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Sci Rep
2017 Aug 17;71:8623. doi: 10.1038/s41598-017-08299-x.
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TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria.
Barboza R
,
Lima FA
,
Reis AS
,
Murillo OJ
,
Peixoto EPM
,
Bandeira CL
,
Fotoran WL
,
Sardinha LR
,
Wunderlich G
,
Bevilacqua E
,
Lima MRD
,
Alvarez JM
,
Costa FTM
,
Gonçalves LA
,
Epiphanio S
,
Marinho CRF
.
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Malaria-associate pregnancy has a significant impact on infant morbidity and mortality. The detrimental effects of malaria infection during pregnancy have been shown to correlate with immune activation in the placental tissue. Herein we sought to evaluate the effect of Toll-like receptors (TLRs) activation on placental malaria (PM) development by using the Plasmodium berghei NK65GFP infection model. We observed that activation of the innate immune system by parasites leads to PM due to local inflammation. We identified TLR4 activation as the main pathway involved in the inflammatory process in the placental tissue since the absence of functional TLR4 in mice leads to a decrease in the pro-inflammatory responses, which resulted in an improved pregnancy outcome. Additionally, a similar result was obtained when infected pregnant mice were treated with IAXO-101, a TLR4/CD14 blocker. Together, this study illustrates the importance of TLR4 signalling for the generation of the severe inflammatory response involved in PM pathogenesis. Therefore, our results implicate that TLR4 blockage could be a potential candidate for therapeutic interventions to reduce malaria-induced pathology both in the mother and the fetus.
Figure 1. Inflammatory cell infiltration in P. berghei infected placenta. Images from the placental labyrinth layer from WT infected mice. Transmission electron microscopy (TEM) in the labyrinth region (A,B) showing the maternal-fetal interface with presence of iRBCs in the maternal blood space (MBS), but not in fetal blood vessels (FBV). Bar in (A) = 10 µm and (B) = 2.5 µm. Immunofluorescence of placentas (C,D) from infected WT mice with GFP-labelled P. berghei NK65GFP (green), DAPI (blue) and anti-CD11b (red) revealing the accumulation of parasites (C) and infiltration of monocytes/macrophages (D) on maternal blood sinuses; Bar in (C,D) = 100 µm. (GC) Giant cell.
Figure 2. TLRs immunohistochemistry. TLR2, TLR4, and TLR9 immunolabeling in placentas of non-infected and infected mice. Pregnant mice were i.v. infected or not with 1 × 105 P. berghei NK65GFP iRBCs on the 13th gestational day. Scores of TLR2, TLR4, and TLR9 expression were defined by using protein expression level of positively stained cells (absent = 0, faint = 1, moderate = 2, intense = 3). We considered as “low expression” TLR intensity scores of 0, 1 or 2, and as “high expression” scores of 3. ×200 magnification, ×400 inset. Bar = 100 μm. Dec = decidua; St = Spongiotrophoblast.
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