Life Sciences Commons^™

The Antimalarial Mmv688533 Provides Potential For Single-Dose Cures With A High Barrier To, James M. Murithi, Cécile Pascal, Jade Bath, Xavier Boulenc, Nina F. Gnädig, Charisse Flerida A. Pasaje, Kelly Rubiano, Tomas Yeo, Sachel Mok, Sylvie Klieber, Paul Desert, María Belén Jiménez-Díaz, Jutta Marfurt, Mélanie Rouillier, Mohammed H. Cherkaoui-Rbati, Nathalie Gobeau, Sergio Wittlin, Anne-Catrin Uhlemann, Ric N. Price, Grennady Wirjanata, Rintis Noviyanti, Patrick Tumwebaze, Roland A. Cooper, Philip J. Rosenthal, Laura M. Sanz, Francisco-Javier Gamo, Jayan Joseph, Shivendra Singh, Sridevi Bashyam, Jean Michel Augereau, Elie Giraud, Tanguy Bozec, Thierry Vermat, Gilles Tuffal, Jean-Michel Guillon, Jérôme Menegotto, Laurent Sallé, Guillaume Louit, Marie-José Cabanis, Marie Françoise Nicolas, Michel Doubovetzky, Rita Merino, Nadir Bessila, Iñigo Angulo-Barturen, Delphine Baud, Lidiya Bebrevska, Fanny Escudié, Jacquin C. Niles, Benjamin Blasco, Simon Campbell, Gilles Courtemanche, Laurent Fraisse, Alain Pellet, David A. Fidock, Didier Leroy

Natural Sciences and Mathematics | Faculty Scholarship

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in …

Plasmodium Impairs Antibacterial Innate Immunity To Systemic Infections In Part Through Hemozoin-Bound Bioactive Molecules., Christopher Lynn Harding

Electronic Theses and Dissertations

Despite efforts to decrease the global health burden of malaria, infections with Plasmodium species continue to cause over 200 million episodes of malaria each year which resulted in 405,000 deaths in 2018 [1]. One complication of malaria is increased susceptibility to invasive bacterial infections. Plasmodium infections impair host immunity to non-Typhoid Salmonella (NTS) through activities of heme oxygenase I (HO-I) )-induced release of immature granulocytes and myeloid cell-derived IL-10. Yet, it is not known if these mechanisms are specific to NTS. We show here, that Plasmodium yoelii 17XNL (Py) infected mice had impaired clearance of systemic Listeria monocytogenes (Lm) during …

Observing The Effects Of Antimalarial Drug Availability On Women’S Work Absenteeism, Rei Imada

CMC Senior Theses

This study aims to provide insight on how availability of antimalarial drugs can help alleviate the economic burden of malaria. Much of the existing literature that looks into the effects of antimalarial drug availability focuses on the associated health benefits, but fails to draw a link to the economic benefits that may also be incurred. Using data from the 2015-2016 Tanzania Demographic and Health Survey and Malaria Indicator Survey, this study performs a series of multiple regressions to observe how increased availability of artemisinin-based combination therapies (ACTs), a front-line antimalarial drug in most African countries, affects likelihood of work absenteeism …

Frequency Of G6pd Mediterranean In Individuals With And Without Malaria In Southern Pakistan, Bushra Moiz, Haroon Muhammad Arshad, Ahmed Raheem Raheem, Hasan Hayat, Najia Karim Ghanchi, M Asim Beg

Department of Pathology and Laboratory Medicine

Background: Pakistan has an estimated annual burden of 1.5 million malaria cases. The current situation calls for an efective malaria control and eradication programme in this country. Currently, primaquine is an attractive option for eliminating reservoirs of Plasmodium vivax hypnozoites and killing gametocytes of Plasmodium falciparum. However, this drug causes haemolysis in individuals who are glucose-6-phosphate (G6PD) defcient. It is important to map G6PD defciency and malaria distribution in Pakistan to design an efective malaria eradication regimen. Frequency of G6PD defciency (G6PDd) in malaria patients has not been reported from Pakistan in any meaningful way. The purpose of this study …

