Peripheral Blood Cell Signatures of Plasmodium falciparum Infection during Pregnancy

Samad Ibitokou,Stefania Varani,Sèm Ezinmègnon,Laurent Brutus,Marita Troye-Blomberg,Achille Massougbodji,John Lusingu,Nadine Fievet,Sophie Borgella,Christentze Schmiegelow,Mayke Oesterholt,Philippe Deloron,Carine Agbowaï,Adrian J F Luty

doi:10.1371/journal.pone.0049621

Abstract

Sequestration of Plasmodium falciparum-infected erythrocytes in placental intervillous spaces causes inflammation and pathology. Knowledge of the profiles of immune cells associated with the physiopathology of pregnancy-associated malaria (PAM) is scarce. We conducted a longitudinal, prospective study, both in Benin and Tanzania, including ∼1000 pregnant women in each site with systematic follow-up at scheduled antenatal visits until delivery. We used ex vivo flow cytometry to identify peripheral blood mononuclear cell (PBMC) profiles that are associated with PAM and anaemia, determining the phenotypic composition and activation status of PBMC in selected sub-groups with and without PAM both at inclusion and at delivery in a total of 302 women. Both at inclusion and at delivery PAM was associated with significantly increased frequencies both of B cells overall and of activated B cells. Infection-related profiles were otherwise quite distinct at the two different time-points. At inclusion, PAM was associated with anaemia, with an increased frequency of immature monocytes and with a decreased frequency of regulatory T cells (Treg). At delivery, infected women presented with significantly fewer plasmacytoid dendritic cells (DC), more myeloid DC expressing low levels of HLA-DR, and more effector T cells (Teff) compared to uninfected women. Independent associations with an increased risk of anaemia were found for altered antigen-presenting cell frequencies at inclusion, but for an increased frequency of Teff at delivery. Our findings emphasize the prominent role played by B cells during PAM whenever it arises during pregnancy, whilst also revealing signature changes in other circulating cell types that, we conclude, primarily reflect the relative duration of the infections. Thus, the acute, recently-acquired infections present at delivery were marked by changes in DC and Teff frequencies, contrasting with infections at inclusion, considered chronic in nature, that were characterized by an abundance of immature monocytes and a paucity of Treg in PBMC.

Highlights

Pregnancy is characterized by still generally poorly defined changes in the immunological equilibrium needed to protect the mother and the fetus from invading pathogens whilst at the same time tolerating the highly immunogenic paternal alloantigens in order to sustain fetal integrity
As expected because of the bias inherent to the criteria used for their selection at inclusion (P. falciparum infections are more common in primigravidae, who are by definition younger), the sub-group of 131 Beninese women was of significantly lower gravidity and was significantly younger than the whole cohort (Table 1), but at delivery no such differences were apparent (Table 1)
In the discussion that follows, we discuss the profiles of the different cell types we observed sequentially, focusing on those that our analysis revealed to vary significantly as a function of the presence of infection with P. falciparum, whilst comparing and contrasting the profiles observed at inclusion versus delivery

Summary

Introduction

Pregnancy is characterized by still generally poorly defined changes in the immunological equilibrium needed to protect the mother and the fetus from invading pathogens whilst at the same time tolerating the highly immunogenic paternal alloantigens in order to sustain fetal integrity. Through their capacity to modulate immunological responses, maternally-derived regulatory T cells (Treg) are thought to play a pivotal role in the tolerance of the fetus by the mother’s immune system, a role reflected by their reportedly dramatic increase in numbers during pregnancy [1,2,3,4]. Data from recently conducted longitudinal studies have revealed increasing evidence of significant changes in both the quantity and the quality of Treg, DC and other cell types during normal pregnancies in high-income countries [5,6,7,8]

Methods

Results

Conclusion