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https://www.readbyqxmd.com/read/29422648/unravelling-the-immune-signature-of-plasmodium-falciparum-transmission-reducing-immunity
#1
Will J R Stone, Joseph J Campo, André Lin Ouédraogo, Lisette Meerstein-Kessel, Isabelle Morlais, Dari Da, Anna Cohuet, Sandrine Nsango, Colin J Sutherland, Marga van de Vegte-Bolmer, Rianne Siebelink-Stoter, Geert-Jan van Gemert, Wouter Graumans, Kjerstin Lanke, Adam D Shandling, Jozelyn V Pablo, Andy A Teng, Sophie Jones, Roos M de Jong, Amanda Fabra-García, John Bradley, Will Roeffen, Edwin Lasonder, Giuliana Gremo, Evelin Schwarzer, Chris J Janse, Susheel K Singh, Michael Theisen, Phil Felgner, Matthias Marti, Chris Drakeley, Robert Sauerwein, Teun Bousema, Matthijs M Jore
Infection with Plasmodium can elicit antibodies that inhibit parasite survival in the mosquito, when they are ingested in an infectious blood meal. Here, we determine the transmission-reducing activity (TRA) of naturally acquired antibodies from 648 malaria-exposed individuals using lab-based mosquito-feeding assays. Transmission inhibition is significantly associated with antibody responses to Pfs48/45, Pfs230, and to 43 novel gametocyte proteins assessed by protein microarray. In field-based mosquito-feeding assays the likelihood and rate of mosquito infection are significantly lower for individuals reactive to Pfs48/45, Pfs230 or to combinations of the novel TRA-associated proteins...
February 8, 2018: Nature Communications
https://www.readbyqxmd.com/read/29422384/efficacy-and-safety-of-primaquine-and-methylene-blue-for-prevention-of-plasmodium-falciparum-transmission-in-mali-a-phase-2-single-blind-randomised-controlled-trial
#2
Alassane Dicko, Michelle E Roh, Halimatou Diawara, Almahamoudou Mahamar, Harouna M Soumare, Kjerstin Lanke, John Bradley, Koualy Sanogo, Daouda T Kone, Kalifa Diarra, Sekouba Keita, Djibrilla Issiaka, Sekou F Traore, Charles McCulloch, Will J R Stone, Jimee Hwang, Olaf Müller, Joelle M Brown, Vinay Srinivasan, Chris Drakeley, Roly Gosling, Ingrid Chen, Teun Bousema
BACKGROUND: Primaquine and methylene blue are gametocytocidal compounds that could prevent Plasmodium falciparum transmission to mosquitoes. We aimed to assess the efficacy and safety of primaquine and methylene blue in preventing human to mosquito transmission of P falciparum among glucose-6-phosphate dehydrogenase (G6PD)-normal, gametocytaemic male participants. METHODS: This was a phase 2, single-blind, randomised controlled trial done at the Clinical Research Centre of the Malaria Research and Training Centre (MRTC) of the University of Bamako (Bamako, Mali)...
February 5, 2018: Lancet Infectious Diseases
https://www.readbyqxmd.com/read/29420756/potent-plasmodium-falciparum-gametocytocidal-compounds-identified-by-exploring-the-kinase-inhibitor-chemical-space-for-dual-active-antimalarials
#3
Mariëtte E van der Watt, Janette Reader, Alisje Churchyard, Sindisiwe H Nondaba, Sonja B Lauterbach, Jandeli Niemand, Sijuade Abayomi, Riëtte A van Biljon, Jessica I Connacher, Roelof D J van Wyk, Claire Le Manach, Tanya Paquet, Diego González Cabrera, Christel Brunschwig, Anjo Theron, Sonia Lozano-Arias, Janneth F I Rodrigues, Esperanza Herreros, Didier Leroy, James Duffy, Leslie J Street, Kelly Chibale, Dalu Mancama, Theresa L Coetzer, Lyn-Marie Birkholtz
Objectives: Novel chemical tools to eliminate malaria should ideally target both the asexual parasites and transmissible gametocytes. Several imidazopyridazines (IMPs) and 2-aminopyridines (2-APs) have been described as potent antimalarial candidates targeting lipid kinases. However, these have not been extensively explored for stage-specific inhibition of gametocytes in Plasmodium falciparum parasites. Here we provide an in-depth evaluation of the gametocytocidal activity of compounds from these chemotypes and identify novel starting points for dual-acting antimalarials...
February 6, 2018: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29389671/a-controlled-human-malaria-infection-model-enabling-evaluation-of-transmission-blocking-interventions
#4
Katharine A Collins, Claire Yt Wang, Matthew Adams, Hayley Mitchell, Melanie Rampton, Suzanne Elliott, Isaie J Reuling, Teun Bousema, Robert Sauerwein, Stephan Chalon, Jörg J Möhrle, James S McCarthy
BACKGROUND: Drugs and vaccines that can interrupt the transmission of Plasmodium falciparum will be important for malaria control and elimination. However, models for early clinical evaluation of candidate transmission-blocking interventions are currently unavailable. Here we describe a new model for evaluating malaria transmission from humans to Anopheles mosquitoes using controlled human malaria infection (CHMI). METHODS: Seventeen healthy malaria-naïve volunteers underwent CHMI by intravenous inoculation of P...
