Cytokine Signatures of Tertian Malaria Infection Profiled During Pregnancy

Malaria caused by Plasmodium vivax is a neglected tropical disease, especially during pregnancy, of worldwide distribution. P. vivax is a protozoal parasite and a human pathogen. This parasite is the most frequent and widely distributed cause of recurring malaria.

Severe vivax malaria or tertian 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.

Medical scientists at the Hospital Clínic de Barcelona (Barcelona, Spain) and their international colleagues 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.

The biomarkers were analyzed in thawed plasmas with a multiplex suspension detection system Cytokine Magnetic 30-Plex Panel (Invitrogen, Madrid, Spain) which allows the detection of different biomarker. In addition, the cytokine TGF-β1 was analyzed in all plasmas except those from India, with a DuoSet ELISA kit (R&D Systems, Minneapolis, MN, USA). P. vivax and P. falciparum (studied as a possible confounder in co-infected women) parasitaemia were assessed at every visit in Giemsa-stained blood slides that were read onsite. Submicroscopic malaria infections were also determined at enrolment and delivery by real time-PCR in a group of participants, which included the immunological subcohort. Malaria symptoms and hemoglobin (Hb, g/dL) levels were also recorded at enrolment and delivery, as well as neonatal birth weight (g).

The team reported that at recruitment, they found that P. vivax–infected pregnant women had higher plasma concentrations of proinflammatory (IL-6, IL-1β, CCL4, CCL2, CXCL10) and T_H1-related cytokines (mainly IL-12) than uninfected women. This biomarker signature was essentially lost at delivery and was not associated with birth weight or hemoglobin levels. Anti-inflammatory 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.

The authors concluded that their data showed that while TH1 and pro-inflammatory responses are dominant during P. vivax infection in pregnancy, anti-inflammatory cytokines may compensate excessive inflammation avoiding poor delivery outcomes, and skewness toward a T_H2 response that 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. The study was published on May 4, 2020 in the journal PLOS Neglected Tropical Diseases.

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