Impaired placental autophagy in placental malaria

Kris Genelyn Dimasuay, Lan Gong, Fredrick Rosario, Emma McBryde, Tim Spelman, Jocelyn Glazier, Stephen J. Rogerson, James G. Beeson, Thomas Jansson, Rodney J. Devenish, Philippe Boeuf

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Placental malaria is a major cause of low birthweight, principally due to impaired fetal growth. Intervillositis, a local inflammatory response to placental malaria, is central to the pathogenesis of poor fetal growth as it impairs transplacental amino acid transport. Given the link between inflammation and autophagy, we investigated whether placental malaria-associated intervillositis increased placental autophagy as a potential mechanism in impaired fetal growth. Methods: We examined placental biopsies collected after delivery from uninfected women (n = 17) and from women with Plasmodium falciparum infection with (n = 14) and without (n = 7) intervillositis. Western blotting and immunofluorescence staining coupled with advanced image analysis were used to quantify the expression of autophagic markers (LC3-II, LC3-I, Rab7, ATG4B and p62) and the density of autophagosomes (LC3-positive puncta) and lysosomes (LAMP1-positive puncta). Results: Placental malaria with intervillositis was associated with higher LC3-II:LC3-I ratio, suggesting increased autophagosome formation. We found higher density of autophagosomes and lysosomes in the syncytiotrophoblast of malaria-infected placentas with intervillositis. However, there appear to be no biologically relevant increase in LC3B/LAMP1 colocalization and expression of Rab7, a molecule involved in autophagosome/lysosome fusion, was lower in placental malaria with intervillositis, indicating a block in the later stage of autophagy. ATG4B and p62 expression showed no significant difference across histological groups suggesting normal autophagosome maturation and loading of cargo proteins into autophagosomes. The density of autophagosomes and lysosomes in the syncytiotrophoblast was negatively correlated with placental amino acid uptake. Conclusions Placental malaria-associated intervillositis is associated with dysregulated autophagy that may impair transplacental amino acid transport, possibly contributing to poor fetal growth.

Original languageEnglish
Article numbere0187291
Number of pages20
JournalPLoS ONE
Volume12
Issue number11
DOIs
Publication statusPublished - 10 Nov 2017

Keywords

  • malaria
  • autophagic cell death
  • placenta
  • lysosomes
  • monocytes
  • imflammation
  • histology
  • malarial parasites

Cite this

Dimasuay, K. G., Gong, L., Rosario, F., McBryde, E., Spelman, T., Glazier, J., ... Boeuf, P. (2017). Impaired placental autophagy in placental malaria. PLoS ONE, 12(11), [e0187291]. https://doi.org/10.1371/journal.pone.0187291
Dimasuay, Kris Genelyn ; Gong, Lan ; Rosario, Fredrick ; McBryde, Emma ; Spelman, Tim ; Glazier, Jocelyn ; Rogerson, Stephen J. ; Beeson, James G. ; Jansson, Thomas ; Devenish, Rodney J. ; Boeuf, Philippe. / Impaired placental autophagy in placental malaria. In: PLoS ONE. 2017 ; Vol. 12, No. 11.
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abstract = "Background: Placental malaria is a major cause of low birthweight, principally due to impaired fetal growth. Intervillositis, a local inflammatory response to placental malaria, is central to the pathogenesis of poor fetal growth as it impairs transplacental amino acid transport. Given the link between inflammation and autophagy, we investigated whether placental malaria-associated intervillositis increased placental autophagy as a potential mechanism in impaired fetal growth. Methods: We examined placental biopsies collected after delivery from uninfected women (n = 17) and from women with Plasmodium falciparum infection with (n = 14) and without (n = 7) intervillositis. Western blotting and immunofluorescence staining coupled with advanced image analysis were used to quantify the expression of autophagic markers (LC3-II, LC3-I, Rab7, ATG4B and p62) and the density of autophagosomes (LC3-positive puncta) and lysosomes (LAMP1-positive puncta). Results: Placental malaria with intervillositis was associated with higher LC3-II:LC3-I ratio, suggesting increased autophagosome formation. We found higher density of autophagosomes and lysosomes in the syncytiotrophoblast of malaria-infected placentas with intervillositis. However, there appear to be no biologically relevant increase in LC3B/LAMP1 colocalization and expression of Rab7, a molecule involved in autophagosome/lysosome fusion, was lower in placental malaria with intervillositis, indicating a block in the later stage of autophagy. ATG4B and p62 expression showed no significant difference across histological groups suggesting normal autophagosome maturation and loading of cargo proteins into autophagosomes. The density of autophagosomes and lysosomes in the syncytiotrophoblast was negatively correlated with placental amino acid uptake. Conclusions Placental malaria-associated intervillositis is associated with dysregulated autophagy that may impair transplacental amino acid transport, possibly contributing to poor fetal growth.",
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author = "Dimasuay, {Kris Genelyn} and Lan Gong and Fredrick Rosario and Emma McBryde and Tim Spelman and Jocelyn Glazier and Rogerson, {Stephen J.} and Beeson, {James G.} and Thomas Jansson and Devenish, {Rodney J.} and Philippe Boeuf",
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Dimasuay, KG, Gong, L, Rosario, F, McBryde, E, Spelman, T, Glazier, J, Rogerson, SJ, Beeson, JG, Jansson, T, Devenish, RJ & Boeuf, P 2017, 'Impaired placental autophagy in placental malaria' PLoS ONE, vol. 12, no. 11, e0187291. https://doi.org/10.1371/journal.pone.0187291

Impaired placental autophagy in placental malaria. / Dimasuay, Kris Genelyn; Gong, Lan; Rosario, Fredrick; McBryde, Emma; Spelman, Tim; Glazier, Jocelyn; Rogerson, Stephen J.; Beeson, James G.; Jansson, Thomas; Devenish, Rodney J.; Boeuf, Philippe.

