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Category: publications

The inner membrane complex protein, IMC55, is dispensable for intraerythrocytic development of Plasmodium falciparum

  Plasmodium falciparum, an obligate intracellular Apicomplexan parasite and the causative agent of malaria, must reside and replicate within a host cell during the intraerythrocytic stage. At the end of its replicative cycle, the parasite breaks down two biological membranes using a proteolytic cascade to release invasive daughter cells known as merozoites to continue its asexual …

Structure-Guided Optimization of Novel Inhibitors of Plasmodium Lysyl-tRNA Synthetase with Multistage Activity against Malaria Parasites

A fused dihydropyrrolidino-pyrimidine hit with low lipophilicity and excellent ligand efficiency was identified in a biochemical screen of the Global Health Chemical Diversity Library (GHCDL) against Plasmodium lysyl-tRNA synthetase (KRS). Structure-guided lead optimization delivered analogues with potent parasite growth inhibition, excellent biochemical and cellular selectivity (>1000-fold), and oral efficacy in the malaria NOD-scid-IL2Rγnull (SCID) mouse model. Structural …

A dual-aptazyme system for genetic complementation reveals stage-specific roles for the Trypanosoma cruzi cytoskeleton-associated protein 5.5

  Parasitic trypanosomatids, such as Trypanosoma cruzi, Trypanosoma brucei, and Leishmania spp., cause devastating tropical diseases, with T. cruzi being increasingly recognized as a public health concern in the United States due to established sylvatic cycles and rising autochthonous transmission. Although T. brucei has long served as the model trypanosomatid due to the array of molecular tools available for its study, T. cruzi shares …

First continuous in vitro culture of Plasmodium coatneyi reveals insights into barriers to human infection

Plasmodium coatneyi is an important model for severe malaria due to its P. falciparum-like sequestration, yet research has been limited by the lack of in vitro culture systems. Recently, molecular evidence of human P. coatneyi infections (3.5%, 3/85 of identified simian malarias in Malaysian archival samples), suggested a zoonotic potential. We report the first continuous …

Legacy 4(1 H)-Quinolone Scaffolds Activity against Acute and Chronic Toxoplasma gondii Infection

Toxoplasma gondii is a protozoan parasite capable of infecting most warm-blooded animals, including humans, and can cause severe disease in immunocompromised individuals and the developing fetus. Current treatments for toxoplasmosis are effective only against the acute stage of infection and have limited or no activity against the latent bradyzoite stage found within tissue cysts. The mitochondrion …

Infants under 24 months with severe malaria have a serological profile of active infection with Epstein Barr Virus

Background: Primary Epstein Barr Virus (EBV) infection occurs during late adolescence and is characterized by the symptomatic manifestation of infectious mononucleosis (IM). Primary EBV infection in malaria-endemic areas often occurs in young children by the age of 2 and is generally asymptomatic. Primary EBV infection in children of this age results in humoral immune suppression to …

Composition and role of the vacuolar transporter chaperone complex in polyphosphate synthesis and infectivity in Trypanosoma cruzi

  Inorganic polyphosphate (polyP) is a linear polymer composed of three to several hundred orthophosphate units linked by high-energy phosphoanhydride bonds and is found in both prokaryotes and eukaryotes. In Trypanosoma cruzi, the causative agent of Chagas disease, polyP plays important roles in osmoregulation and persistence within host tissues and is synthesized by a polyP polymerase …

A protein disulfide isomerase coordinates redox homeostasis and ER calcium regulation for optimal lytic cycle progression in Toxoplasma gondii

  The endoplasmic reticulum (ER) maintains an oxidative environment that facilitates the formation of disulfide bonds, a critical process for proper protein folding. Protein disulfide isomerases (PDIs) are ER-resident enzymes that facilitate the formation, breakage, and rearrangement of disulfide bonds between cysteine residues, thereby stabilizing protein structures. Although PDIs are functionally diverse, they all contain …

Spatiotemporal dynamics of signal dependent exocytosis and parasitophorous vacuolar membrane rupture during Plasmodium falciparum egress

  Malaria, caused by intracellular Plasmodium falciparum parasites, remains a major global health concern. These parasites reside and replicate within a vacuole in host red blood cells. Egress of daughter parasites out of the vacuolar and host membranes is tightly regulated via a complex mechanism. Prior studies have suggested that a cyclic-GMP driven calcium signaling …

Evolutionary remodeling of ubiquinone biosynthesis in Toxoplasma gondii reveals an essential bi-functional monooxygenase

Apicomplexan parasites like Toxoplasma gondii harbor a divergent mitochondrial proteome, much of which remains uncharacterized despite its essentiality for parasite survival. One such essential pathway is ubiquinone (UQ) biosynthesis. Here, we characterize the UQ synthesis machinery in T. gondii and show that conserved enzymes, TgCoq3 and TgCoq5, are essential for growth and mitochondrial function, and …