scholarly journals Nanobody generation and structural characterization of Plasmodium falciparum 6-cysteine protein Pf12p

2021 ◽  
Vol 478 (3) ◽  
pp. 579-595
Author(s):  
Melanie H. Dietrich ◽  
Li-Jin Chan ◽  
Amy Adair ◽  
Sravya Keremane ◽  
Phillip Pymm ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Vaccine Development ◽  
Structural Information ◽  
Family Members ◽  
Structural Features ◽  
Protein Family ◽  
Parasite Life Cycle ◽  
D2 Domain

Surface-associated proteins play critical roles in the Plasmodium parasite life cycle and are major targets for vaccine development. The 6-cysteine (6-cys) protein family is expressed in a stage-specific manner throughout Plasmodium falciparum life cycle and characterized by the presence of 6-cys domains, which are β-sandwich domains with conserved sets of disulfide bonds. Although several 6-cys family members have been implicated to play a role in sexual stages, mosquito transmission, evasion of the host immune response and host cell invasion, the precise function of many family members is still unknown and structural information is only available for four 6-cys proteins. Here, we present to the best of our knowledge, the first crystal structure of the 6-cys protein Pf12p determined at 2.8 Å resolution. The monomeric molecule folds into two domains, D1 and D2, both of which adopt the canonical 6-cys domain fold. Although the structural fold is similar to that of Pf12, its paralog in P. falciparum, we show that Pf12p does not complex with Pf41, which is a known interaction partner of Pf12. We generated 10 distinct Pf12p-specific nanobodies which map into two separate epitope groups; one group which binds within the D2 domain, while several members of the second group bind at the interface of the D1 and D2 domain of Pf12p. Characterization of the structural features of the 6-cys family and their associated nanobodies provide a framework for generating new tools to study the diverse functions of the 6-cys protein family in the Plasmodium life cycle.

scholarly journals Nanobody generation and structural characterization of Plasmodium falciparum 6-cysteine protein Pf12p

2020 ◽  
Author(s):  
Melanie H Dietrich ◽  
Li-Jin Chan ◽  
Amy Adair ◽  
Sravya Keremane ◽  
Phillip Pymm ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Vaccine Development ◽  
Structural Information ◽  
Family Members ◽  
Structural Features ◽  
Protein Family ◽  
Parasite Life Cycle ◽  
D2 Domain

Surface-associated proteins play critical roles in the Plasmodium parasite life cycle and are major targets for vaccine development. The 6-cysteine (6-cys) protein family is expressed in a stage-specific manner throughout Plasmodium falciparum life cycle and characterized by the presence of 6-cys domains, which are β-sandwich domains with conserved sets of disulfide bonds. Although several 6-cys family members have been implicated to play a role in sexual stages, mosquito transmission, evasion of the host immune response and host cell invasion, the precise function of many family members is still unknown and structural information is only available for four 6-cys proteins. Here, we present to the best of our knowledge, the first crystal structure of the 6-cys protein Pf12p determined at 2.8 Å resolution. The monomeric molecule folds into two domains, D1 and D2, both of which adopt the canonical 6-cys domain fold. Although the structural fold is similar to that of Pf12, its paralog in P. falciparum, we show that Pf12p does not complex with Pf41, which is a known interaction partner of Pf12. We generated ten distinct Pf12p-specific nanobodies which map into two separate epitope groups; one group which binds within the D2 domain, while several members of the second group bind at the interface of the D1 and D2 domain of Pf12p. Characterization of the structural features of the 6-cys family and their associated nanobodies provide a framework for generating new tools to study the diverse functions of the 6-cys protein family in the Plasmodium life cycle.

scholarly journals Malaria vaccine development.

1994 ◽  
Vol 7 (3) ◽  
pp. 303-310 ◽  
Author(s):  
T R Jones ◽  
S L Hoffman
Keyword(s):  
Life Cycle ◽  
Vaccine Development ◽  
Host Cells ◽  
Host Immune System ◽  
Parasite Life Cycle ◽  
Liver Stage ◽  
Life Cycle Stages ◽  
Promising Area ◽  
The Right

The malaria parasite life cycle presents several targets for attack, but these different parts of the life cycle are susceptible to different types of host immune response. For example, the sporozoite is most sensitive to immune antibody, while liver stage parasites can be eliminated by cytotoxic T lymphocytes. Attachment of merozoites to erythrocytes, on the other hand, can be blocked by antibody. Convincing experimental evidence shows that completely protective immunity to malaria can be induced. The challenge now is to design recombinant or synthetic vaccines that induce the right types of immune responses to specific life cycle stages. This requires the identification and characterization of B- and T-lymphocyte epitopes expressed by the parasite or by parasitized host cells. These epitopes must be incorporated into a delivery system that maximizes the interaction between the vaccine epitopes and the host immune system. Many epitopes from several parts of the life cycle are already characterized; development of multivalent vaccines, that is, vaccines which contain immunogens from more than one part of the life cycle, is a promising area for research efforts.

