Biomarkers of Plasmodium falciparum Infection during Pregnancy in Women Living in Northeastern Tanzania

Abstract

In pregnant women, Plasmodium falciparum infections are an important cause of maternal morbidity as well as fetal and neonatal mortality. Erythrocytes infected by these malaria-causing parasites accumulate through adhesive interactions in placental intervillous spaces, thus evading detection in peripheral blood smears. Sequestered infected erythrocytes induce inflammation, offering the possibility of detecting inflammatory mediators in peripheral blood that could act as biomarkers of placental infection. In a longitudinal, prospective study in Tanzania, we quantified a range of different cytokines, chemokines and angiogenic factors in peripheral plasma samples, taken on multiple sequential occasions during pregnancy up to and including delivery, from P. falciparum-infected women and matched uninfected controls. The results show that during healthy, uninfected pregnancies the levels of most of the panel of molecules we measured were largely unchanged except at delivery. In women with P. falciparum, however, both comparative and longitudinal assessments consistently showed that the levels of IL-10 and IP-10 increased significantly whilst that of RANTES decreased significantly, regardless of gestational age at the time the infection was detected. ROC curve analysis indicated that a combination of increased IL-10 and IP-10 levels and decreased RANTES levels might be predictive of P. falciparum infections. In conclusion, our data suggest that host biomarkers in peripheral blood may represent useful diagnostic markers of P. falciparum infection during pregnancy, but placental histology results would need to be included to verify these findings.

Placental Cytokine and Chemokine Profiles Reflect Pregnancy Outcomes in Women Exposed to Plasmodium falciparum Infection

“…Low levels of placental IFN-␥ and IL-5 at delivery could thus represent a cytokine signature reflecting the pathological development/induction of SGA during pregnancy. The higher placental IL-10 and IP-10 concentrations associated with PAM that we observed here are consistent with our own earlier observations concerning cytokine/chemokine levels in the peripheral plasma of STOPPAM cohort subgroups (18,29) and confirm the findings of other studies (17,30). The present results thus further strengthen the idea that IL-10 and IP-10 could serve as useful diagnostic markers of P. falciparum infection during pregnancy.…”

“…In this context, recent studies have investigated a broader spectrum of circulating and/or placental proteins, including cytokines and chemokines, aiming to find potential biomarkers for inflammatory placental malaria (17,18) and/or possible links with poor PAM-associated pregnancy outcomes (19,20). For instance, increased concentrations of circulating endoglin and CXCL9 have been associated with fetal growth restriction and low-birth-weight deliveries, respectively (21)(22)(23).…”

Submicroscopic Infections with Plasmodium falciparum during Pregnancy and Their Association with Circulating Cytokine, Chemokine, and Cellular Profiles

“…Plasma levels of IL-1␤, IL-6, IL-8, IL-10, IL-12p70, and TNF-␣ cytokines were analyzed using a human inflammatory kit (cytometric bead assay [CBA]; BD Biosciences, San Diego, CA, USA), and levels of regulated on activation normal T cell expressed and secreted (RANTES), monokine induced by IFN-␥ (MIG), monocyte chemotactic protein 1 (MCP-1), and IFN-␥-inducible protein 10 (IP-10) were analyzed with a human chemokines kit (CBA; BD Biosciences). The procedure used adhered to the manufacturer's recommendations and has been described in detail elsewhere (17).…”

“…Plasma concentrations of alpha interferon (IFN-␣) and gamma interferon (IFN-␥) were determined using commercial enzymelinked immunosorbent assay (ELISA) kits (Mabtech, Stockholm, Sweden), as were those of soluble vascular endothelial growth factor receptor 1 (sVEGF-R1)/Flt1, soluble urokinase plasminogen activator receptor (suPAR), angiopoietin 1 (Ang-1), and Ang-2 (R&D, Minneapolis, MN). The methods used conformed to the manufacturer's recommendations and have been described in detail elsewhere (17).…”

“…P. falciparum-infected erythrocytes induce inflammation, characterized particularly by monocytic infiltration of the infected placenta (7)(8)(9)(10). One other well-described consequence of PAM is an altered cytokine/ chemokine balance in peripheral blood and placental blood (11)(12)(13)(14)(15)(16)(17).…”