Delayed death in the malaria parasite Plasmodium falciparum is caused by disruption of prenylation-dependent intracellular trafficking

by Kit Kennedy, Simon A. Cobbold, Eric Hanssen, Jakob Birnbaum, Natalie J. Spillman, Emma McHugh, Hannah Brown, Leann Tilley, Tobias Spielmann, Malcolm J. McConville, Stuart A. Ralph Apicomplexan parasites possess a plastid organelle called the apicoplast. Inhibitors that selectively target apicoplast housekeeping functions, including DNA replication and protein translation, are lethal for the parasite, and several (doxycycline, clindamycin, and azithromycin) are in clinical u se as antimalarials. A major limitation of such drugs is that treated parasites only arrest one intraerythrocytic development cycle (approximately 48 hours) after treatment commences, a phenotype known as the ‘delayed death’ effect. The molecular basis of delayed death is a long-standing mystery in parasitology, and establishing the mechanism would aid rational clinical implementation of apicoplast-targeted drugs. Parasites undergoing delayed death transmit defective apicoplasts to their daughter cells and cannot produce the sole, blood-stage essential metabolic product of the apicoplast: the isoprenoid precursor isopentenyl-pyrophosphate. How the isoprenoid precursor depletion kills the parasite remains unknown. We investigated the requirements for the range of isoprenoids in the human malaria parasitePlasmodium falciparum and characterised the molecular and morphological phenotype of parasites experiencing delayed death. Metabolomic profiling reveals disruption of digestive vacuole functi...
Source: PLoS Biology: Archived Table of Contents - Category: Biology Authors: Source Type: research

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Induction of memory CD8+ T cells is important for controlling infections such as malaria and HIV/AIDS and for cancer immunotherapy. Accurate assessment of antigen-specific (Ag-specific) CD8+ T cells is critical for vaccine optimization and for defining correlates of protection. However, conditions for determining Ag-specific CD8+ T cell responses ex vivo using intracellular cytokine staining (ICS) may be variable, especially in humans with complex antigens. Here, we used an attenuated whole parasite malaria vaccine model in humans and various experimental infections in mice to show that the duration of antigenic stimulatio...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
CONCLUSION: The VK210 variant is the most frequently observed in the studied region and there is significant genetic variability in the CRR of the P. vivax CSP. Moreover, the antimalarial drug sensitivity profiles of the isolates does not seem to be related to the VK210 subtypes. PMID: 31411308 [PubMed - in process]
Source: Memorias do Instituto Oswaldo Cruz - Category: Infectious Diseases Authors: Tags: Mem Inst Oswaldo Cruz Source Type: research
Moji Kiyoshi Kita Plasmodium knowlesi (Pk) is a malaria parasite that naturally infects macaque monkeys in Southeast Asia. Pk malaria, the zoonosis transmitted from the infected monkeys to the humans by Anopheles mosquito vectors, is now a serious health problem in Malaysian Borneo. To create a strategic plan to control Pk malaria, it is important to estimate the occurrence of the disease correctly. The rise of Pk malaria has been explained as being due to ecological changes, especially deforestation. In this research, we analysed the time-series satellite images of MODIS (MODerate-resolution Imaging Spectroradiomete...
Source: International Journal of Environmental Research and Public Health - Category: Environmental Health Authors: Tags: Article Source Type: research
Drug resistance within the major malaria parasites Plasmodium vivax and Plasmodium falciparum threatens malaria control and elimination in Southeast Asia. Plasmodium vivax first-line treatment drug is chloroquine...
Source: Malaria Journal - Category: Infectious Diseases Authors: Tags: Research Source Type: research
NICE proposes use of antiseptic creams instead Related items fromOnMedica Single-dose malaria drug eliminates parasite from liver Patients often avoid vaccinations due to fear of side effects Double check patients with ‘penicillin’ allergy to avoid MRSA risk Ibuprofen not a safe alternative to antibiotics for uncomplicated UTIs Inhaled corticosteroids linked to higher infection risk
Source: OnMedica Latest News - Category: UK Health Source Type: news
Conclusions: The three-fold hematocrit conversion of hemoglobin estimation is a less reliable method than the measured hemoglobin in anemic children in the study setting.
Source: Nigerian Journal of Clinical Practice - Category: Rural Health Authors: Source Type: research
Conclusion: AZ-PQ is a promising candidate for IPTp. PMID: 31405866 [PubMed - as supplied by publisher]
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research
Authors: Bhardwaj N, Ahmed MZ, Sharma S, Nayak A, Anvikar AR, Pande V Abstract Background &objectives: Plasmodiumfalciparum malaria causes wide variety of clinical symptoms ranging from a mild febrile illness to life-threatening complications. For prevention of the severity and early diagnosis, evaluation of potential biomarkers is much needed. C-reactive protein (CRP) is an acute phase protein and well-recognized marker of inflammation in the body. It is synthesized by liver in response to pro-inflammatory responses and has correlation with complications associated with malaria. The study was aimed to assess, ...
Source: Journal of Vector Borne Diseases - Category: Infectious Diseases Tags: J Vector Borne Dis Source Type: research
Publication date: Available online 9 August 2019Source: Journal of Global Antimicrobial ResistanceAuthor(s): Nader Pestehchian, Mohammad Reza Vafaei, Pardis Nematolahy, Jaleh Varshosaz, Hossein Ali Yousefi, Vahab Ziaei Bide, Hamed KalaniAbstractObjectivesThe aim of the present study was to evaluate the efficacy of pyrimethamine-loaded poloxamer 407 nanomicelles onPlasmodium berghei strain NICD as a model for human malaria.MethodsInitially, pyrimethamine-loaded nanomicelles were prepared and their zeta potential, particle size, and polydispersity index were measured. For antiplasmodial assessment, 54 mice were divided rando...
Source: Journal of Global Antimicrobial Resistance - Category: Infectious Diseases Source Type: research
Date: Thursday, 09 26, 2019; Speaker: David Sibley, Professor, Washington University; David Sacks, Senior Investigator, Laboratory of Parasitic Diseases, NIAID; Ana Rodriguez, Professor, New York University, Langone Health; Sean T. Prigge, Professor, Johns Hopkins Bloomberg School of Public Health; Heather Painter, Senior Staff Member, U.S. Food&Drug Administration; Joel Vega-Rodriguez, Chief, Molecular Parasitology and Entomology Unit, Laboratory of Malaria and Vector Research; Photini Sinnis, Professor, Johns Hopkins Bloomberg Shcool of Public HealthUniversity; Boris Striepen, Professor, University of Pennsylvania; 5...
Source: NIH Calendar of Events - Category: American Health Source Type: events
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