A Variant Pfcrt Isoform Can Contribute To Plasmodium Falciparum Resistance To The First-Line Partner Drug Piperaquine, Satish K. Dhingra, Devasha Redhi, Jill M. Combrinck, Tomas Yeo, John Okombo, Philipp P. Henrich, Ann N. Cowell, Purva Gupta, Matthew L. Stegman, Jonathan M. Hoke, Roland A. Cooper, Elizabeth Winzeler, Sachel Mok, Timothy J. Egan, David A. Fidock

Collected Faculty and Staff Scholarship

Current efforts to reduce the global burden of malaria are threatened by the rapid spread throughout Asia of Plasmodium falciparum resistance to artemisininbased combination therapies, which includes increasing rates of clinical failure with dihydroartemisinin plus piperaquine (PPQ) in Cambodia. Using zinc finger nucleasebased gene editing, we report that addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites. Resistance was demonstrated as significantly higher PPQ concentrations causing 90% inhibition of parasite growth (IC90) or 50% parasite killing (50% lethal dose [LD50]). This mutation also reversed Dd2-mediated CQ …

A Variant Pfcrt Isoform Can Contribute To Plasmodium Falciparum Resistance To The First-Line Partner Drug Piperaquine, Satish K. Dhingra, Devasha Redhi, Jill M. Combrinck, Tomas Yeo, John Okombo, Philipp P. Henrich, Annie N. Cowell, Purva Gupta, Matthew L. Stegman, Jonathan M. Hoke, Roland A. Cooper, Elizabeth Winzeler, Sachel Mok, Timothy J. Egan, David A. Fidock

Biological Sciences Faculty Publications

Current efforts to reduce the global burden of malaria are threatened by the rapid spread throughout Asia of Plasmodium falciparum resistance to artemisinin-based combination therapies, which includes increasing rates of clinical failure with dihydroartemisinin plus piperaquine (PPQ) in Cambodia. Using zinc finger nuclease-based gene editing, we report that addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites. Resistance was demonstrated as significantly higher PPQ concentrations causing 90% inhibition of parasite growth (IC₉₀) or 50% parasite killing (50% lethal dose [LD₅₀]). This mutation …

Lack Of Resistance Of Plasmodium Falciparum To Dihydroartemisinin In Uganda Based On Parasitogolgical And Molecular Assays, Roland A. Cooper, Melissa D. Conrad, Quentin D. Watson, Stephanie J. Huezo, Harriet Ninsiima, Patrick Tumwebaze, Samuel L. Nsobya, Philip J. Rosenthal

Collected Faculty and Staff Scholarship

• Artemisinin-­‐based combination therapy is now standard treatment for falciparum malaria. However, this regimen is threatened by resistance to artemisinins, manifest as delayed clearance of parasitemia after therapy, in southeast Asia.

• Artemisinin resistance in southeast Asia is associated with increased parasitemias in culture, compared to those in sensi0ve parasites, 72 hours a=er a 6 hour pulse with 700 nM dihydroartemisinin (DHA), and with propeller domain polymorphisms in the Plasmodium falciparum kelch (K13; PF3D7_1343700) gene

• Given that artemether/lumefantrine has been adopted as standard therapy for malaria within the last decade in Uganda, we characterized artemisinin sensiBvity in fresh P. falciparum isolates from …

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Hemocyte Differentiation Mediates The Mosquito Late-Phase Immune Response Against Plasmodium In Anopheles Gambiae, Ryan C. Smith, Carolina Barillas-Mury, Marcelo Jacobs-Lorena

