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NOT Open Access | A Plasmodium homolog of ER tubule-forming proteins is required for parasite virulence

May 21, 2020 - 06:48 -- NOT Open Access
Shi X, Hai L, Govindasamy K, Gao J, Coppens I, Hu J, Wang Q, Bhanot P
Mol Microbiol. 2020 May 20

Reticulon and REEP family of proteins stabilize the high curvature of endoplasmic reticulum (ER) tubules. P. berghei  Yop1 (Pb Yop1) is a REEP5 homolog in Plasmodium . Here we characterize its function using a gene‐knockout (Pb yop1∆). Pb yop1∆ asexual stage parasites display abnormal ER architecture and an enlarged digestive vacuole. The erythrocytic cycle of Pb yop1∆ parasites is severely attenuated and the incidence of experimental cerebral malaria is significantly decreased in Pb yop1∆‐infected mice.

Not Open Access | A protein palmitoylation cascade regulates microtubule cytoskeleton integrity in Plasmodium

May 13, 2020 - 14:51 -- NOT Open Access
Wang X, Qian P, Cui H, Yao L, Yuan J
EMBO J. 2020 May 12:e104168

Morphogenesis of many protozoans depends on a polarized establishment of cytoskeletal structures. In malaria‐causing parasites, this can be observed when a round zygote develops into an elongated motile ookinete within the mosquito stomach. This morphogenesis is mediated by the pellicle cytoskeletal structures, including the inner membrane complex (IMC) and the underlying subpellicular microtubules (SPMs).

NOT Open Access | Activation mechanism of plasmepsins, pepsin-like aspartic proteases from Plasmodium, follows a unique trans-activation pathway

May 13, 2020 - 13:54 -- NOT Open Access
Rathore I, Mishra V, Patel C, Xiao H, Gustchina A, Wlodawer A, Yada RY, Bhaumik P
FEBS J. 2020 May 9

Plasmodium parasites that cause malaria produce plasmepsins (PMs), pepsin‐like aspartic proteases that are important antimalarial drug targets due to their role in host hemoglobin degradation. The enzymes are synthesized as inactive zymogens (pro‐PMs) and the mechanism of their conversion to the active, mature forms has not been clearly elucidated. Our structural investigations of vacuolar pro‐PMs with truncated prosegment (pro‐tPMs) reveal that the formation of the S‐shaped dimer is their innate property. Further structural studies, biochemical analysis, and molecular dynamics simulations indicate that disruption of the Tyr‐Asp loop (121p‐4), coordinated with the movement of the loop L1 (237‐247) and helix H2 (101p‐113p) are responsible for the extension of the pro‐mature region (harboring the cleavage site).

NOT Open Access | Endocytosis in Plasmodium and Toxoplasma Parasites

April 29, 2020 - 09:02 -- NOT Open Access
Spielmann T, Gras S, Sabitzki R, Meissner M
Trends Parasitol. 2020 Apr 24. pii: S1471-4922(20)30075-1

Endocytosis is critical for many functions in eukaryotic cells. Uptake of host cell cytosol, an indispensable endocytic process in malaria blood-stage parasites, has been known for a long time. However, it is only recently that the proteins involved in this process have started to emerge.

NOT Open Access | Morphological and molecular characterization of Plasmodium cathemerium (lineage PADOM02) from the sparrow Passer domesticus with complete sporogony in Culex pipiens complex

April 29, 2020 - 05:32 -- NOT Open Access
Aly MZY, Mohamed III, Sebak SI, Vanstreels RET, El Gendy AM
Parasitology. 2020 Apr 27:1-9

Avian malaria is a mosquito-borne disease caused by Plasmodium spp. protozoa. Although these parasites have been extensively studied in North America and Eurasia, knowledge on the diversity of Plasmodium, its vectors and avian hosts in Africa is scarce. In this study, we report on natural malarial infections in free-ranging sparrows (Passer domesticus) sampled at Giza Governorate, Egypt. Parasites were morphologically characterized as Plasmodium cathemerium based on the examination of thin blood smears from the avian host.