A transgenic Plasmodium falciparum NF54 strain that expresses GFP–luciferase throughout the parasite life cycle

2012 ◽  
Vol 186 (2) ◽  
pp. 143-147 ◽  
Author(s):  
Ashley M. Vaughan ◽  
Sebastian A. Mikolajczak ◽  
Nelly Camargo ◽  
Viswanathan Lakshmanan ◽  
Mark Kennedy ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Parasite Life Cycle

scholarly journals Trypanosoma cruzi: Molecular characterization of an RNA binding protein differentially expressed in the parasite life cycle

2007 ◽  
Vol 117 (1) ◽  
pp. 99-105 ◽  
Author(s):  
Leticia Pérez-Díaz ◽  
María Ana Duhagon ◽  
Pablo Smircich ◽  
José Sotelo-Silveira ◽  
Carlos Robello ◽  
...  
Keyword(s):  
Life Cycle ◽  
Trypanosoma Cruzi ◽  
Molecular Characterization ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Differentially Expressed ◽  
Parasite Life Cycle

scholarly journals A Multidomain Adhesion Protein Family Expressed in Plasmodium falciparum Is Essential for Transmission to the Mosquito

2004 ◽  
Vol 199 (11) ◽  
pp. 1533-1544 ◽  
Author(s):  
Gabriele Pradel ◽  
Karen Hayton ◽  
L. Aravind ◽  
Lakshminarayan M. Iyer ◽  
Mitchell S. Abrahamsen ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Genome Sequence ◽  
Cellular Localization ◽  
Coagulation Factor ◽  
Protein Family ◽  
Sexual Stage ◽  
Parasite Life Cycle ◽  
Specific Expression ◽  
Factor C ◽  
Adhesive Proteins

The recent sequencing of several apicomplexan genomes has provided the opportunity to characterize novel antigens essential for the parasite life cycle that might lead to the development of new diagnostic and therapeutic markers. Here we have screened the Plasmodium falciparum genome sequence for genes encoding extracellular multidomain putative adhesive proteins. Three of these identified genes, named PfCCp1, PfCCp2, and PfCCp3, have multiple adhesive modules including a common Limulus coagulation factor C domain also found in two additional Plasmodium genes. Orthologues were identified in the Cryptosporidium parvum genome sequence, indicating an evolutionary conserved function. Transcript and protein expression analysis shows sexual stage–specific expression of PfCCp1, PfCCp2, and PfCCp3, and cellular localization studies revealed plasma membrane–associated expression in mature gametocytes. During gametogenesis, PfCCps are released and localize surrounding complexes of newly emerged microgametes and macrogametes. PfCCp expression markedly decreased after formation of zygotes. To begin to address PfCCp function, the PfCCp2 and PfCCp3 gene loci were disrupted by homologous recombination, resulting in parasites capable of forming oocyst sporozoites but blocked in the salivary gland transition. Our results describe members of a conserved apicomplexan protein family expressed in sexual stage Plasmodium parasites that may represent candidates for subunits of a transmission-blocking vaccine.

PHIST c protein family members localize to different subcellular organelles and bind Plasmodium falciparum major virulence factor Pf EMP ‐1

FEBS Journal ◽  
2017 ◽  
Vol 285 (2) ◽  
pp. 294-312 ◽  
Author(s):  
Vikash Kumar ◽  
Jasweer Kaur ◽  
Amrit P. Singh ◽  
Vineeta Singh ◽  
Anjali Bisht ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Virulence Factor ◽  
Family Members ◽  
Protein Family ◽  
C Protein ◽  
Subcellular Organelles ◽  
Major Virulence Factor

scholarly journals Growth Rate of Plasmodium falciparum: Analysis of Parasite Growth Data from Malaria Volunteer Infection Studies

2019 ◽  
Author(s):  
Leesa F Wockner ◽  
Isabell Hoffmann ◽  
Lachlan Webb ◽  
Benjamin Mordmüller ◽  
Sean C Murphy ◽  
...  
Keyword(s):  
Growth Rate ◽  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Sine Wave ◽  
Parasite Growth ◽  
Cycle Duration ◽  
Multiplication Rate ◽  
Growth Data ◽  
Parasite Life Cycle ◽  
Log Linear

