopathology. In contrast, Th2/Treg related pathways were upregulated as shown by higher expression of IL4 and TGF-β family genes. Maternal infection also upregulated expression of pathways and integrin genes involved in transport of leukocytes in between endothelial cells but downregulated endosome vesicle formation related genes that are necessary for endocytosis of immunoglobulins across the BBB. Taken together, pup brain gene expression indicates that maternal nematode infection enhanced movement of leukocytes across the neonatal BBB and promoted a Th2/Treg environment that presumably minimizes the proinflammatory Th1 response in the pup brain.

Highlights

Chronic gastrointestinal (GI) nematode infections are extremely important in low-income countries where human hookworm infections exacerbate anemia during pregnancy[1] and in ruminants where GI nematodes lower birth weight[2]
Given that H. bakeri induces a Th2/Treg response in the infected h ost[18], that maternal immune elements are transferred to the neonate, and that Th2 responses favour long-term potentiation (LTP), we hypothesized that neonatal brain gene expression in response to maternal infection might reflect a heightened Th2/Treg profile and dampened Th1/Th17 associated neuro-inflammation, especially if movement of either leukocytes or immunoglobulins across the blood–brain barrier (BBB) was compromised
Unlike many maternal stressors that are associated with neonatal neuro-inflammation[30,31,32,33], we showed that maternal nematode infection downregulated expression of only a few cell surface markers and chemokine ligand genes indicating a very limited impact on innate immune genes

Summary

Introduction

Chronic gastrointestinal (GI) nematode infections are extremely important in low-income countries where human hookworm infections exacerbate anemia during pregnancy[1] and in ruminants where GI nematodes lower birth weight[2]. Given that H. bakeri induces a Th2/Treg response in the infected h ost[18], that maternal immune elements are transferred to the neonate, and that Th2 responses favour LTP, we hypothesized that neonatal brain gene expression in response to maternal infection might reflect a heightened Th2/Treg profile and dampened Th1/Th17 associated neuro-inflammation, especially if movement of either leukocytes or immunoglobulins across the BBB was compromised. The goal of this secondary analysis was to explore an existing brain gene expression database for evidence that maternal H. bakeri infection altered the profile of T helper cell responses in the P7 brain. This allowed us to identify differentially expressed sets of genes that would be expected to alter function

Methods

Results

Conclusion