Macrophage migration inhibitory factor (MIF) exerts multiple effects on immune cells, as well as having functions outside the immune system. MIF can promote inflammation through the induction of other cytokines, including TNF, IL-6, and IL-1 family cytokines. Here, we show that inhibition of MIF regulates the release of IL-1α, IL-1β, and IL-18, not by affecting transcription or translation of these cytokines, but via activation of the NLRP3 inflammasome. MIF is required for the interaction between NLRP3 and the intermediate filament protein vimentin, which is critical for NLRP3 activation. Further, we demonstrate that MIF interacts with NLRP3, indicating a role for MIF in inflammasome activation independent of its role as a cytokine. These data advance our understanding of how MIF regulates inflammation and identify it as a factor critical for NLRP3 inflammasome activation.

In coastal Papua New Guinea, malaria and anaemia are important causes of adverse pregnancy outcomes.

No abstract

Placental malaria-associated inflammation disturbs maternal and fetal levels of IGFs, which regulate fetal growth. This may be one mechanism by which placental malaria leads to fetal growth restriction.

Azithromycin (AZI) is an azalide antibiotic with antimalarial activity that is considered safe in pregnancy.To assess its pharmacokinetic properties when administered as intermittent preventive treatment in pregnancy (IPTp), two 2-g doses were given 24 h apart to 31 pregnant and 29 age-matched nonpregnant Papua New Guinean women. All subjects also received single-dose sulfadoxine-pyrimethamine (SP) (1,500 mg or 75 mg) or chloroquine (450-mg base daily for 3 days). Blood samples were taken at 0, 1, 2, 3, 6, 12, 24, 32, 40, 48, and 72 h and on days 4, 5, 7, 10, and 14 for AZI assay by ultra-high-performance liquid chromatography-tandem mass spectrometry. The treatments were well tolerated. Using population pharmacokinetic modeling, a threecompartment model with zero-order followed by first-order absorption and no lag time provided the best fit. The areas under the plasma concentration-time curve (AUC 0-ؕ ) (28.7 and 31.8 mg ⅐ h liter ؊1 for pregnant and nonpregnant subjects, respectively) were consistent with the results of previous studies, but the estimated terminal elimination half-lives (78 and 77 h, respectively) were generally longer. The only significant relationship for a range of potential covariates, including malarial parasitemia, was with pregnancy, which accounted for an 86% increase in the volume of distribution of the central compartment relative to bioavailability without a significant change in the AUC 0-ؕ . These data suggest that AZI can be combined with compounds with longer half-lives, such as SP, in combination IPTp without the need for dose adjustment.

