IL-1 axis activation during placental malaria induces poor pregnancy outcomes that are obliterated after treatment with Anakinra.

Malaria in pregnancy (MiP) is one of the major causes of mortality and morbidity in tropical regions, causing maternal anemia, intrauterine growth retardation, preterm birth, and low birth weight (LBW). The integration of the information systems on pregnancy and malaria could prove to be a useful method of improved decision making for better maternal-child health. A population-based observational study acquired information retrospectively from all live births that occurred between 2006 and 2014 in Cruzeiro do Sul (Acre, Brazil). Social and clinical data of the mother and newborn was extracted from the Information System of Live Births. Malaria episodes information was obtained from the Brazilian Epidemiological Surveillance Information System Malaria. A deterministic record linkage was performed to assess malaria impact on pregnancy. The studied population presented a malaria incidence of 8.9% (1283 pregnant women infected), of which 63.9% infected by Plasmodium (P.) vivax. Reduction of newborn birth weight at term (small for gestational age (SGA) and LBW) has been found associated with P. vivax infection during pregnancy (SGA—OR 1.24, 95% CI 1.02–1.52, p = 0.035; term LBW—OR 1.39, 95% CI 1.03–1.88, p = 0.033). Additionally, P. falciparum infection during pregnancy has been found to be associated with preterm births (OR 1.54, 95% CI 1.09–2.18, p = 0.016), which is related with late preterm births (OR 1.59, 95% CI 1.11–2.27, p = 0.011). Despite the decrease of malaria cases during the evaluation period and regardless of Plasmodium species, we present evidence of the deleterious effects of MiP in a low transmission area in the Amazonian region.

Background: Malaria in Brazil represents one of the highest percentages of Latin America cases, where approximately 84% of infections are attributed toPlasmodium(P.) vivax. Despite the high incidence, many aspects of gestational malaria resulting fromP.vivaxinfections remain poorly studied. As such, we aimed to evaluate the consequences ofP.vivaxinfections during gestation on the health of mothers and their neonates in an endemic area of the Amazon.Methods and findings: We have conducted an observational cohort study in Brazilian Amazon between January 2013 and April 2015. 600 pregnant women were enrolled and followed until delivery. After applying exclusion criteria, 329 mother-child pairs were included in the analysis. Clinical data regarding maternal infection, newborn’s anthropometric measures, placental histopathological characteristics, and angiogenic and inflammatory factors were evaluated. The presence of plasma IgG against theP.vivax(Pv) MSP1₁₉protein was used as marker of exposure and possible associations with pregnancy outcomes were analyzed. Multivariate logistic regression analysis revealed thatP.vivaxinfections during the first trimester of pregnancy are associated with adverse gestational outcomes such as premature birth (adjusted odds ratio [aOR] 8.12, 95% confidence interval [95%CI] 2.69–24.54,p< 0.0001) and reduced head circumference (aOR 3.58, 95%CI 1.29–9.97,p= 0.01). Histopathology analysis showed marked differences between placentas fromP.vivax-infected and non-infected pregnant women, especially regarding placental monocytes infiltrate. Placental levels of vasomodulatory factors such as angiopoietin-2 (ANG-2) and complement proteins such as C5a were also altered at delivery. Plasma levels of anti-PvMSP1₁₉IgG in infected pregnant women were shown to be a reliable exposure marker; yet, with no association with improved pregnancy outcomes.Conclusions: This study indicates thatP.vivaxmalaria during the first trimester of pregnancy represents a higher likelihood of subsequent poor pregnancy outcomes associated with marked placental histologic modification and angiogenic/inflammatory imbalance. Additionally, our findings support the idea that antibodies against PvMSP1₁₉are not protective against poor pregnancy outcomes induced byP.vivaxinfections.

Annually, many pregnancies occur in areas of Plasmodium spp. transmission, particularly in underdeveloped countries with widespread poverty. Estimations have suggested that several million women are at risk of developing malaria during pregnancy. In particular cases, systemic infection caused by Plasmodium spp. may extend to the placenta, dysregulating local homeostasis and promoting the onset of placental malaria; these processes are often associated with increased maternal and fetal mortality, intrauterine growth restriction, preterm delivery, and reduced birth weight. The endeavor to understand and characterize the mechanisms underlying disease onset and placental pathology face several ethical and logistical obstacles due to explicit difficulties in assessing human gestation and biological material. Consequently, the advent of murine experimental models for the study of malaria during pregnancy has substantially contributed to our understanding of this complex pathology. Herein, we summarize research conducted during recent decades using murine models of malaria during pregnancy and highlight the most relevant findings, as well as discuss similarities to humans and the translational capacity of achieved results.

Placental malaria (PM) remains a severe public health problem in areas of high malaria transmission. Despite the efforts to prevent infection poor outcomes in Plasmodium endemic areas, there is still a considerable number of preterm births and newborns with low birth weight resulting from PM. Although local inflammation triggered in response to malaria is considered crucial in inducing placental damage, little is known about the differential influence of maternal and fetal immune responses to the disease progression. Therefore, using a PM mouse model, we sought to determine the contribution of maternal and fetal innate immune responses to PM development. For this, we conducted a series of cross-breeding experiments between mice that had differential expression of the MyD88 adaptor protein to obtain mother and correspondent fetuses with distinct genetic backgrounds. By evaluating fetal weight and placental vascular spaces, we have shown that the expression of MyD88 in fetal tissue has a significant impact on PM outcomes. Our results highlighted the existence of a distinct contribution of maternal and fetal immune responses to PM onset. Thus, contributing to the understanding of how inflammatory processes lead to the dysregulation of placental homeostasis ultimately impairing fetal development.

Plasmodium falciparum infection during pregnancy leads to abortions, stillbirth, low birth weight, and maternal mortality. Infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) via var2CSA protein exposed on the P. falciparum IE membrane. Plasmodium berghei IE infection in pregnant BALB/c mice is a model for severe placental malaria (PM). Here, we describe a transgenic P. berghei parasite expressing the full-length var2CSA extracellular region (domains DBL1X to DBL6ε) fused to a P. berghei exported protein (EMAP1) and characterize a var2CSA-based mouse model of PM. BALB/c mice were infected at midgestation with different doses of P. berghei- var2CSA ( P. berghei -VAR) or P. berghei wild-type IEs. Infection with 10 ⁴ P. berghei -VAR IEs induced a higher incidence of stillbirth and lower fetal weight than P. berghei . At doses of 10 ⁵ and 10 ⁶ IEs, P. berghei -VAR-infected mice showed increased maternal mortality during pregnancy and fetal loss, respectively. Parasite loads in infected placentas were similar between parasite lines despite differences in maternal outcomes. Fetal weight loss normalized for parasitemia was higher in P. berghei -VAR-infected mice than in P. berghei -infected mice. In vitro assays showed that higher numbers of P. berghei -VAR IEs than P. berghei IEs adhered to placental tissue. Immunization of mice with P. berghei -VAR elicited IgG antibodies reactive to DBL1-6 recombinant protein, indicating that the topology of immunogenic epitopes is maintained between DBL1-6–EMAP1 on P. berghei -VAR and recombinant DBL1-6 (recDBL1-6). Our data suggested that impairments in pregnancy caused by P. berghei -VAR infection were attributable to var2CSA expression. This model provides a tool for preclinical evaluation of protection against PM induced by approaches that target var2CSA.