Exploring the Mechanisms of Multiple Insecticide Resistance in a Highly Plasmodium-Infected Malaria Vector Anopheles funestus Sensu Stricto from Sahel of Northern Nigeria

April 27, 2020 - 13:20 -- Open Access
Ibrahim SS, Mukhtar MM, Irving H, Riveron JM, Fadel AN, Tchapga W, Hearn J, Muhammad A, Sarkinfada F, Wondji CS
Genes (Basel). 2020 Apr 22;11(4). pii: E454

The Nigerian Government is scaling up the distribution of insecticide-treated bed nets for malaria control, but the lack of surveillance data, especially in the Sudan/Sahel region of the country, may hinder targeting priority populations. Here, the vectorial role and insecticide resistance profile of a population of a major malaria vector Anopheles funestus sensu stricto from Sahel of Nigeria was characterised.

Broad spectrum immunomodulatory effects of Anopheles gambiae microRNAs and their use for transgenic suppression of Plasmodium

April 27, 2020 - 13:18 -- Open Access
Dong S, Fu X, Dong Y, Simões ML, Zhu J, Dimopoulos G
PLoS Pathog 16(4): e1008453

Malaria, caused by the protozoan parasite Plasmodium and transmitted by Anopheles mosquitoes, represents a major threat to human health. Plasmodium’s infection cycle in the Anopheles vector is critical for transmission of the parasite between humans. The midgut-stage bottleneck of infection is largely imposed by the mosquito’s innate immune system. microRNAs (miRNAs, small noncoding RNAs that bind to target RNAs to regulate gene expression) are also involved in regulating immunity and the anti-Plasmodium defense in mosquitoes.

NOT Open Access | Detection of Protein Aggregation in Live Plasmodium Parasites

April 15, 2020 - 14:14 -- NOT Open Access
Biosca A, Bouzón-Arnáiz I, Spanos L, Siden-Kiamos I, Iglesias V, Ventura S, Fernàndez-Busquets X
Antimicrob Agents Chemother. 2020 Apr 13. pii: AAC.02135-19

The rapid evolution of resistance in the malaria parasite to every single drug developed against it calls for the urgent identification of new molecular targets. Using a stain specific for the detection of intracellular amyloid deposits in live cells we have detected the presence of abundant protein aggregates in Plasmodium falciparum blood stages and female gametes cultured in vitro, in the blood stages of mice infected by Plasmodium yoelii, and in the mosquito stages of the murine malaria species Plasmodium berghei.

A phase 1, placebo controlled, randomised, single ascending dose study and a volunteer infection study to characterize the safety, pharmacokinetics and antimalarial activity of the Plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048

April 6, 2020 - 15:38 -- Open Access
McCarthy JS, Donini C, Möhrle JJ, et al.
Clin Infect Dis. 2020 Apr 2. pii: ciaa368

MMV390048 is the first Plasmodium phosphatidylinositol 4-kinase inhibitor to reach clinical development as a new antimalarial. We aimed to characterize the safety, pharmacokinetics and antimalarial activity of a tablet formulation of MMV390048.

Safety, Tolerability, Pharmacokinetics, and Antimalarial Activity of the Novel Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048 in Healthy Volunteers

March 30, 2020 - 10:47 -- Open Access
Sinxadi P, Donini C, Johnstone H, Langdon G, Wiesner L, Allen E, Duparc S, Chalon S, McCarthy JS, Lorch U, Chibale K, Möhrle J, Barnes KI
Antimicrob Agents Chemother. 2020 Mar 24;64(4). pii: e01896-19

MMV390048 is a novel antimalarial compound that inhibits Plasmodium phosphatidylinositol-4-kinase. The safety, tolerability, pharmacokinetic profile, and antimalarial activity of MMV390048 were determined in healthy volunteers in three separate studies. A first-in-human, double-blind, randomized, placebo-controlled, single-ascending-dose study was performed. Additionally, a volunteer infection study investigated the antimalarial activity of MMV390048 using the Plasmodium falciparum induced blood-stage malaria (IBSM) model.


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