In: PLoS ONE, Vol. 12, No. 11, e0187291, 10.11.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Impaired placental autophagy in placental malaria

AU - Dimasuay, Kris Genelyn

AU - Gong, Lan

AU - Rosario, Fredrick

AU - McBryde, Emma

AU - Spelman, Tim

AU - Glazier, Jocelyn

AU - Rogerson, Stephen J.

AU - Beeson, James G.

AU - Jansson, Thomas

AU - Devenish, Rodney J.

AU - Boeuf, Philippe

PY - 2017/11/10

Y1 - 2017/11/10

N2 - Background: Placental malaria is a major cause of low birthweight, principally due to impaired fetal growth. Intervillositis, a local inflammatory response to placental malaria, is central to the pathogenesis of poor fetal growth as it impairs transplacental amino acid transport. Given the link between inflammation and autophagy, we investigated whether placental malaria-associated intervillositis increased placental autophagy as a potential mechanism in impaired fetal growth. Methods: We examined placental biopsies collected after delivery from uninfected women (n = 17) and from women with Plasmodium falciparum infection with (n = 14) and without (n = 7) intervillositis. Western blotting and immunofluorescence staining coupled with advanced image analysis were used to quantify the expression of autophagic markers (LC3-II, LC3-I, Rab7, ATG4B and p62) and the density of autophagosomes (LC3-positive puncta) and lysosomes (LAMP1-positive puncta). Results: Placental malaria with intervillositis was associated with higher LC3-II:LC3-I ratio, suggesting increased autophagosome formation. We found higher density of autophagosomes and lysosomes in the syncytiotrophoblast of malaria-infected placentas with intervillositis. However, there appear to be no biologically relevant increase in LC3B/LAMP1 colocalization and expression of Rab7, a molecule involved in autophagosome/lysosome fusion, was lower in placental malaria with intervillositis, indicating a block in the later stage of autophagy. ATG4B and p62 expression showed no significant difference across histological groups suggesting normal autophagosome maturation and loading of cargo proteins into autophagosomes. The density of autophagosomes and lysosomes in the syncytiotrophoblast was negatively correlated with placental amino acid uptake. Conclusions Placental malaria-associated intervillositis is associated with dysregulated autophagy that may impair transplacental amino acid transport, possibly contributing to poor fetal growth.

AB - Background: Placental malaria is a major cause of low birthweight, principally due to impaired fetal growth. Intervillositis, a local inflammatory response to placental malaria, is central to the pathogenesis of poor fetal growth as it impairs transplacental amino acid transport. Given the link between inflammation and autophagy, we investigated whether placental malaria-associated intervillositis increased placental autophagy as a potential mechanism in impaired fetal growth. Methods: We examined placental biopsies collected after delivery from uninfected women (n = 17) and from women with Plasmodium falciparum infection with (n = 14) and without (n = 7) intervillositis. Western blotting and immunofluorescence staining coupled with advanced image analysis were used to quantify the expression of autophagic markers (LC3-II, LC3-I, Rab7, ATG4B and p62) and the density of autophagosomes (LC3-positive puncta) and lysosomes (LAMP1-positive puncta). Results: Placental malaria with intervillositis was associated with higher LC3-II:LC3-I ratio, suggesting increased autophagosome formation. We found higher density of autophagosomes and lysosomes in the syncytiotrophoblast of malaria-infected placentas with intervillositis. However, there appear to be no biologically relevant increase in LC3B/LAMP1 colocalization and expression of Rab7, a molecule involved in autophagosome/lysosome fusion, was lower in placental malaria with intervillositis, indicating a block in the later stage of autophagy. ATG4B and p62 expression showed no significant difference across histological groups suggesting normal autophagosome maturation and loading of cargo proteins into autophagosomes. The density of autophagosomes and lysosomes in the syncytiotrophoblast was negatively correlated with placental amino acid uptake. Conclusions Placental malaria-associated intervillositis is associated with dysregulated autophagy that may impair transplacental amino acid transport, possibly contributing to poor fetal growth.

KW - malaria

KW - autophagic cell death

KW - placenta

KW - lysosomes

KW - monocytes

KW - imflammation

KW - histology

KW - malarial parasites

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Dimasuay KG, Gong L, Rosario F, McBryde E, Spelman T, Glazier J et al. Impaired placental autophagy in placental malaria. PLoS ONE. 2017 Nov 10;12(11). e0187291. https://doi.org/10.1371/journal.pone.0187291