Cytokine signatures of Plasmodium vivax infection during pregnancy and delivery outcomes

Abstract

Plasmodium vivax malaria is a neglected disease, particularly during pregnancy. Severe vivax malaria is associated with inflammatory responses but in pregnancy immune alterations make it uncertain as to what cytokine signatures predominate, and how the type and quantity of blood immune mediators influence delivery outcomes. We measured the plasma concentrations of a set of thirty-one biomarkers, comprising cytokines, chemokines and growth factors, in 987 plasma samples from a cohort of 572 pregnant women from five malaria-endemic tropical countries and related these concentrations to delivery outcomes (birth weight and hemoglobin levels) and malaria infection. Samples were collected at recruitment (first antenatal visit) and at delivery (periphery, cord and placenta). At recruitment, we found that P. vivax-infected pregnant women had higher plasma concentrations of proinflammatory (IL-6, IL-1β, CCL4, CCL2, CXCL10) and T H 1-related cytokines (mainly IL-12) than uninfected women. This biomarker signature was essentially lost at delivery and was not associated with birth weight nor hemoglobin levels. Antiinflammatory cytokines (IL-10) were positively associated with infection and poor delivery outcomes. CCL11 was the only biomarker to show a negative association with P. vivax infection and its concentration at recruitment was positively associated with hemoglobin levels at delivery. Birth weight was negatively associated with peripheral IL-4 levels at delivery. Our multi-biomarker multicenter study is the first comprehensive one to characterize the immunological signature of P. vivax

Adverse pregnancy outcomes are associated with Plasmodium vivax malaria in a prospective cohort of women from the Brazilian Amazon

“…It is plausible that cytokines at delivery are already downregulated, which is in line with previous observations that showed inflammatory cytokines associated with episodes of P . vivax malaria during pregnancy that are lost at delivery [ 60 ]. Yet, a decrease in the plasma levels of IL-12 and C5a at delivery, particularly upon infections that occur during the first and third trimesters, was observed by us.…”

“…IL-12 has been previously associated with P . vivax infections during pregnancy [ 60 ], and C5a is considered a hypothetical key driver of PM pathogenesis, being associated with placental insufficiency and SGA babies, and correlated negatively and positively with ANG-1 and ANG-2, respectively [ 61 , 62 ]. Moreover, our study shows that both placental C5a and ANG-2 are diminished at delivery when women are infected for the first time during the first trimester.…”

Overview of Epidemiology of Malaria Associated with Pregnancy in Northwestern Colombia, 1985-2020

“…The frequency of GM with TBS can range between 1.0% and 23.0% 9,36,41 and, with PCR, it rises to 49%. 24,28,47 MP with TBS has been reported in a range of 2% to 12%, which with PCR rises to 57%.…”

“…A multicenter study with 572 pregnant women from 5 endemic countries for malaria (including Colombia), some with P. vivax infection and others without infection, indicates that in GM vivax the predominant immune response is Th1 and pro-inflammatory, when it is balanced with antiinflammatory cytokines can prevent negative outcomes during labor, while exacerbating the Th2 response may present deleterious effects during delivery. 36 Gnidehou's study in Colombia reported the presence of anti-VAR2CSA antibodies in pregnant women, men and children exposed to malaria, which inhibit the adhesion of infected erythrocytes to chondroitin sulfate A (CSA) in vitro. 37 However, a later study indicated that said IgG antibodies against VAR2CSA were not specific for plasmodial infection, highlighting that the specific antibodies are limited to the gestational period.…”

IL-4, IL-10, CCL2 and TGF-β as potential biomarkers for severity in Plasmodium vivax malaria

“…Likewise, higher concentrations of IL-10 were associated with complications in pregnant women with P . vivax malaria [ 21 ]. The identification of reliable biomarkers requires substantial evidence of their usefulness and efficiency under different epidemiological conditions before it can be generalized as a tool that supports the patient’s clinical management.…”