To Migrate or to Invade: Those Are the Options

Prudêncio, Miguel; Mota, Maria M.

doi:10.1016/j.chom.2007.10.008

Cited by 7 publications

(4 citation statements)

References 10 publications

(16 reference statements)

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“…Sporozoite entry of mammalian cells has been well studied in vitro (60,61) and characterized to include both traversal of cells in which no parasitophorous vacuole is formed and infection of cells accompanied by formation of a parasitophorous vacuole (62)(63)(64)(65). However, the definitive role for the CS protein within this traversal and infection process is unclear.…”

Section: Discussionmentioning

confidence: 99%

Structure of the Plasmodium falciparum Circumsporozoite Protein, a Leading Malaria Vaccine Candidate

Plassmeyer

Reiter

Shimp

et al. 2009

Journal of Biological Chemistry

141

135

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The Plasmodium falciparum circumsporozoite protein (CSP) is critical for sporozoite function and invasion of hepatocytes. Given its critical nature, a phase III human CSP malaria vaccine trial is ongoing. The CSP is composed of three regions as follows: an N terminus that binds heparin sulfate proteoglycans, a four amino acid repeat region (NANP), and a C terminus that contains a thrombospondin-like type I repeat (TSR) domain. Despite the importance of CSP, little is known about its structure. Therefore, recombinant forms of CSP were produced by expression in both Escherichia coli (Ec) and then refolded (EcCSP) or in the methylotrophic yeast Pichia pastoris (PpCSP) for structural analyses. To analyze the TSR domain of recombinant CSP, conformation-dependent monoclonal antibodies that recognized unfixed P. falciparum sporozoites and inhibited sporozoite invasion of HepG2 cells in vitro were identified. These monoclonal antibodies recognized all recombinant CSPs, indicating the recombinant CSPs contain a properly folded TSR domain structure. Characterization of both EcCSP and PpCSP by dynamic light scattering and velocity sedimentation demonstrated that both forms of CSP appeared as highly extended proteins (R h 4.2 and 4.58 nm, respectively). Furthermore, high resolution atomic force microscopy revealed flexible, rod-like structures with a ribbon-like appearance. Using this information, we modeled the NANP repeat and TSR domain of CSP. Consistent with the biochemical and biophysical results, the repeat region formed a rod-like structure about 21-25 nm in length and 1.5 nm in width. Thus native CSP appears as a glycosylphosphatidylinositol-anchored, flexible rod-like protein on the sporozoite surface.

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Section: Discussionmentioning

confidence: 99%

Structure of the Plasmodium falciparum Circumsporozoite Protein, a Leading Malaria Vaccine Candidate

Plassmeyer

Reiter

Shimp

et al. 2009

Journal of Biological Chemistry

141

135

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“…Malaria is transmitted by the bite of an infected Anopheles mosquito, which harbors sporozoites in its salivary glands. From the point of injection into the skin, sporozoites migrate via blood vessels to the liver, cross the sinusoidal cell layer separating the blood and the liver, and finally invade hepatocytes where asexual reproduction leads to the release of thousands of merozoites into the bloodstream ( Prudêncio and Mota, 2007 ). Merozoites infect mature red blood cells and, through asexual reproduction, generate daughter merozoites to initiate a new infective cycle.…”

Section: Introductionmentioning

confidence: 99%

A Specific PfEMP1 Is Expressed in P. falciparum Sporozoites and Plays a Role in Hepatocyte Infection

et al. 2018

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SummaryHeterochromatin plays a central role in the process of immune evasion, pathogenesis, and transmission of the malaria parasite Plasmodium falciparum during blood stage infection. Here, we use ChIP sequencing to demonstrate that sporozoites from mosquito salivary glands expand heterochromatin at subtelomeric regions to silence blood-stage-specific genes. Our data also revealed that heterochromatin enrichment is predictive of the transcription status of clonally variant genes members that mediate cytoadhesion in blood stage parasites. A specific member (here called NF54varsporo) of the var gene family remains euchromatic, and the resultant PfEMP1 (NF54_SpzPfEMP1) is expressed at the sporozoite surface. NF54_SpzPfEMP1-specific antibodies efficiently block hepatocyte infection in a strain-specific manner. Furthermore, human volunteers immunized with infective sporozoites developed antibodies against NF54_SpzPfEMP1. Overall, we show that the epigenetic signature of var genes is reset in mosquito stages. Moreover, the identification of a strain-specific sporozoite PfEMP1 is highly relevant for vaccine design based on sporozoites.

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“…Following this entry into the space of Disse, sporozoites will often traverse additional hepatocytes before forming a parasitophorous vacuole (PV) during productive invasion of a final hepatocyte and converting into the extra-erythrocytic form (EEF). 26 While the PPLP1 knockout strain was able to form EEF normally in cultured hepatocytes, the number of liver EEF was drastically reduced in vivo during infection but could be restored to wild-type levels by destruction of the Kupffer cells within the sinusoids. 12 Work by Amino et al showed that the kinetics of cell entry strongly favored PV formation by PPLP1 knockout sporozoites, while wild-type controls were more likely to traverse several host cells before forming a PV during cell entry.…”

Section: Structurementioning

confidence: 99%