Total and Putative Surface Proteomics of Malaria Parasite Salivary Gland Sporozoites

Lindner, Scott E.; Swearingen, Kristian E.; Harupa, Anke; Vaughan, Ashley M.; Sinnis, Photini; Moritz, Robert L.; Kappe, Stefan H. I.

doi:10.1074/mcp.m112.024505

Cited by 174 publications

(288 citation statements)

References 81 publications

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“…Although P. falciparum Alba1 appears to be specifically involved in the maturation of the merozoite, it is expressed throughout the parasite's erythrocytic cycle (19), suggesting that it plays a role in RNA homeostasis throughout blood stage development. Alba1 is also expressed in sporozoites (38) and liver stages (31), suggesting that it has multiple roles in the parasite life cycle. It is possible that Alba1 function in liver stages is linked to PlasMei2.…”

Section: Discussionmentioning

confidence: 99%

A Plasmodium yoelii Mei2-Like RNA Binding Protein Is Essential for Completion of Liver Stage Schizogony

et al. 2016

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bPlasmodium parasites employ posttranscriptional regulatory mechanisms as their life cycle transitions between host cell invasion and replication within both the mosquito vector and mammalian host. RNA binding proteins (RBPs) provide one mechanism for modulation of RNA function. To explore the role of Plasmodium RBPs during parasite replication, we searched for RBPs that might play a role during liver stage development, the parasite stage that exhibits the most extensive growth and replication. We identified a parasite ortholog of the Mei2 (Meiosis inhibited 2) RBP that is conserved among Plasmodium species (PlasMei2) and exclusively transcribed in liver stage parasites. Epitope-tagged Plasmodium yoelii PlasMei2 was expressed only during liver stage schizogony and showed an apparent granular cytoplasmic location. Knockout of PlasMei2 (plasmei2 ؊ ) in P. yoelii only affected late liver stage development. The P. yoelii plasmei2 ؊ liver stage size increased progressively until late in development, similar to wild-type parasite development. However, P. yoelii plasmei2 ؊ liver stage schizonts exhibited an abnormal DNA segregation phenotype and failed to form exoerythrocytic merozoites. Consequently the cellular integrity of P. yoelii plasmei2 ؊ liver stages became increasingly compromised late in development and the majority of P. yoelii plasmei2 ؊ underwent cell death by the time wild-type liver stages mature and release merozoites. This resulted in a complete block of P. yoelii plasmei2 Malaria is caused by unicellular eukaryotic parasites of the genus Plasmodium. The life cycles of the Plasmodium parasites that cause human disease (including the major human parasite Plasmodium falciparum) and other mammalian parasites such as rodent malaria parasites (including P. berghei and P. yoelii) are similar. The parasites progress through an elaborate life cycle, part within an anopheline mosquito vector and part within the mammalian host. Within the host, the sporozoite stage first infects hepatocytes, within which the parasite then develops as a liver stage (also known as an exoerythrocytic form), an acyclic process that occurs once during a malaria infection. Intrahepatocytic parasite development progresses in a cellular process known as schizogony, an endomitotic process characterized by an enormous increase in cell mass with concomitant DNA replication and organelle replication but without cytokinesis. It is only in the final hours of liver stage schizogony that organelles and DNA completely segregate and are apportioned into tens of thousands of rapidly differentiating exoerythrocytic invasive merozoites. These are released and initiate the infection of erythrocytes. Erythrocytic schizogony is cyclic and generates approximately 20 to 30 new merozoites in each cycle. Parasite schizogony and merozoite formation in both hepatocytes and erythrocytes likely employ shared gene regulatory networks and cell regulatory mechanisms, but it is possible that because exoerythrocytic schizogony exceeds erythrocytic schizogony by m...

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Section: Discussionmentioning

confidence: 99%

A Plasmodium yoelii Mei2-Like RNA Binding Protein Is Essential for Completion of Liver Stage Schizogony

et al. 2016

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“…To date, only a few sporozoite Ab targets have been investigated and identification of new target antigens should be a key priority in the near term (26). For example, recent work has identified a number of putative surface-exposed proteins on the sporozoite (27), posing the possibility of novel potential target antigens to block sporozoite infection via Abs. Passive immunization with Abs allows analysis of Ab efficacy without the effects of cell-mediated immunity.…”

