Human babesiosis is a tick-borne multisystem disease, and current treatments have both adverse side effects and a significant rate of drug failure. Lawres et al. report that endochin-like quinolones, in combination with atovaquone, cure experimental babesiosis in immunodeficient mice.

The prevalence of heart failure (HF) and its subtype, HF with preserved ejection fraction (HFpEF), is on the rise due to aging of the population. HFpEF is convergence of several pathophysiological processes, which are not yet clearly identified. HFpEF is usually seen in association with systemic diseases, such as diabetes, hypertension, atrial fibrillation, sleep apnea, renal and pulmonary disease. The proportion of HF patients with HFpEF varies by patient demographics, study settings (cohort vs. clinical trial, outpatient clinics vs. hospitalised patients) and cut points used to define preserved function. There is an expanding body of literature about prevalence and prognostic significance of both cardiovascular and non-cardiovascular comorbidities in HFpEF patients. Current therapeutic approaches are targeted towards alleviating the symptoms, treating the associated comorbid conditions, and reducing recurrent hospital admissions. There is lack of evidence-based therapies that show a reduction in the mortality amongst HFpEF patients; however, an improvement in exercise tolerance and quality of life is seen with few interventions. In this review, we highlight the epidemiology and current treatment options for HFpEF.

Efficient transmission of Plasmodium species between humans and Anopheles mosquitoes is a major contributor to the global burden of malaria. Gametocytogenesis, the process by which parasites switch from asexual replication within human erythrocytes to produce male and female gametocytes, is a critical step in malaria transmission and Plasmodium genetic diversity. Nothing is known about the pathways that regulate gametocytogenesis and only few of the current drugs that inhibit asexual replication are also capable of inhibiting gametocyte development and blocking malaria transmission. Here we provide genetic and pharmacological evidence indicating that the pathway for synthesis of phosphatidylcholine in Plasmodium falciparum membranes from host serine is essential for parasite gametocytogenesis and malaria transmission. Parasites lacking the phosphoethanolamine N-methyltransferase enzyme, which catalyzes the limiting step in this pathway, are severely altered in gametocyte development, are incapable of producing mature-stage gametocytes, and are not transmitted to mosquitoes. Chemical screening identified 11 inhibitors of phosphoethanolamine N-methyltransferase that block parasite intraerythrocytic asexual replication and gametocyte differentiation in the low micromolar range. Kinetic studies in vitro as well as functional complementation assays and lipid metabolic analyses in vivo on the most promising inhibitor NSC-158011 further demonstrated the specificity of inhibition. These studies set the stage for further optimization of NSC-158011 for development of a class of dual activity antimalarials to block both intraerythrocytic asexual replication and gametocytogenesis.H uman malaria parasites exhibit a complex life cycle consisting of asexual phases within human hepatocytes and erythrocytes, with the latter directly responsible for disease manifestations. Within red blood cells, these parasites can also undergo gametocytogenesis, a process during which they interrupt their asexual replication and differentiate to form morphologically and functionally distinct sexual-stage gametocytes (1). These sexual forms serve as precursors for male and female gametes, which develop in the mosquito where they undergo mating, meiosis and several mitotic cycles to produce sporozoites. In Plasmodium falciparum, the causative agent of the most severe form of human malaria, the progression from immature stage I to mature stage V gametocytes takes ∼10 d (2). However, the biological processes that regulate gametocytogenesis remain unknown. Thorough understanding of these processes is crucial to the development of a new generation of dual activity antimalarials that can inhibit both infection and transmission.Phosphatidylcholine (PC), the predominant phospholipid produced by malaria parasites, plays essential structural and regulatory roles in parasite development and differentiation (reviewed in ref.3). Lipid metabolic and genetic studies in P. falciparum have demonstrated the presence of two pathways for PC biosynthesis (Fig. S1): ...

