Impaired placental autophagy in placental malaria

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.

[1]  Lindsay A. Parnell,et al.  Autophagy regulation of physiological and pathological processes in the female reproductive tract , 2017, American journal of reproductive immunology.

[2]  D. Sabatini,et al.  mTOR Signaling in Growth, Metabolism, and Disease , 2017, Cell.

[3]  J. Glazier,et al.  Inhibition of placental mTOR signaling provides a link between placental malaria and reduced birthweight , 2017, BMC Medicine.

[4]  C. Bucci,et al.  Multiple Roles of the Small GTPase Rab7 , 2016, Cells.

[5]  Diwei Ho,et al.  Therapeutic and safety considerations of nanoparticle-mediated drug delivery in pregnancy. , 2015, Nanomedicine.

[6]  A. Gilman‐Sachs,et al.  Altered autophagic flux enhances inflammatory responses during inflammation-induced preterm labor , 2015, Scientific Reports.

[7]  G. Kim,et al.  The role of autophagy in the placenta as a regulator of cell death , 2014, Clinical and experimental reproductive medicine.

[8]  P. Walker,et al.  Estimated risk of placental infection and low birthweight attributable to Plasmodium falciparum malaria in Africa in 2010: a modelling study. , 2014, The Lancet. Global health.

[9]  Colin Mathers,et al.  Every Newborn: progress, priorities, and potential beyond survival , 2014, The Lancet.

[10]  Jenny Hill,et al.  The contribution of malaria control to maternal and newborn health , 2014 .

[11]  Yu-Hsiang Chang,et al.  ATG4B promotes colorectal cancer growth independent of autophagic flux , 2014, Autophagy.

[12]  A. Cuervo,et al.  Autophagy and human disease: emerging themes. , 2014, Current opinion in genetics & development.

[13]  J. Glazier,et al.  Insight into the pathogenesis of fetal growth restriction in placental malaria: decreased placental glucose transporter isoform 1 expression. , 2014, The Journal of infectious diseases.

[14]  Y. Wu,et al.  Regulation of autophagy by the Rab GTPase network , 2014, Cell Death and Differentiation.

[15]  S. Oddo,et al.  Autophagic/lysosomal dysfunction in Alzheimer’s disease , 2013, Alzheimer's Research & Therapy.

[16]  C. Hulme,et al.  Identification of autophagic vacuoles and regulators of autophagy in villous trophoblast from normal term pregnancies and in fetal growth restriction , 2013, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[17]  A. Salminen,et al.  Maturation of autophagosomes and endosomes: a key role for Rab7. , 2013, Biochimica et biophysica acta.

[18]  J. Sled,et al.  Complement activation and the resulting placental vascular insufficiency drives fetal growth restriction associated with placental malaria. , 2013, Cell host & microbe.

[19]  M. Molyneux,et al.  Plasmodium falciparum Malaria Elicits Inflammatory Responses that Dysregulate Placental Amino Acid Transport , 2013, PLoS pathogens.

[20]  Y. Kanai,et al.  Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells , 2013, The Journal of physiology.

[21]  Frances M. Platt,et al.  Lysosomal storage disorders: The cellular impact of lysosomal dysfunction , 2012, The Journal of cell biology.

[22]  D. Rubinsztein,et al.  Autophagy modulation as a potential therapeutic target for diverse diseases , 2012, Nature Reviews Drug Discovery.

[23]  M. Longtine,et al.  Survival by self-destruction: a role for autophagy in the placenta? , 2012, Placenta.

[24]  T. Hung,et al.  Increased Autophagy in Placentas of Intrauterine Growth-Restricted Pregnancies , 2012, PloS one.

[25]  Kevin W Eliceiri,et al.  NIH Image to ImageJ: 25 years of image analysis , 2012, Nature Methods.

[26]  M. Prescott,et al.  The Intriguing Life of Autophagosomes , 2012, International journal of molecular sciences.

[27]  M. Molyneux,et al.  Performance Characteristics of Combinations of Host Biomarkers to Identify Women with Occult Placental Malaria: A Case-Control Study from Malawi , 2011, PloS one.

[28]  A. Marconi,et al.  Autophagy in term normal human placentas. , 2011, Placenta.

[29]  S. Rogerson,et al.  Malaria in pregnancy: small babies, big problem. , 2011, Trends in parasitology.

[30]  K. Heidenreich,et al.  IGF-I stimulates Rab7-RILP interaction during neuronal autophagy , 2011, Neuroscience Letters.

[31]  N. Mizushima,et al.  Methods in Mammalian Autophagy Research , 2010, Cell.

[32]  R. Albrecht,et al.  Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes. , 2009, Cell host & microbe.

[33]  J. Rathmell,et al.  Autophagy: Not good OR bad, but good AND bad , 2009, Autophagy.

[34]  Eeva-Liisa Eskelinen,et al.  Autophagy: a lysosomal degradation pathway with a central role in health and disease. , 2009, Biochimica et biophysica acta.

[35]  A. Ballabio,et al.  Lysosomal disorders: from storage to cellular damage. , 2009, Biochimica et biophysica acta.

[36]  S. Oh,et al.  Autophagy-Related Proteins, LC3 and Beclin-1, in Placentas From Pregnancies Complicated by Preeclampsia , 2008, Reproductive Sciences.

[37]  D. Klionsky,et al.  Autophagosome formation: core machinery and adaptations , 2007, Nature Cell Biology.

[38]  G. Bjørkøy,et al.  p62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy* , 2007, Journal of Biological Chemistry.

[39]  F. T. Ter Kuile,et al.  Epidemiology and burden of malaria in pregnancy. , 2007, The Lancet. Infectious diseases.

[40]  P. Saftig,et al.  Role for Rab7 in maturation of late autophagic vacuoles , 2004, Journal of Cell Science.

[41]  M. Colombo,et al.  Rab7 is required for the normal progression of the autophagic pathway in mammalian cells , 2004, Journal of Cell Science.

[42]  A. Cuervo.  Autophagy: in sickness and in health. , 2004, Trends in cell biology.

[43]  T. Wardlaw,et al.  Low birthweight: country regional and global estimates. , 2004 .

[44]  M. Molyneux,et al.  Host Response to Malaria During Pregnancy: Placental Monocyte Recruitment Is Associated with Elevated β Chemokine Expression1 , 2003, The Journal of Immunology.

[45]  M. Molyneux,et al.  Placental Tumor Necrosis Factor Alpha but Not Gamma Interferon Is Associated with Placental Malaria and Low Birth Weight in Malawian Women , 2003, Infection and Immunity.

[46]  M. Molyneux,et al.  Placental monocyte infiltrates in response to Plasmodium falciparum malaria infection and their association with adverse pregnancy outcomes. , 2003, The American journal of tropical medicine and hygiene.

[47]  C. Menéndez,et al.  The burden of malaria in pregnancy in malaria-endemic areas. , 2001, The American journal of tropical medicine and hygiene.

[48]  B. Deurs,et al.  Rab7: a key to lysosome biogenesis. , 2000, Molecular biology of the cell.

[49]  C. Sibley,et al.  Association between the Activity of the System A Amino Acid Transporter in the Microvillous Plasma Membrane of the Human Placenta and Severity of Fetal Compromise in Intrauterine Growth Restriction , 1997, Pediatric Research.

[50]  C. Sibley,et al.  Amino Acid (System A) Transporter Activity in Microvillous Membrane Vesicles from the Placentas of Appropriate and Small for Gestational Age Babies , 1993, Pediatric Research.

[51]  P. A. Grannum.  The placenta. , 1989, Clinics in diagnostic ultrasound.