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Front Microbiol
2019 Jan 01;10:68. doi: 10.3389/fmicb.2019.00068.
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Fetal-Derived MyD88 Signaling Contributes to Poor Pregnancy Outcomes During Gestational Malaria.
Barboza R
,
Hasenkamp L
,
Barateiro A
,
Murillo O
,
Peixoto EPM
,
Lima FA
,
Reis AS
,
Gonçalves LA
,
Epiphanio S
,
Marinho CRF
.
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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.
FIGURE 1. Breeding scheme. A schematic of the breeding strategy used to generate mice containing combinations of the maternal and fetal MyD88 genotypes. (A) MyD88 deficient (MyD88-/-) males (black square) mated with C57Bl/6 (MyD88+/+) females (white circle), generation I, to produce a heterozygous progeny (MyD88+/-, half-shaded symbols). MyD88+/- females (half-shaded circle) from generation II were backcrossed with MyD88-/- males (black square) to obtain fetus with MyD88+/- (half-shaded diamond) and MyD88-/- (black diamond) genotypes, generation III. (B) C57Bl/6 (MyD88+/+) males (white square) mated with MyD88 deficient (MyD88-/-) females (black circle), generation I, to obtain fetus with MyD88+/- (half-shaded diamond) genetic background, generation II. Diamond represents pregnancy (P) of a fetus with unknown sex. The arrows depict the MyD88 maternal genotype for each MyD88 fetal genotype (IIIA, IIB).
FIGURE 2. MyD88 expression influences disease progression in mice infected with P. berghei NK65. (A,B) Non-pregnant C57Bl/6 (WT), MyD88 deficient (MyD88-/-) and heterozygous (MyD88-/-) mice were infected intravenously with 105
P. berghei NK65GFP iRBCs. Evaluation of Kaplan-Meier survival curves (A) and parasitemia levels (B). (C) Pregnant WT, MyD88+/- and MyD88-/- mice were intravenously infected at gestational day 13 (G13) with 105
P. berghei NK65GFP iRBCs. Parasitemia was measured at G19 before C-section and compared with non-pregnant mice, also with 6 days of infection. Plain bars represent non-pregnant mice, and square-patterned bars represent pregnant mice. In B and C data are presented as mean ± SD. The statistical differences were achieved by a Long-rank (Mantel-Cox) test (A) and Two-way analysis of variance (ANOVA) with the Bonferroni’s post hoc test (B,C). ∗∗P-value <0.01 and ∗∗∗P-value < 0.001 when compared with WT (B) or non-pregnant mice (C); #P-value < 0.05 and ###P-value < 0.001 when compared with MyD88+/- mice (B).
FIGURE 3. MyD88 expression is associated with reduced placental vascular space and fetal weight in mice infected with P. berghei NK65. Pregnant C57Bl/6 (WT), and MyD88 deficient (MyD88-/-) and heterozygous (MyD88-/-) mice were intravenously infected (inf) with 105
P. berghei NK65GFP iRBCs at gestational day 13 (G13) and C-section performed at G19. The placenta/fetus share the same maternal MyD88 genotype. (A) Placental vascular spaces (n: WTinf – 33; MyD88+/-inf – 38; MyD88-/-inf – 39) and (B) fetal weight (n: WTinf – 35; MyD88+/-inf – 40; MyD88-/-inf – 28) measures. Data are presented as scatter plot with indication of the median ± SD; each dot represents an independent measurement. Dotted line represents mean values of the control group (non-infected pregnant WT mice; n: 34, vascular space, and 32, fetal weight). The statistical differences were achieved by a One-way analysis of variance (ANOVA) with post hoc Tukey’s test. ∗∗∗P-value < 0.001.
FIGURE 4. Fetal MyD88 expression is detrimental to disease development in an experimental mouse model of PM. To ascertain the differential contribution of the maternal- and fetal-derived MyD88 expression different combinations of maternal/fetal genotypes were evaluated. Pregnant mice were intravenously infected with 105
P. berghei NK65GFP iRBCs at gestational day (G13), with the following maternal-fetus pairs: WT/WT (1), MyD88+/-/MyD88+/- (2), MyD88-/-/MyD88+/- (3), MyD88+/-/MyD88-/- (4), and MyD88-/-/MyD88-/- (5). C-section was performed at G19 and fetus were genotyped and evaluated. (A) Placental vascular spaces and (B) fetal weight measures. Infected WT maternal-fetus pair is a positive control (1) and non-infected WT and MyD88-/- maternal-fetus pairs are negative controls (6 and 7, respectively). Data are presented as mean ± sem. The statistical differences were achieved by a One-way analysis of variance (ANOVA) with Tukey’s post hoc test. ∗P-value < 0.05; ∗∗P-value < 0.01; ∗∗∗P-value < 0.001.
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