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Model forIn VivoAssessment of Humoral Protection against Malaria Sporozoite Challenge by Passive Transfer of Monoclonal Antibodies and Immune Serum

et al. 2014

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fEvidence from clinical trials of malaria vaccine candidates suggests that both cell-mediated and humoral immunity to pre-erythrocytic parasite stages can provide protection against infection. Novel pre-erythrocytic antibody (Ab) targets could be key to improving vaccine formulations, which are currently based on targeting antigens such as the circumsporozoite protein (CSP). However, methods to assess the effects of sporozoite-specific Abs on pre-erythrocytic infection in vivo remain underdeveloped. Here, we combined passive transfer of monoclonal Abs (MAbs) or immune serum with a luciferase-expressing Plasmodium yoelii sporozoite challenge to assess Ab-mediated inhibition of liver infection in mice. Passive transfer of a P. yoelii CSP MAb showed inhibition of liver infection when mice were challenged with sporozoites either intravenously or by infectious mosquito bite. However, inhibition was most potent for the mosquito bite challenge, leading to a more significant reduction of liver-stage burden and even a lack of progression to blood-stage parasitemia. This suggests that Abs provide effective protection against a natural infection. Inhibition of liver infection was also achieved by passive transfer of immune serum from whole-parasite-immunized mice. Furthermore, we demonstrated that passive transfer of a MAb against P. falciparum CSP inhibited liver-stage infection in a humanized mouse/P. falciparum challenge model. Together, these models constitute unique and sensitive in vivo methods to assess serum-transferable protection against Plasmodium sporozoite challenge.

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“…Here, we characterized a novel sporozoite surface transmembrane protein, SSP3, which we previously identified in the putative surface proteome of P. yoelii and P. falciparum salivary gland sporozoites (15). Localization of SSP3 changes as the sporozoites develop within the mosquito.…”

Section: Discussionmentioning

confidence: 99%

“…We biotinylated surface-exposed proteins in live sporozoites, enriched the biotinylated proteins using streptavidin beads, and analyzed them by mass spectrometry (15). One of the potential surface proteins identified by this method was SSP3.…”

Section: Ssp3 Is a Predicted Type I Transmembrane Proteinmentioning

confidence: 99%

“…Using chemical labeling and mass spectrometry, we have recently identified several novel putative surface-exposed proteins in the rodent malaria parasite Plasmodium yoelii and in the human malaria parasite Plasmodium falciparum (15). One potential surface protein detected in this screen was the putative type I transmembrane protein PY01796 (also denoted S23), which was previously identified in a screen for sporozoite-specific transcripts in P. yoelii (16).…”

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SSP3 Is a Novel Plasmodium yoelii Sporozoite Surface Protein with a Role in Gliding Motility

et al. 2014

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e Plasmodium sporozoites develop within oocysts in the mosquito midgut wall and then migrate to the salivary glands. After transmission, they embark on a complex journey to the mammalian liver, where they infect hepatocytes. Proteins on the sporozoite surface likely mediate multiple steps of this journey, yet only a few sporozoite surface proteins have been described. Here, we characterize a novel, conserved sporozoite surface protein (SSP3) in the rodent malaria parasite Plasmodium yoelii. SSP3 is a putative type I transmembrane protein unique to Plasmodium. By using epitope tagging and SSP3-specific antibodies in conjunction with immunofluorescence microscopy, we showed that SSP3 is expressed in mosquito midgut oocyst sporozoites, exhibiting an intracellular localization. In sporozoites derived from the mosquito salivary glands, however, SSP3 localized predominantly to the sporozoite surface as determined by immunoelectron microscopy. However, the ectodomain of SSP3 appeared to be inaccessible to antibodies in nonpermeabilized salivary gland sporozoites. Antibody-induced shedding of the major surface protein circumsporozoite protein (CSP) exposed the SSP3 ectodomain to antibodies in some sporozoites. Targeted deletion of SSP3 adversely affected in vitro sporozoite gliding motility, which, surprisingly, impacted neither their cell traversal capacity, host cell invasion in vitro, nor infectivity in vivo. Together, these data reveal a previously unappreciated complexity of the Plasmodium sporozoite surface proteome and the roles of surface proteins in distinct biological activities of sporozoites.

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Total and Putative Surface Proteomics of Malaria Parasite Salivary Gland Sporozoites

Cited by 174 publications

References 81 publications

A Plasmodium yoelii Mei2-Like RNA Binding Protein Is Essential for Completion of Liver Stage Schizogony

A Plasmodium yoelii Mei2-Like RNA Binding Protein Is Essential for Completion of Liver Stage Schizogony

Model forIn VivoAssessment of Humoral Protection against Malaria Sporozoite Challenge by Passive Transfer of Monoclonal Antibodies and Immune Serum

SSP3 Is a Novel Plasmodium yoelii Sporozoite Surface Protein with a Role in Gliding Motility

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