Dataset Information

The repeat region of the circumsporozoite protein is critical for sporozoite formation and maturation in Plasmodium.

ABSTRACT: The circumsporozoite protein (CSP) is the major surface protein of the sporozoite stage of malaria parasites and has multiple functions as the parasite develops and then migrates from the mosquito midgut to the mammalian liver. The overall structure of CSP is conserved among Plasmodium species, consisting of a species-specific central tandem repeat region flanked by two conserved domains: the NH2-terminus and the thrombospondin repeat (TSR) at the COOH-terminus. Although the central repeat region is an immunodominant B-cell epitope and the basis of the only candidate malaria vaccine in Phase III clinical trials, little is known about its functional role(s). We used the rodent malaria model Plasmodium berghei to investigate the role of the CSP tandem repeat region during sporozoite development. Here we describe two mutant parasite lines, one lacking the tandem repeat region (?Rep) and the other lacking the NH2-terminus as well as the repeat region (?N?Rep). We show that in both mutant lines oocyst formation is unaffected but sporozoite development is defective.

SUBMITTER: Ferguson DJ

PROVIDER: S-EPMC4250072 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The repeat region of the circumsporozoite protein is critical for sporozoite formation and maturation in Plasmodium.

Ferguson David J P DJ Balaban Amanda E AE Patzewitz Eva-Maria EM Wall Richard J RJ Hopp Christine S CS Poulin Benoit B Mohmmed Asif A Malhotra Pawan P Coppi Alida A Sinnis Photini P Tewari Rita R

PloS one 20141201 12

The circumsporozoite protein (CSP) is the major surface protein of the sporozoite stage of malaria parasites and has multiple functions as the parasite develops and then migrates from the mosquito midgut to the mammalian liver. The overall structure of CSP is conserved among Plasmodium species, consisting of a species-specific central tandem repeat region flanked by two conserved domains: the NH2-terminus and the thrombospondin repeat (TSR) at the COOH-terminus. Although the central repeat regio ...[more]

PMID: 25438048

Similar Datasets

Project description:Malaria-causing Plasmodium parasites have a complex life cycle and present numerous antigen targets that may contribute to protective immune responses. The currently recommended vaccine-RTS,S-functions by targeting the Plasmodium falciparum circumsporozoite protein (CSP), which is the most abundant surface protein of the sporozoite form responsible for initiating infection of the human host. Despite showing only moderate efficacy, RTS,S has established a strong foundation for the development of next-generation subunit vaccines. Our previous work characterizing the sporozoite surface proteome identified additional non-CSP antigens that may be useful as immunogens individually or in combination with CSP. In this study, we examined eight such antigens using the rodent malaria parasite Plasmodium yoelii as a model system. We demonstrate that despite conferring weak protection individually, coimmunizing each of several of these antigens alongside CSP could significantly enhance the sterile protection achieved by CSP immunization alone. Thus, our work provides compelling evidence that a multiantigen preerythrocytic vaccine approach may enhance protection compared to CSP-only vaccines. This lays the groundwork for further studies aimed at testing the identified antigen combinations in human vaccination trials that assess efficacy with controlled human malaria infection. IMPORTANCE The currently approved malaria vaccine targets a single parasite protein (CSP) and results in only partial protection. We tested several additional vaccine targets in combination with CSP to identify those that could enhance protection from infection upon challenge in the mouse malaria model. In identifying several such enhancing vaccine targets, our work indicates that a multiprotein immunization approach may be a promising avenue to achieving higher levels of protection from infection. Our work identified several candidate leads for follow-up in the models relevant for human malaria and provides an experimental framework for efficiently carrying out such screens for other combinations of vaccine targets.

Project description:BackgroundThe malaria vaccine candidate RTS,S/AS01 (GSK Vaccines) induces high IgG concentration against the circumsporozoite protein (CSP) of Plasmodium falciparum. In human vaccine recipients circulating anti-CSP antibody concentrations are associated with protection against infection but appear not to be the correlate of protection. However, in a humanized mouse model of malaria infection prophylactic administration of a human monoclonal antibody (MAL1C), derived from a RTS,S/AS01-immunized volunteer, directed against the CSP repeat region, conveyed full protection in a dose-dependent manner suggesting that antibodies alone are able to prevent P. falciparum infection when present in sufficiently high concentrations. A competition ELISA was developed to measure the presence of MAL1C-like antibodies in polyclonal sera from RTS,S/AS01 vaccine recipients and study their possible contribution to protection against infection.ResultsMAL1C-like antibodies present in polyclonal vaccine-induced sera were evaluated for their ability to compete with biotinylated monoclonal antibody MAL1C for binding sites on the capture antigen consisting of the recombinant protein encompassing 32 NANP repeats of CSP (R32LR). Serum samples were taken at different time points from participants in two RTS,S/AS01 vaccine studies (NCT01366534 and NCT01857869). Vaccine-induced protection status of the study participants was determined based on the outcome of experimental challenge with infected mosquito bites after vaccination. Optimal conditions were established to reliably detect MAL1C-like antibodies in polyclonal sera. Polyclonal anti-CSP antibodies and MAL1C-like antibody content were measured in 276 serum samples from RTS,S/AS01 vaccine recipients using the standard ELISA and MAL-1C competition ELISA, respectively. A strong correlation was observed between the results from these assays. However, no correlation was found between the results of either assay and protection against infection.ConclusionsThe competition ELISA to measure MAL1C-like antibodies in polyclonal sera from RTS,S/AS01 vaccine recipients was robust and reliable but did not reveal the elusive correlate of protection.

Dataset Information

The repeat region of the circumsporozoite protein is critical for sporozoite formation and maturation in Plasmodium.

Publications

The repeat region of the circumsporozoite protein is critical for sporozoite formation and maturation in Plasmodium.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets