Expression dynamics and physiologically relevant functional study of STEVOR in asexual stages of<i>Plasmodium falciparum</i>infection

Singh, Himanshu; Madnani, Kripa Gopal; Lim, Ying Bena; Cao, Jianshu; Preiser, Peter R.; Lim, Chwee Teck

doi:10.1111/cmi.12715

Cited by 12 publications

(12 citation statements)

References 48 publications

(138 reference statements)

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“…We analyzed four selected STEVOR proteins with highly similar transcriptional profiles using, to our knowledge for the first time, well-characterized STEVOR variant-specific antisera in conjunction with corresponding transgenic parasite lines. In agreement with numerous previous studies, we observed a localization of all variants at the erythrocyte membrane in trophozoite stages, underlining their putative function in cell-cell interactions (9–11, 13, 26, 54). Similar to our results, GFP-tagged STEVOR versions were previously shown to be retained at the Maurer’s clefts, indicating that the interaction of the STEVOR C terminus with the erythrocyte cytoskeleton (55) is hampered by GFP tagging and precludes transport to the IE membrane (15).…”

Section: Discussionsupporting

confidence: 93%

Dissecting the Gene Expression, Localization, Membrane Topology, and Function of the Plasmodium falciparum STEVOR Protein Family

Wichers

Scholz

Strauss

et al. 2019

mBio

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During its intraerythrocytic development, the malaria parasite Plasmodium falciparum exposes variant surface antigens (VSAs) on infected erythrocytes to establish and maintain an infection. One family of small VSAs is the polymorphic STEVOR proteins, which are marked for export to the host cell surface through their PEXEL signal peptide. Interestingly, some STEVORs have also been reported to localize to the parasite plasma membrane and apical organelles, pointing toward a putative function in host cell egress or invasion. Using deep RNA sequencing analysis, we characterized P. falciparum stevor gene expression across the intraerythrocytic development cycle, including free merozoites, in detail and used the resulting stevor expression profiles for hierarchical clustering. We found that most stevor genes show biphasic expression oscillation, with maximum expression during trophozoite stages and a second peak in late schizonts. We selected four STEVOR variants, confirmed the expected export of these proteins to the host cell membrane, and tracked them to a secondary location, either to the parasite plasma membrane or the secretory organelles of merozoites in late schizont stages. We investigated the function of a particular STEVOR that showed rhoptry localization and demonstrated its role at the parasite-host interface during host cell invasion by specific antisera and targeted gene disruption. Experimentally determined membrane topology of this STEVOR revealed a single transmembrane domain exposing the semiconserved as well as variable protein regions to the cell surface. IMPORTANCE Malaria claims about half a million lives each year. Plasmodium falciparum, the causative agent of the most severe form of the disease, uses proteins that are translocated to the surface of infected erythrocytes for immune evasion. To circumvent the detection of these gene products by the immune system, the parasite evolved a complex strategy that includes gene duplications and elaborate sequence polymorphism. STEVORs are one family of these variant surface antigens and are encoded by about 40 genes. Using deep RNA sequencing of blood-stage parasites, including free merozoites, we first established stevor expression of the cultured isolate and compared it with published transcriptomes. We reveal a biphasic expression of most stevor genes and confirm this for individual STEVORs at the protein level. The membrane topology of a rhoptry-associated variant was experimentally elucidated and linked to host cell invasion, underlining the importance of this multifunctional protein family for parasite proliferation.

