TY - JOUR
T1 - Exploitation of a newly-identified entry pathway into the malaria parasite-infected erythrocyte to inhibit parasite egress
AU - Glushakova, Svetlana
AU - Busse, Brad L.
AU - Garten, Matthias
AU - Beck, Josh R.
AU - Fairhurst, Rick M.
AU - Goldberg, Daniel E.
AU - Zimmerberg, Joshua
N1 - Funding Information:
We thank Kamran Melikov and Paul Blank for fruitful discussions. This study was funded by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Josh R. Beck acknowledges funding from the National Institutes of Health (NIH K99 HL133453). DEG funded by NIH grant AI-112508.
Funding Information:
Inhibitors. Compound 2 (4-[7-[(dimethylamino)methyl]-2-(4-fluorphenyl) imidazo[1,2-a] pyridine-3-yl] pyrimidin-2-amine; MRT00072329) was provided by Dr. Simon Osborne, Medical Research Council Technology (MRCT), United Kingdom and E-64, a cysteine protease inhibitor, was purchased from Sigma (E3132).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - While many parasites develop within host cells to avoid antibody responses and to utilize host cytoplasmic resources, elaborate egress processes have evolved to minimize the time between escaping and invading the next cell. In human erythrocytes, malaria parasites perforate their enclosing erythrocyte membrane shortly before egress. Here, we show that these pores clearly function as an entry pathway into infected erythrocytes for compounds that inhibit parasite egress. The natural glycosaminoglycan heparin surprisingly inhibited malaria parasite egress, trapping merozoites within infected erythrocytes. Labeled heparin neither bound to nor translocated through the intact erythrocyte membrane during parasite development, but fluxed into erythrocytes at the last minute of the parasite lifecycle. This short encounter was sufficient to significantly inhibit parasite egress and dispersion. Heparin blocks egress by interacting with both the surface of intra-erythrocytic merozoites and the inner aspect of erythrocyte membranes, preventing the rupture of infected erythrocytes but not parasitophorous vacuoles, and independently interfering with merozoite disaggregation. Since this action of heparin recapitulates that of neutralizing antibodies, membrane perforation presents a brief opportunity for a new strategy to inhibit parasite egress and replication.
AB - While many parasites develop within host cells to avoid antibody responses and to utilize host cytoplasmic resources, elaborate egress processes have evolved to minimize the time between escaping and invading the next cell. In human erythrocytes, malaria parasites perforate their enclosing erythrocyte membrane shortly before egress. Here, we show that these pores clearly function as an entry pathway into infected erythrocytes for compounds that inhibit parasite egress. The natural glycosaminoglycan heparin surprisingly inhibited malaria parasite egress, trapping merozoites within infected erythrocytes. Labeled heparin neither bound to nor translocated through the intact erythrocyte membrane during parasite development, but fluxed into erythrocytes at the last minute of the parasite lifecycle. This short encounter was sufficient to significantly inhibit parasite egress and dispersion. Heparin blocks egress by interacting with both the surface of intra-erythrocytic merozoites and the inner aspect of erythrocyte membranes, preventing the rupture of infected erythrocytes but not parasitophorous vacuoles, and independently interfering with merozoite disaggregation. Since this action of heparin recapitulates that of neutralizing antibodies, membrane perforation presents a brief opportunity for a new strategy to inhibit parasite egress and replication.
UR - http://www.scopus.com/inward/record.url?scp=85029898421&partnerID=8YFLogxK
U2 - 10.1038/s41598-017-12258-x
DO - 10.1038/s41598-017-12258-x
M3 - Article
C2 - 28947749
AN - SCOPUS:85029898421
VL - 7
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 12250
ER -