scholarly journals A Plasmodium Actin-depolymerizing Factor That Binds Exclusively to Actin Monomers

2005 ◽  
Vol 16 (9) ◽  
pp. 4013-4023 ◽  
Author(s):  
Herwig Schüler ◽  
Ann-Kristin Mueller ◽  
Kai Matuschewski
Keyword(s):  
Plasmodium Falciparum ◽  
Reverse Genetics ◽  
Biochemical Properties ◽  
Model System ◽  
Actin Binding ◽  
Nucleotide Exchange ◽  
Rodent Malaria ◽  
Vital Functions ◽  
Binding Residues ◽  
Malaria Model

ADF/cofilins (AC) are essential F- and G-actin binding proteins that modulate microfilament turnover. The genome of Plasmodium falciparum, the parasite causing malaria, contains two members of the AC family. Interestingly, P. falciparum ADF1 lacks the F-actin binding residues of the AC consensus. Reverse genetics in the rodent malaria model system suggest that ADF1 performs vital functions during the pathogenic red blood cell stages, whereas ADF2 is not present in these stages. We show that recombinant PfADF1 interacts with monomeric actin but does not bind to actin polymers. Although other AC proteins inhibit nucleotide exchange on monomeric actin, the Plasmodium ortholog stimulates nucleotide exchange. Thus, PfADF1 differs in its biochemical properties from previously known AC proteins and seems to promote turnover exclusively by interaction with actin monomers. These findings provide important insights into the low cytosolic abundance and unique turnover characteristics of actin polymers in parasites of the phylum Apicomplexa.

scholarly journals Mapping of safe and early chemo-attenuated live Plasmodium falciparum immunization identifies immune signature of vaccine efficacy

2020 ◽  
Author(s):  
Steffen Borrmann ◽  
Zita Sulyok ◽  
Katja Müller ◽  
Mihaly Sulyok ◽  
Rolf Fendel ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Single Dose ◽  
Vaccine Efficacy ◽  
Human Subjects ◽  
Vaccine Dose ◽  
Effector Memory ◽  
Liver Stage ◽  
Rodent Malaria ◽  
Immune Signatures ◽  
Malaria Model

AbstractPotent protection against malaria can be induced by attenuated live-immunization with Plasmodium falciparum (Pf) sporozoites (SPZ). However, a better understanding of the critical processes involved in the establishment of protective immunity is needed. We explored the safety and vaccine efficacy of early chemo-attenuation of PfSPZ under atovaquone-proguanil (AP). AP caused early arrest of P. berghei liver stages. Despite the absence of replication, robust protection in mice correlated with parasite-specific effector-memory CD8+ T-cell responses. In a phase I clinical trial a single dose of AP prevented Pf infections in the liver of adult, human subjects who received three doses of 5.12×104 or 1.5×105 PfSPZ by direct venous inoculation combined with oral AP. However, only 2 of 8 (25%) and 2 of 10 (20%), respectively, were protected against controlled human malaria infection (CHMI) 10 weeks after the last vaccine dose, despite levels of IgG antibodies to the Pf circumsporozoite protein (PfCSP) comparable to those achieved in fully protected volunteers after immunization with 5.12×104 PfSPZ with chloroquine chemoprophylaxis active only against subsequent blood stages. We identify lower IgG recognition of the secreted liver stage-specific antigens LISP2 and LSA1 and the multi-stage antigen MSP5 as immune signatures of inferior vaccine efficacy compared to PfSPZ with chloroquine chemoprophylaxis. In conclusion, we show that immune signatures of liver stage antigens, but neither an established rodent malaria model nor concentrations of antibodies against the major surface protein of sporozoites, permit prediction of vaccine efficacy. Thus, this study provides a clear rationale for the development of live sporozoite vaccination protocols that boost exposure to Pf liver stage antigens.Significance StatementOur research demonstrates that attenuation of liver infection of high doses of Plasmodium falciparum sporozoites by concomitant single-dose administration of atovaquone-proguanil is safe in humans. However, vaccine efficacy was modest when compared to an identical protocol using chloroquine that acts only on the subsequent blood infection. Immune signatures of secreted P. falciparum liver stage antigens, but neither an established rodent malaria model nor concentrations of sporozoite antibodies, permit prediction of vaccine efficacy.

scholarly journals In vitro synergistic effect of fluoroquinolone analogues in combination with artemisinin against Plasmodium falciparum; their antiplasmodial action in rodent malaria model

2015 ◽  
Vol 14 (1) ◽  
pp. 48 ◽  
Author(s):  
Drishti Agarwal ◽  
Manish Sharma ◽  
Sandeep K Dixit ◽  
Roshan K Dutta ◽  
Ashok K Singh ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Synergistic Effect ◽  
Rodent Malaria ◽  
Malaria Model

scholarly journals Profilin Binding to Poly-l-Proline and Actin Monomers along with Ability to Catalyze Actin Nucleotide Exchange Is Required for Viability of Fission Yeast

2001 ◽  
Vol 12 (4) ◽  
pp. 1161-1175 ◽  
Author(s):  
Jia Lu ◽  
Thomas D. Pollard
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Fission Yeast ◽  
Point Mutations ◽  
Biochemical Properties ◽  
Actin Binding ◽  
Temperature Sensitive ◽  
Nucleotide Exchange ◽  
Wild Type ◽  
Lower Affinity ◽  
Essential Function

We tested the ability of 87 profilin point mutations to complement temperature-sensitive and null mutations of the single profilin gene of the fission yeast Schizosaccharomyces pombe. We compared the biochemical properties of 13 stable noncomplementing profilins with an equal number of complementing profilin mutants. A large quantitative database revealed the following: 1) in a profilin null background fission yeast grow normally with profilin mutations having >10% of wild-type affinity for actin or poly-l-proline, but lower affinity for either ligand is incompatible with life; 2) in thecdc3-124 profilin ts background, fission yeast function with profilin having only 2–5% wild-type affinity for actin or poly-l-proline; and 3) special mutations show that the ability of profilin to catalyze nucleotide exchange by actin is an essential function. Thus, poly-l-proline binding, actin binding, and actin nucleotide exchange are each independent requirements for profilin function in fission yeast.