No abstract

Summary Phospholipid biosynthesis is critical for the development, differentiation and pathogenesis of several eukaryotic pathogens. Genetic studies have validated the pathway for phosphatidylethanolamine synthesis from phosphatidylserine catalyzed by phosphatidylserine decarboxylase enzymes (PSD) as a suitable target for development of antimicrobials; however no inhibitors of this class of enzymes have been discovered. We show that the Plasmodium falciparum PSD can restore the essential function of the yeast gene in strains requiring PSD for growth. Genetic, biochemical and metabolic analyses demonstrate that amino acids between positions 40 and 70 of the parasite enzyme are critical for proenzyme processing and decarboxylase activity. We used the essential role of Plasmodium PSD in yeast as a tool for screening a library of anti-malarials. One of these compounds is 7-chloro-N-(4-ethoxyphenyl)-4-quinolinamine, an inhibitor with potent activity against P. falciparum, and low toxicity toward mammalian cells. We synthesized an analog of this compound and showed that it inhibits PfPSD activity and eliminates Plasmodium yoelii infection in mice. These results highlight the importance of 4-quinolinamines as a novel class of drugs targeting membrane biogenesis via inhibition of PSD activity

The apicomplexan intraerythrocytic parasite Babesia microti is an emerging human pathogen and the primary cause of human babesiosis, a malaria-like illness endemic in the United States. The pathogen is transmitted to humans by the tick vector, Ixodes scapularis, and by transfusion of blood from asymptomatic B. microti-infected donors. Whereas the nuclear and mitochondrial genomes of this parasite have been sequenced, assembled and annotated, its apicoplast genome remained incomplete, mainly due to its low representation and high A+T content. Here we report the complete sequence and annotation of the apicoplast genome of the B. microti R1 isolate. The genome consists of a 28.7 kb circular molecule encoding primarily functions important for maintenance of the apicoplast DNA, transcription, translation and maturation of organellar proteins. Genome analysis and annotation revealed a unique gene structure and organization of the B. microti apicoplast genome and suggest that all metabolic and non-housekeeping functions in this organelle are nuclear-encoded. B. microti apicoplast functions are significantly different from those of the host, suggesting that they might be useful as targets for development of potent and safe therapies for the treatment of human babesiosis.

Background: Pantothenate transport is essential for Plasmodium development. The transporter that mediates entry of pantothenate is unknown. Results: PfPAT encodes the primary pantothenate transporter of P. falciparum. Conclusion:PfPAT plays an essential function in parasite development and thus is a valid target for antimalarial therapy. Significance: PfPAT is the first pantothenate transporter identified and characterized in protozoan parasites and a valid target for therapy.

BACKGROUND Babesia microti is a protozoan parasite responsible for the majority of reported cases of human babesiosis and a major risk to the blood supply. Laboratory screening of blood donors may help prevent transfusion-transmitted babesiosis but there is no Food and Drug Administration–approved screening method yet available. Development of a sensitive, specific, and highly automated B. microti antibody assay for diagnosis of acute babesiosis and blood screening could have an important impact on decreasing the health burden of B. microti infection. STUDY DESIGN AND METHODS Herein, we take advantage of recent advances in B. microti genomic analyses, field surveys of the reservoir host, and human studies in endemic areas to apply a targeted immunomic approach to the discovery of B. microti antigens that serve as signatures of active or past babesiosis infections. Of 19 glycosylphosphatidylinositol (GPI)-anchored protein candidates (BmGPI1-19) identified in the B. microti proteome, 17 were successfully expressed, printed on a microarray chip, and used to screen sera from uninfected and B. microti–infected mice and humans to determine immune responses that are associated with active and past infection. RESULTS Antibody responses to various B. microti BmGPI antigens were detected and BmGPI12 was identified as the best biomarker of infection that provided high sensitivity and specificity when used in a microarray antibody assay. CONCLUSION BmGPI12 alone or in combination with other BmGPI proteins is a promising candidate biomarker for detection of B. microti antibodies that might be useful in blood screening to prevent transfusion-transmitted babesiosis.