IntroductionDuring pregnancy, immunoglobulin G (IgG) is transferred from the mother to the fetus, providing protection from disease in early infancy. Plasmodium falciparum infections may reduce maternofetal antibody transfer efficiency, but mechanisms remain unclear.MethodsMother-cord paired serum samples collected at delivery from Papua New Guinea (PNG) and the Thailand-Myanmar Border Area (TMBA) were tested for IgG1 and IgG3 to four P. falciparum antigens and measles antigen, as well as total serum IgG. Multivariable linear regression was conducted to assess the association of peripheral P. falciparum infection during pregnancy or placental P. falciparum infection assessed at delivery with maternofetal antibody transfer efficiency. Path analysis assessed the extent to which associations between P. falciparum infection and antibody transfer were mediated by gestational age at delivery or levels of maternal total serum IgG.ResultsMaternofetal antibody transfer efficiency of IgG1 and IgG3 was lower in PNG compared to TMBA (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.88 to 0.09, median of -0.20 log2 units). Placental P. falciparum infections were associated with substantially lower maternofetal antibody transfer efficiency in PNG primigravid women (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.62 to -0.10, median of -0.36 log2 units), but not multigravid women. The lower antibody transfer efficiency amongst primigravid women with placental infection was only partially mediated by gestational age at delivery (proportion indirect effect ranged from 0% to 18%), whereas no mediation effects of maternal total serum IgG were observed.DiscussionPrimigravid women may be at risk of impaired maternofetal antibody transport with placental P. falciparum infection. Direct effects of P. falciparum on the placenta, rather than earlier gestational age and elevated serum IgG, are likely responsible for the majority of the reduction in maternofetal antibody transfer efficiency with placental infection.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The literature on placental and milk transfer of chloroquine and its major bioactive metabolite desethylchloroquine is sparse and incomplete. WHAT THIS STUDY ADDS• We have provided data on the transplacental transfer of chloroquine and desethylchloroquine in Melanesian women (n = 19), measured transfer of these drugs into breast milk (n = 16) and estimated absolute and relative infant doses for the breastfed infant.• The data for desethylchloroquine are novel.• In all three areas we have significantly increased both quantity and quality of the available database. AIMSTo investigate the transfer of chloroquine and its major bioactive metabolite desethylchloroquine across the placenta and into breast milk. METHODSIn Papua New Guinea, chloroquine (CQ; 25 mg base kg ) is recommended for prophylaxis of malaria during pregnancy, and at the Alexishafen Health Centre women are routinely prescribed CQ at the time of delivery. Fetal-cord and maternal serum samples were collected at delivery (n = 19) and milk samples were collected from day 3 to day 17-21 after delivery (n = 16). CQ and its primary active metabolite desethylchloroquine (DECQ) were quantified by high-performance liquid chromatography. For both CQ and DECQ cord/maternal ratios (C/M) were calculated to characterize placental transfer, and infant exposure via milk was estimated by standard methods. RESULTSThe median (interquartile range) C/M was 1.1 (0.9, 1.6) for CQ and 1.2 (0.5, 1.8) for DECQ. The average concentration in milk over the time of sampling was 167 mg l -1 (27, 340) for CQ and 54 mg l -1 (22, 106) for DECQ. Estimated absolute and relative infant doses were 34 mg kg -1 day -1 (7, 50) and 15 mg kg -1 day -1 (4, 26), and 2.3% (0.5, 3.6) and 1.0% (0.4, 2.0) for CQ and DECQ (as CQ equivalents), respectively. CONCLUSIONInfant exposure to CQ and DECQ during pregnancy will be similar to that in the maternal circulation, and dependent on maternal dose and frequency. The median CQ + DECQ relative infant dose of 3.2% (as CQ equivalents) was low, confirming that use of CQ during lactation is compatible with breastfeeding.

BackgroundMalaria in early pregnancy is difficult to study but has recently been associated with fetal growth restriction (FGR). The pathogenic mechanisms underlying malarial FGR are poorly characterized, but may include impaired placental development. We used in vitro methods that model migration and invasion of placental trophoblast into the uterine wall to investigate whether soluble factors released into maternal blood in malaria infection might impair placental development. Because trophoblast invasion is enhanced by a number of hormones and chemokines, and is inhibited by pro-inflammatory cytokines, many of which are dysregulated in malaria in pregnancy, we further compared concentrations of these factors in blood between malaria-infected and uninfected pregnancies.Methodology/Principal FindingsWe measured trophoblast invasion, migration and viability in response to treatment with serum or plasma from two independent cohorts of Papua New Guinean women infected with Plasmodium falciparum or Plasmodium vivax in early pregnancy. Compared to uninfected women, serum and plasma from women with P. falciparum reduced trophoblast invasion (P = .06) and migration (P = .004). P. vivax infection did not alter trophoblast migration (P = .64). The P. falciparum-specific negative effect on placental development was independent of trophoblast viability, but associated with high-density infections. Serum from P. falciparum infected women tended to have lower levels of trophoblast invasion promoting hormones and factors and higher levels of invasion-inhibitory inflammatory factors.Conclusion/SignificanceWe demonstrate that in vitro models of placental development can be adapted to indirectly study the impact of malaria in early pregnancy. These infections could result in impaired trophoblast invasion with reduced transformation of maternal spiral arteries due to maternal hormonal and inflammatory disturbances, which may contribute to FGR by limiting the delivery of maternal blood to the placenta. Future prevention strategies for malaria in pregnancy should include protection in the first half of pregnancy.