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_H1-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 T_H1 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 T_H2 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. Cytokine and growth factor plasma concentrations were evaluated in women from five countries endemic for malaria vivax, at different moments and blood compartments during pregnancy. P. vivax infection during pregnancy was associated with a pro-inflammatory and T_H1 response, together with an antiinflammatory response. Nevertheless, at delivery most associations between cytokines and infection were lost. Of note, CCL11/eotaxin, a chemokine not generally analyzed in malaria studies, presented a lower concentration in P. vivax-infected women and a protective association with hemoglobin levels at delivery. Moreover, IL-4 levels had a negative association with birth weight. Data suggest that a compensated inflammatory/antiinflammatory response in P. vivax infection during pregnancy might avoid poor delivery outcomes, while a predominance of T_H2 responses may be detrimental for birth weight. Further research is warranted to unravel the role of CCL11 in malaria infection or exposure.