Isolation and characterization of protective cytolytic T cells in a rodent malaria model system

1990 ◽  
Vol 25 (1-3) ◽  
pp. 27-31 ◽  
Author(s):  
Pedro Romero ◽  
Janet L. Maryanski ◽  
Anne-Sophie Cordey ◽  
Giampietro Corradin ◽  
Ruth S. Nussenzweig ◽  
...  
Keyword(s):  
T Cells ◽  
Model System ◽  
Rodent Malaria ◽  
Isolation And Characterization ◽  
Malaria Model

Myosin I

1997 ◽  
Vol 273 (2) ◽  
pp. C347-C359 ◽  
Author(s):  
L. M. Coluccio
Keyword(s):  
Phosphorylation Site ◽  
Mass Range ◽  
Biochemical Properties ◽  
Actin Binding ◽  
Sequence Analyses ◽  
Heavy Chains ◽  
Amino Terminal ◽  
Lower Eukaryotes ◽  
Myosin I ◽  
Present Understanding

The class I myosins are single-headed, actin-binding, mechanochemical “motor” proteins with heavy chains in the molecular mass range of 110-130 kDa; they do not form filaments. Each myosin I heavy chain is associated with one to six light chains that bind to specific motifs known as IQ domains. In vertebrate myosin I isoforms, the light chain is calmodulin, which is thought to regulate motor activity. Proteins similar to calmodulin are associated with myosin I isoforms from lower eukaryotes. Some myosin I isoforms from lower eukaryotes are regulated by phosphorylation; however, the phosphorylation site is not present in vertebrate myosin I isoforms. Based on sequence analyses of the amino terminal “head” domains, myosin I can be subdivided into several subclasses. Analyses of the biochemical properties of the isolated molecules and localization studies support the proposal of roles for these molecules in intracellular trafficking and changes in membrane structure. Our present understanding of the properties of these molecules and their proposed roles is reviewed here.

scholarly journals In Vivo Efficacy and Pharmacokinetics of the 2-Aminomethylphenol Antimalarial JPC-3210 in the Aotus Monkey-Human Malaria Model

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Fiona J. McCallum ◽  
Geoffrey W. Birrell ◽  
Marina Chavchich ◽  
Ivor Harris ◽  
Nicanor Obaldia ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Oral Dose ◽  
In Vivo Efficacy ◽  
Content Type ◽  
Treatment And Prevention ◽  
Elimination Half ◽  
Long Acting ◽  
Further Development ◽  
Malaria Model

ABSTRACT Nonimmune Aotus monkeys infected with Plasmodium falciparum and Plasmodium vivax were cured of their infections when treated with a single oral dose of 5 mg/kg and 10 mg/kg of the 2-aminomethylphenol, JPC-3210, respectively. Corresponding mean blood elimination half-lives of JPC-3210 were lengthy at 19.1 days and 20.5 days, respectively. This in vivo potency and lengthy half-life supports the further development of JPC-3210 as a promising, long-acting blood schizontocidal antimalarial for malaria treatment and prevention.

scholarly journals Malaria Parasites Can Develop Stable Resistance to Artemisinin but Lack Mutations in Candidate Genes atp6 (Encoding the Sarcoplasmic and Endoplasmic Reticulum Ca2+ ATPase), tctp, mdr1, and cg10

2006 ◽  
Vol 50 (2) ◽  
pp. 480-489 ◽  
Author(s):  
A. Afonso ◽  
P. Hunt ◽  
S. Cheesman ◽  
A. C. Alves ◽  
C. V. Cunha ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasmodium Falciparum ◽  
Copy Number ◽  
Malaria Parasite ◽  
Field Studies ◽  
Rodent Malaria Parasite ◽  
Malaria Parasites ◽  
Rodent Malaria ◽  
First Time ◽  
Genetic Modulators

ABSTRACT Resistance of Plasmodium falciparum to drugs such as chloroquine and sulfadoxine-pyrimethamine is a major problem in malaria control. Artemisinin (ART) derivatives, particularly in combination with other drugs, are thus increasingly used to treat malaria, reducing the probability that parasites resistant to the components will emerge. Although stable resistance to artemisinin has yet to be reported from laboratory or field studies, its emergence would be disastrous because of the lack of alternative treatments. Here, we report for the first time, to our knowledge, genetically stable and transmissible ART and artesunate (ATN)-resistant malaria parasites. Each of two lines of the rodent malaria parasite Plosmodium chabaudi chabaudi, grown in the presence of increasing concentrations of ART or ATN, showed 15-fold and 6-fold increased resistance to ART and ATN, respectively. Resistance remained stable after cloning, freeze-thawing, after passage in the absence of drug, and transmission through mosquitoes. The nucleotide sequences of the possible genetic modulators of ART resistance (mdr1, cg10, tctp, and atp6) of sensitive and resistant parasites were compared. No mutations in these genes were identified. In addition we investigated whether changes in the copy number of these genes could account for resistance but found that resistant parasites retained the same number of copies as their sensitive progenitors. We believe that this is the first report of a malaria parasite with genetically stable and transmissible resistance to artemisinin or its derivatives.

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