Ryan C. Smith

Plasmodium parasites must complete development in the mosquito vector for transmission to occur. The mosquito innate immune response is remarkably efficient in limiting parasite numbers. Previous work has identified a LPS-induced TNFα transcription factor (LITAF)-like transcription factor, LITAF-like 3 (LL3), which significantly influences parasite numbers. Here, we demonstrate that LL3 does not influence invasion of the mosquito midgut epithelium or ookinete-to-oocyst differentiation but mediates a late-phase immune response that decreases oocyst survival. LL3 expression in the midgut and hemocytes is activated by ookinete midgut invasion and is independent of the mosquito microbiota, suggesting that LL3 may be a component of …

Investigation Of Dual Stage Acridones As A Potent Malaria Treatment, Stephanie Huezo

Dissertations, Masters Theses, Capstones, and Culminating Projects

The need for potent antimalarials to prevent the emergence of drug resistant Plasmodium falciparum is urgent. Discovery of novel acridone chemotypes have shown promise for a new antimalarial drug treatment. Presently, two acridone chemotypes have intrinsic antimalarial potency against chloroquine sensitive and multidrug resistant parasites. Acridones lacking an N10 side chain are known as chemotype I acridones, whereas, chemotype II acridones are defined as having an alkyl side chain at the same position. The N10 substitution of chemotype II acridones is thought to target heme and inhibit hemozoin formation within the parasite’s digestive vacuole, and is known to provide synergistic …

Impact Of Antimalarial Treatment And Chemoprevention On The Drug Sensitivity Of Malaria Parasites Isolated From Ugandan Children, Patrick Tumwebaze, Melissa D. Conrad, Andrew Walakira, Norbert Leclair, Oswald Byaruhanga, Christine Nakazibwe, Benjamin Kozak, Jessica Bloome, Jaffer Okiring, Abel Kakuru, Victor Bigira, James Kapisi, Jennifer Legac, Jiri Gut, Roland A. Cooper, Moses R. Kamya, Diane V. Havlir, Grant Dorsey, Bryan Greenhouse, Samuel L. Nsobya, Philip J. Rosenthal

Collected Faculty and Staff Scholarship

Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. …

Slavery, Agriculture, And Malaria In The Arabian Peninsula, Benjamin Reilly

Ohio University Press Open Access Books

In Slavery, Agriculture, and Malaria in the Arabian Peninsula, Benjamin Reilly illuminates a previously unstudied phenomenon: the large-scale employment of people of African ancestry as slaves in agricultural oases within the Arabian Peninsula. The key to understanding this unusual system, Reilly argues, is the prevalence of malaria within Arabian Peninsula oases and drainage basins, which rendered agricultural lands in Arabia extremely unhealthy for people without genetic or acquired resistance to malarial fevers. In this way, Arabian slave agriculture had unexpected similarities to slavery as practiced in the Caribbean and Brazil.

This book synthesizes for the first time a body of …

Altered Intraerythrocytic Development Phenotypes Of Artemisinin-Resistant Plasmodium Falciparum Confer A Fitness Advantage, Amanda Hott

USF Tampa Graduate Theses and Dissertations

Resistance to artemisinin combination therapies (ACTs) has emerged in southeast Asia threatening the most widely used treatment against antimalarial-resistant Plasmodium falciparum worldwide. Artemisinin resistance has been associated with a reduced rate of parasite clearance following treatment with an ACT and is attributed to increased survival of ring-stage parasites. Single nucleotide polymorphisms (SNPs) in kelch gene (K13) has been associated with delayed in vivo clearance half-life of artemisinin-resistant P. falciparum and is the only known molecular marker of resistance. The absence of reliable in vitro phenotypes for artemisinin resistance has limited our understanding of the resistance mechanism(s) and fitness costs, therefore …

Dual Engagement Of The Nlrp3 And Aim2 Inflammasomes By Plasmodium-Derived Hemozoin And Dna During Malaria, Parisa Kalantari, Rosane B. Deoliveira, Jennie Chan, Yolanda Corbett, Vijay A. K. Rathinam, Andrea Stutz, Eicke Latz, Ricardo T. Gazzinelli, Douglas T. Golenbock, Katherine A. Fitzgerald