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Section: Discussionsupporting

confidence: 93%

Dissecting the Gene Expression, Localization, Membrane Topology, and Function of the Plasmodium falciparum STEVOR Protein Family

Wichers

Scholz

Strauss

et al. 2019

mBio

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“…This process involves the adhesion of parasite-exported proteins, known as ligands, expressed on the infected RBC (iRBC) membrane to receptors on host cells 3 . iRBCs can either bind to endothelial cells 7 , form rosettes with uninfected RBCs 8 , 9 , or cluster amongst themselves via platelet interactions 10 . Sequestered iRBCs occlude microvasculature 11 , 12 , induce the release of damaging inflammatory mediators 13 , and cause disruptions to host metabolism 14 .…”

Section: Introductionmentioning

confidence: 99%

Single molecule and multiple bond characterization of catch bond associated cytoadhesion in malaria

Lim

Thingna

Cao

et al. 2017

Sci Rep

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The adhesion of malaria infected red blood cells (iRBCs) to host endothelial receptors in the microvasculature, or cytoadhesion, is associated with severe disease pathology such as multiple organ failure and cerebral malaria. Malaria iRBCs have been shown to bind to several receptors, of which intercellular adhesion molecule 1 (ICAM-1) upregulation in brain microvasculature is the only one correlated to cerebral malaria. We utilize a biophysical approach to study the interactions between iRBCs and ICAM-1. At the single molecule level, force spectroscopy experiments reveal that ICAM-1 forms catch bond interactions with Plasmodium falciparum parasite iRBCs. Flow experiments are subsequently conducted to understand multiple bond behavior. Using a robust model that smoothly transitions between our single and multiple bond results, we conclusively demonstrate that the catch bond behavior persists even under flow conditions. The parameters extracted from these experimental results revealed that the rate of association of iRBC-ICAM-1 bonds are ten times lower than iRBC-CD36 (cluster of differentiation 36), a receptor that shows no upregulation in the brains of cerebral malaria patients. Yet, the dissociation rates are nearly the same for both iRBC-receptor interactions. Thus, our results suggest that ICAM-1 may not be the sole mediator responsible for cytoadhesion in the brain.

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“…STEVOR proteins have also been shown to be associated with the erythrocyte membrane in immature gametocytes stages (McRobert et al, 2004; Tiburcio et al, 2012). Although the adhesive domain of STEVOR was detected at the erythrocyte surface in asexual stages where it plays a role in rosetting (Niang et al, 2009; Niang et al, 2014; Singh et al, 2017; Wichers et al, 2019), recent immunofluorescence studies convincingly showed that this domain is not exposed at the surface of erythrocytes infected with immature gametocytes (Neveu et al, 2018). At the mature gametocyte stage, STEVOR proteins are no longer detectable at the erythrocyte membrane, probably as a result of conformational changes upon dephosphorylation (Tiburcio et al, 2012; Naissant et al, 2016; Figure 1B).…”

Section: Protein Export At the Erythrocyte Membranementioning

confidence: 99%

Erythrocyte Membrane Makeover by Plasmodium falciparum Gametocytes

Neveu

Lavazec

2019

Front. Microbiol.

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Plasmodium falciparum sexual parasites, called gametocytes, are the only parasite stages responsible for transmission from humans to Anopheles mosquitoes. During their maturation, P. falciparum gametocytes remodel the structural and mechanical properties of the membrane of their erythrocyte host. This remodeling is induced by the export of several parasite proteins and a dynamic reorganization of the erythrocyte cytoskeleton. Some of these modifications are specific for sexual stages and play a key role for gametocyte maturation, sequestration in internal organs, subsequent release in the bloodstream and ability to persist in circulation. Here we discuss the mechanisms developed by gametocytes to remodel their host cell and the functional relevance of these modifications.

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Expression dynamics and physiologically relevant functional study of STEVOR in asexual stages ofPlasmodium falciparuminfection

Cited by 12 publications

References 48 publications

Dissecting the Gene Expression, Localization, Membrane Topology, and Function of the Plasmodium falciparum STEVOR Protein Family

Dissecting the Gene Expression, Localization, Membrane Topology, and Function of the Plasmodium falciparum STEVOR Protein Family

Single molecule and multiple bond characterization of catch bond associated cytoadhesion in malaria

Erythrocyte Membrane Makeover by Plasmodium falciparum Gametocytes

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