Abstract Background Growth rate of malaria parasites in the blood of infected subjects is an important measure of efficacy of drugs and vaccines. Methods We used log-linear and sine-wave models to estimate the parasite growth rate of the 3D7 strain of Plasmodium falciparum using data from 177 subjects from 14 induced blood stage malaria (IBSM) studies conducted at QIMR Berghofer. We estimated parasite multiplication rate per 48 hour (PMR48), PMR per life-cycle (PMRLC), and parasite life-cycle duration. We compared these parameters to those from studies conducted elsewhere with infections induced by IBSM (n=66), sporozoites via mosquito bite (n=336) or injection (n=51). Results The parasite growth rate of 3D7 in QIMR Berghofer studies was 0.75/day (95% CI: 0.73–0.77/day), PMR48 was 31.9 (95% CI: 28.7–35.4), PMRLC was 16.4 (95% CI: 15.1–17.8) and parasite life-cycle was 38.8 hour (95% CI: 38.3–39.2 hour). These parameters were similar to estimates from IBSM studies elsewhere (0.71/day, 95% CI: 0.67–0.75/day; PMR48 26.6, 95% CI: 22.2–31.8), but significantly higher (P < 0.001) than in sporozoite studies (0.47/day, 95% CI: 0.43–0.50/day; PMR48 8.6, 95% CI: 7.3–10.1). Conclusion Parasite growth rates were similar across different IBSM studies and higher than infections induced by sporozoite.

scholarly journals Pleiotropic roles of cold shock proteins with special emphasis on unexplored cold shock protein member of Plasmodium falciparum

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Ankita Behl ◽  
Vikash Kumar ◽  
Maxim Shevtsov ◽  
Shailja Singh
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Cold Shock ◽  
Gene Expression Regulation ◽  
Protein Family ◽  
Cold Shock Protein ◽  
Parasite Life Cycle ◽  
Cold Shock Proteins ◽  
Shock Proteins

Abstract The cold shock domain (CSD) forms the hallmark of the cold shock protein family that provides the characteristic feature of binding with nucleic acids. While much of the information is available on bacterial, plants and human cold shock proteins, their existence and functions in the malaria parasite remains undefined. In the present review, the available information on functions of well-characterized cold shock protein members in different organisms has been collected and an attempt was made to identify the presence and role of cold shock proteins in malaria parasite. A single Plasmodium falciparum cold shock protein (PfCoSP) was found in P. falciparum which is reported to be essential for parasite survival. Essentiality of PfCoSP underscores its importance in malaria parasite life cycle. In silico tools were used to predict the features of PfCoSP and to identify its homologues in bacteria, plants, humans, and other Plasmodium species. Modelled structures of PfCoSP and its homologues in Plasmodium species were compared with human cold shock protein ‘YBOX-1’ (Y-box binding protein 1) that provide important insights into their functioning. PfCoSP model was subjected to docking with B-form DNA and RNA to reveal a number of residues crucial for their interaction. Transcriptome analysis and motifs identified in PfCoSP implicate its role in controlling gene expression at gametocyte, ookinete and asexual blood stages of malaria parasite. Overall, this review emphasizes the functional diversity of the cold shock protein family by discussing their known roles in gene expression regulation, cold acclimation, developmental processes like flowering transition, and flower and seed development, and probable function in gametocytogenesis in case of malaria parasite. This enables readers to view the cold shock protein family comprehensively.

scholarly journals Functional analysis of Plasmodium falciparum merozoite antigens: implications for erythrocyte invasion and vaccine development

2002 ◽  
Vol 357 (1417) ◽  
pp. 25-33 ◽  
Author(s):  
Alan F. Cowman ◽  
Deborah L. Baldi ◽  
Manoj Duraisingh ◽  
Julie Healer ◽  
Kerry E. Mills ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Vaccine Development ◽  
Loss Of Function ◽  
Parasite Life Cycle ◽  
Erythrocyte Invasion ◽  
New Information ◽  
Falciparum Merozoite ◽  
Merozoite Antigens ◽  
New Strategies

Malaria is a major human health problem and is responsible for over 2 million deaths per year. It is caused by a number of species of the genus Plasmodium , and Plasmodium falciparum is the causative agent of the most lethal form. Consequently, the development of a vaccine against this parasite is a priority. There are a number of stages of the parasite life cycle that are being targeted for the development of vaccines. Important candidate antigens include proteins on the surface of the asexual merozoite stage, the form that invades the host erythrocyte. The development of methods to manipulate the genome of Plasmodium species has enabled the construction of gain–of–function and loss–of–function mutants and provided new strategies to analyse the role of parasite proteins. This has provided new information on the role of merozoite antigens in erythrocyte invasion and also allows new approaches to address their potential as vaccine candidates.

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