Katherine A. Fitzgerald

Hemozoin (Hz) is the crystalline detoxification product of hemoglobin in Plasmodium-infected erythrocytes. We previously proposed that Hz can carry plasmodial DNA into a subcellular compartment that is accessible to Toll-like receptor 9 (TLR9), inducing an inflammatory signal. Hz also activates the NLRP3 inflammasome in primed cells. We found that Hz appears to colocalize with DNA in infected erythrocytes, even before RBC rupture or phagolysosomal digestion. Using synthetic Hz coated in vitro with plasmodial genomic DNA (gDNA) or CpG oligodeoxynucleotides, we observed that DNA-complexed Hz induced TLR9 translocation, providing a priming and an activation signal for inflammasomes. After phagocytosis, Hz and …

Immunization Against A Merozoite Sheddase Promotes Multiple Invasion Of Red Blood Cells And Attenuates Plasmodium Infection In Mice, Ryan C. Smith, Daisy D. Colón-López, Jürgen Bosch

Ryan C. Smith

Subtilisin-like protease 2 (SUB2) is a conserved serine protease utilized by Plasmodium parasites as a surface sheddase required for successful merozoite invasion of host red blood cells and has been implicated in ookinete invasion of the mosquito midgut. To determine if SUB2 is a suitable vaccine target to interfere with malaria parasite development, the effects of SUB2-immunization on the Plasmodium life cycle were examined in its vertebrate and invertebrate hosts. Swiss Webster mice were immunized with SUB2 peptides conjugated to Keyhole limpet hemocyanin (KLH) or KLH alone, and then challenged with Plasmodium berghei. To determine the effects of immunization on …

The Genome Of Anopheles Darlingi, The Main Neotropical Malaria Vector, Osvaldo Marinotti, Adam R. Wespiser, Daniel R. Caffrey, Douglas T. Golenbock, Neal S. Silverman

Neal Silverman

Anopheles darlingi is the principal neotropical malaria vector, responsible for more than a million cases of malaria per year on the American continent. Anopheles darlingi diverged from the African and Asian malaria vectors approximately 100 million years ago (mya) and successfully adapted to the New World environment. Here we present an annotated reference A. darlingi genome, sequenced from a wild population of males and females collected in the Brazilian Amazon. A total of 10 481 predicted protein-coding genes were annotated, 72% of which have their closest counterpart in Anopheles gambiae and 21% have highest similarity with other mosquito species. In …

Regulation Of Anti-Plasmodium Immunity By A Litaf-Like Transcription Factor In The Malaria Vector Anopheles Gambiae, Ryan C. Smith, Abraham G. Eappen, Andrea J. Radtke, Marcelo Jacobs-Lorena

Ryan C. Smith

The mosquito is the obligate vector for malaria transmission. To complete its development within the mosquito, the malaria parasite Plasmodium must overcome the protective action of the mosquito innate immune system. Here we report on the involvement of the Anopheles gambiae orthologue of a conserved component of the vertebrate immune system, LPS-induced TNFα transcription factor (LITAF), and its role in mosquito anti-Plasmodium immunity. An. gambiae LITAF-like 3 (LL3) expression is up-regulated in response to midgut invasion by both rodent and human malaria parasites. Silencing of LL3 expression greatly increases parasite survival, indicating that LL3 is part of an anti-Plasmodium defense …

Mutation In The Plasmodium Falciparum Crt Protein Determines The Stereospecific Activity Of Antimalarial Cinchona Alkaloids, Carol E. Griffin, Jonathan M. Hoke, Upeka Samarakoon, Junhui Duan, Jianbing Mu, Michael T. Ferdig, David C. Warhurst, Roland Cooper

Collected Faculty and Staff Scholarship

The Cinchona alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (-)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (-)-isomers in vitro and in vivo against Plasmodium falciparum malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparum chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward P. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the in vitro susceptibility …

