Cytokine signatures of Plasmodium vivax infection during pregnancy and delivery outcomes

PLoS Negl Trop Dis. 2020 May 4;14(5):e0008155. doi: 10.1371/journal.pntd.0008155. eCollection 2020 May.

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 TH1-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 infection in pregnancy thus far. In conclusion, data show that while TH1 and pro-inflammatory responses are dominant during P. vivax infection in pregnancy, antiinflammatory cytokines may compensate excessive inflammation avoiding poor delivery outcomes, and skewness toward a TH2 response may trigger worse delivery outcomes. CCL11, a chemokine largely neglected in the field of malaria, emerges as an important marker of exposure or mediator in this condition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Cohort Studies
  • Cytokines / blood*
  • Female
  • Humans
  • Infant, Newborn
  • Interleukin-10 / blood
  • Interleukin-1beta / blood
  • Malaria, Vivax / blood*
  • Malaria, Vivax / immunology
  • Malaria, Vivax / parasitology
  • Malaria, Vivax / physiopathology
  • Male
  • Plasmodium vivax / physiology*
  • Pregnancy
  • Pregnancy Complications, Parasitic / blood*
  • Pregnancy Complications, Parasitic / immunology
  • Pregnancy Complications, Parasitic / parasitology
  • Pregnancy Complications, Parasitic / physiopathology
  • Pregnancy Outcome
  • Th2 Cells / immunology
  • Young Adult

Substances

  • Cytokines
  • IL1B protein, human
  • Interleukin-1beta
  • Interleukin-10

Grant support

This work was supported by the European Union Seventh Framework Programme (FP7/2007-2013, https://ec.europa.eu/research/fp7) under grant agreement 201588 (PI: CM), and co-funding from the Ministerio de Economía y Competitividad (National R&D Internationalization Programme, EUROSALUD 2008, Spain, http://www.mineco.gob.es/) under grant agreement EUS2009-03560 (PI: CM). The Latin American sites received co-funding from the Centers for Disease Control and Prevention (CDC) Foundation (www.cdcfoundation.org, PI: MD), which received a grant from the Malaria in Pregnancy Consortium (MiPc, www.mip-consortium.org) that is partially funded through a grant from the Bill & Melinda Gates Foundation (www.gatesfoundation.org) to the Liverpool School of Tropical Medicine (46099). The studies in PNG also received co-funding from the MiPc. CD was supported by a fellowship from the Ministerio de Economía y Competitividad (RYC-2008-02631) and was an affiliate of the EU FP7 Network of Excellence EviMalaR, and IM was supported by a National Health and Medical Research Council Senior Research Fellowship (GNT1043345, www.nhmrc.gov.au). ISGlobal is a member of the CERCA Program, Generalitat de Catalunya (http://cerca.cat/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.