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liver stage

Probing the distinct chemosensitivity of Plasmodium vivax liver stage parasites and demonstration of 8-aminoquinoline radical cure activity in vitro

October 13, 2021 - 12:50 -- Open Access
Maher SP, Vantaux A, Kyle DE, et al.
Sci Rep. 2021 Oct 7;11(1):19905

Improved control of Plasmodium vivax malaria can be achieved with the discovery of new antimalarials with radical cure efficacy, including prevention of relapse caused by hypnozoites residing in the liver of patients. We screened several compound libraries against P. vivax liver stages, including 1565 compounds against mature hypnozoites, resulting in one drug-like and several probe-like hits useful for investigating hypnozoite biology. Primaquine and tafenoquine, administered in combination with chloroquine, are currently the only FDA-approved antimalarials for radical cure, yet their activity against mature P. vivax hypnozoites has not yet been demonstrated in vitro.

NOT Open Access | Improved Liver Delivery of Primaquine by Phospholipid-Free Small Unilamellar Vesicles with Reduced Hemolytic Toxicity

September 23, 2021 - 08:51 -- NOT Open Access
Al Fayez N, Böttger R, Rouhollahi E, Cullis PR, Witzigmann D, Li SD
Mol Pharm. 2021 Sep 21

Hemolytic toxicity caused by primaquine (PQ) is a high-risk condition that hampers the wide use of PQ to treat liver-stage malaria. This study demonstrated that phospholipid-free small unilamellar vesicles (PFSUVs) composed of Tween80 and cholesterol could encapsulate and deliver PQ to the hepatocytes with reduced exposure to the red blood cells (RBCs). Nonionic surfactant (Tween80) and cholesterol-forming SUVs with a mean diameter of 50 nm were fabricated for delivering PQ. Drug release/retention, drug uptake by RBCs, pharmacokinetics, and liver uptake of PFSUVs-PQ were evaluated in in vitro and in vivo models in comparison to free drugs.

Not Open Access | Inferior T cell immunogenicity of a Plasmodium berghei model liver stage antigen expressed throughout pre-erythrocytic maturation

September 14, 2021 - 14:25 -- NOT Open Access
Gibbins MP, Müller K, Matuschewski K, Silvie O, Hafalla JCR
Parasite Immunol. 2021 Sep 13:e12877

Sporozoite antigens are the basis of a number of malaria vaccines being tested, but the contribution of antigens expressed during subsequent liver stage development to pre-erythrocytic stage immunity is poorly understood.

Flowcytometric and ImageStream RNA-FISH gene expression, quantification and phenotypic characterization of blood and liver stages from human malaria species

September 1, 2021 - 16:22 -- Open Access
Luiza-Batista C, Nardella F, Thiberge S, Serra-Hassoun M, Ferreira MU, Scherf A, Garcia S
J Infect Dis. 2021 Aug 28:jiab431

We adapted the RNA FISH stellaris® method to specifically detect the expression of Plasmodium genes by flowcytometry and ImageStream (FlowFISH). This new method accurately quantified the erythrocytic forms of P. falciparum and vivax, and the sexual stages of P. vivax from patient isolates.

Genome reconstructions of metabolism of Plasmodium RBC and liver stages

September 1, 2021 - 16:14 -- Open Access
Chiappino-Pepe A, Pandey V, Billker O
Curr Opin Microbiol. 2021 Aug 27;63:259-266

Genome scale metabolic models (GEMs) offer a powerful means of integrating genome and biochemical information on an organism to make testable predictions of metabolic functions at different conditions and to systematically predict essential genes that may be targeted by drugs.

Chemoprophylaxis vaccination with a Plasmodium liver stage autophagy mutant affords enhanced and long-lasting protection

August 17, 2021 - 14:24 -- Open Access
Sahu T, Gehrke EJ, Flores-Garcia Y, Mlambo G, Romano JD, Coppens I
NPJ Vaccines. 2021 Aug 10;6(1):98

Genetically attenuated sporozoite vaccines can elicit long-lasting protection against malaria but pose risks of breakthrough infection. Chemoprophylaxis vaccination (CVac) has proven to be the most effective vaccine strategy against malaria.

Antibody interference by a non-neutralizing antibody abrogates humoral protection against Plasmodium yoelii liver stage

August 11, 2021 - 14:59 -- Open Access
Vijayan K, Visweswaran GRR, Kaushansky A, et al.
Cell Rep. 2021 Aug 3;36(5):109489

Both subunit and attenuated whole-sporozoite vaccination strategies against Plasmodium infection have shown promising initial results in malaria-naive westerners but less efficacy in malaria-exposed individuals in endemic areas. Here, we demonstrate proof of concept by using a rodent malaria model in which non-neutralizing antibodies (nNAbs) can directly interfere with protective anti-circumsporozoite protein (CSP) humoral responses.

Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites

January 26, 2021 - 15:14 -- Open Access
Dorjsuren D, Eastman RT, Fidock DA, et al.
Sci Rep. 2021 Jan 22;11(1):2121

The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration-response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages.

Plasmodium vivax liver stage assay platforms using Indian clinical isolates

June 26, 2020 - 15:14 -- Open Access
Pradeep A. Subramani, Neha Vartak-Sharma, Varadharajan Sundaramurthy, et al.
Malaria Journal 2020 19:214, 22 June 2020

Vivax malaria is associated with significant morbidity and economic loss, and constitutes the bulk of malaria cases in large parts of Asia and South America as well as recent case reports in Africa. The widespread prevalence of vivax is a challenge to global malaria elimination programmes. Vivax malaria control is particularly challenged by existence of dormant liver stage forms that are difficult to treat and are responsible for multiple relapses, growing drug resistance to the asexual blood stages and host-genetic factors that preclude use of specific drugs like primaquine capable of targeting Plasmodium vivax liver stages. Despite an obligatory liver-stage in the Plasmodium life cycle, both the difficulty in obtaining P. vivax sporozoites and the limited availability of robust host cell models permissive to P. vivax infection are responsible for the limited knowledge of hypnozoite formation biology and relapse mechanisms, as well as the limited capability to do drug screening. Although India accounts for about half of vivax malaria cases world-wide, very little is known about the vivax liver stage forms in the context of Indian clinical isolates.

An adaptable soft-mold embossing process for fabricating optically-accessible, microfeature-based culture systems and application toward liver stage antimalarial compound testing

February 17, 2020 - 14:43 -- Open Access
Maher SP, Conway AJ, Kyle DE, et al.
Lab Chip. 2020 Feb 14

Advanced cell culture methods for modeling organ-level structure have been demonstrated to replicate in vivo conditions more accurately than traditional in vitro cell culture. Given that the liver is particularly important to human health, several advanced culture methods have been developed to experiment with liver disease states, including infection with Plasmodium parasites, the causative agent of malaria. These models have demonstrated that intrahepatic parasites require functionally stable hepatocytes to thrive and robust characterization of the parasite populations' response to investigational therapies is dependent on high-content and high-resolution imaging (HC/RI). We previously reported abiotic confinement extends the functional longevity of primary hepatocytes in a microfluidic platform and set out to instill confinement in a microtiter plate platform while maintaining optical accessibility for HC/RI; with an end-goal of producing an improved P. vivax liver stage culture model. We developed a novel fabrication process in which a PDMS soft mold embosses hepatocyte-confining microfeatures into polystyrene, resulting in microfeature-based hepatocyte confinement (μHEP) slides and plates.


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