Chloroquine Susceptibility And Reversibility In A Plasmodium Falciparum Genetic Cross, Jigar J. Patel, Drew Thacker, Jon C. Tan, Perri Pleeter, Lisa Checkley, Joseph M. Gonzales, Bingbing Deng, Paul D. Roepe, Roland A. Cooper, Michael T. Ferdig

Collected Faculty and Staff Scholarship

Mutations in the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT), are major determinants of verapamil (VP)-reversible CQ resistance (CQR). In the presence of mutant PfCRT, additional genes contribute to the wide range of CQ susceptibilities observed. It is not known if these genes influence mechanisms of chemosensitization by CQR reversal agents. Using quantitative trait locus (QTL) mapping of progeny clones from the HB3 × Dd2 cross, we show that the P. falciparum multidrug resistance gene 1 (pfmdr1) interacts with the Southeast Asiaderived mutant pfcrt haplotype to modulate CQR levels. A novel chromosome 7 locus is predicted to contribute with the …

Inhibition Of Yeast Hexokinase By The Antimalarial Drug Artemisinin: Probing Mechanism Of Action With A Model Enzyme, Jennifer S. Spence

Biological Sciences Theses & Dissertations

A leading infectious cause of death, malaria threatens approximately half of the world's population, and drug-resistant strains of Plasmodium falciparum have created immense difficulty in chemotherapy of the disease. The artemisinin (ART) class of antimalarials may represent a powerful solution. In addition to their safety, effectiveness, and moderate cost, they are the only drugs in use for which there has been no widespread evidence of clinical resistance. The exact parasiticidal mechanism of ART is highly contested, but evidence suggests that protein alkylation may play a role in cytotoxicity. in vitro essays were performed using yeast hexokinase (HK) to demonstrate a …

Evaluation Of The Efficacy Of Chloroplast-Derived Antigensagainst Malaria, Melissa Schreiber

Electronic Theses and Dissertations

Malaria is the most prevalent vector-borne parasitic disease worldwide and a major cause of death from infections. There is a great need to develop a low cost vaccine for malaria to control transmission of infection and impact of disease, due to the emergence of anti-malarial resistance. Two leading blood stage malarial vaccine candidates are the apical membrane antigen-1 (AMA-1) and the merozoite surface protein-1 (MSP-1). The aim of this project is to express malarial antigens in tobacco plants via plastid transformation and deliver them by subcutaneous or oral gavage of minimally processed transplastomic tissue to evaluate their efficacy to elicit …

A Member Of The Novel Fikk Family Of Plasmodium Falciparum Putative Protein Kinases Exhibits Diacylglycerol Kinase Activity And Is Exported To The Host Erythrocyte, David Floyd Curtis

Electronic Theses and Dissertations

Plasmodium falciparum is one of four species known to cause malaria in humans and is the species that is associated with the most virulent form of the disease. Malaria causes nearly two million deaths each year, many of these occurring among children in under-developed countries of the world. One reason for this is the prevalence of drug resistant strains of malaria that mitigate the efficacy of existing drugs. Hence, the identification of a new generation of pharmacological agents for malaria is extremely urgent. The recent identification of a group of novel protein kinases within the Plasmodium falciparum genome has provided …

Dr. Nott's Theory Of Insect Causation Of Disease, William A. Riley

Harold W. Manter Laboratory: Library Materials

Excerpt:

The danger in using isolated sentences from an article as a basis for interpreting the author's theories, is generally recognized, but sometimes the most careful workers fall into the trap. Once the mistaken interpretation is published, it may be copied over and over again until it rises to the dignity of a dogma.

A striking illustration is afforded by the practical unanimity with which writers on the subject of insects and disease credit Dr. Josiah Nott with being the earliest to formulate definitely the theory of mosquito transmission of yellow fever.

Nuttall, in his classic monograph On the Role …