February 1, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29371619/immunization-with-transgenic-rodent-malaria-parasites-expressing-pfs25-induces-potent-transmission-blocking-activity
#5
K A Sala, F Angrisano, D F Da, I J Taylor, T S Churcher, A M Blagborough
An anti-malarial transmission blocking vaccine (TBV) would be an important tool for disease control or elimination, though current candidates have failed to induce high efficacy in clinical studies. The ookinete surface protein P25 is a primary target for TBV development, but heterologous expression of P25 with appropriate conformation is problematic and a pre-requisite for achieving functional titers. A potential alternative to recombinant/sub-unit vaccine is immunization with a non-pathogenic, whole-parasite vaccine...
January 25, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29347975/single-low-dose-primaquine-for-blocking-transmission-of-plasmodium-falciparum-malaria-a-proposed-model-derived-age-based-regimen-for-sub-saharan-africa
#6
W Robert Taylor, Htee Khu Naw, Kathryn Maitland, Thomas N Williams, Melissa Kapulu, Umberto D'Alessandro, James A Berkley, Philip Bejon, Joseph Okebe, Jane Achan, Alfred Ngwa Amambua, Muna Affara, Davis Nwakanma, Jean-Pierre van Geertruyden, Muhindo Mavoko, Pascal Lutumba, Junior Matangila, Philipe Brasseur, Patrice Piola, Rindra Randremanana, Estrella Lasry, Caterina Fanello, Marie Onyamboko, Birgit Schramm, Zolia Yah, Joel Jones, Rick M Fairhurst, Mahamadou Diakite, Grace Malenga, Malcolm Molyneux, Claude Rwagacondo, Charles Obonyo, Endalamaw Gadisa, Abraham Aseffa, Mores Loolpapit, Marie-Claire Henry, Grant Dorsey, Chandy John, Sodiomon B Sirima, Karen I Barnes, Peter Kremsner, Nicholas P Day, Nicholas J White, Mavuto Mukaka
BACKGROUND: In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. METHODS: Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0...
January 18, 2018: BMC Medicine
https://www.readbyqxmd.com/read/29323879/malaria-derived-gpi-anchor-enhances-anti-pfs25-functional-antibodies-that-block-malaria-transmission
#7
Neeraj Kapoor, Ivana Vanjak, James Rozzelle, Aym Berges, Wei Chan, Gang Yin, Cuong Tran, Aaron K Sato, Alexander R Steiner, Thao P Pham, Ashley J Birkett, Carole Long, Jeff Fairman, Kazutoyo Miura
Malaria, one of the most common vector borne human diseas-es, is a major world health issue. In 2015 alone, more than 200 million people were infected with malaria, out of which, 429,000 died. Even though artemisinin-based combination therapies (ACT) are highly effective at treating malaria infections, novel efforts towards development of vaccines to prevent transmission are still needed. Pfs25, a post-fertilization stage parasite surface antigen, is a leading transmission-blocking vaccine (TBV) candidate. It is postulated that Pfs25 anchors to the cell membrane using a glycosylphosphatidyl-inositol (GPI) linker, which itself possesses proinflammatory properties...
January 11, 2018: Biochemistry
https://www.readbyqxmd.com/read/29320160/efforts-aimed-to-reduce-attrition-in-antimalarial-drug-discovery-a-systematic-evaluation-of-current-antimalarial-targets-portfolio
#8
María Jesus Chaparro, Felix Calderon, Pablo Castañeda, Elena Fernandez Alvaro, Raquel Gabarro, Francisco-Javier Gamo, María G Gómez-Lorenzo, Julio Martín, Esther Fernandez
Malaria remains a major global health problem. In 2015 alone, more than 200 million cases of malaria were reported, and more than 400,000 deaths occurred. Since 2010, emerging resistance to current front-line ACTs (Artemisinin Combination Therapies) has been detected in endemic countries. Therefore, there is an urgency for new therapies based on novel modes of action, able to relieve symptoms as fast as the artemisinins and/or block malaria transmission. During the past few years, the antimalarial community has focused their efforts on phenotypic screening as a pragmatic approach to identify new hits...
January 10, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29316140/a-male-gametocyte-osmiophilic-body-and-microgamete-surface-protein-of-the-rodent-malaria-parasite-plasmodium-yoelii-pymigs-plays-a-critical-role-in-male-osmiophilic-body-formation-and-exflagellation
#9
Mayumi Tachibana, Tomoko Ishino, Eizo Takashima, Takafumi Tsuboi, Motomi Torii
Anopheles mosquitoes transmit Plasmodium parasites of mammals, including the species that cause malaria in humans. Malaria pathology is caused by rapid multiplication of parasites in asexual intraerythrocytic cycles. Sexual stage parasites are also produced during the intraerythrocytic cycle, and are ingested by the mosquito, initiating gametogenesis and subsequent sporogonic stage development. Here, we present a Plasmodium protein, termed microgamete surface protein (MiGS), which has an important role in male gametocyte osmiophilic body (MOB) formation and microgamete function...
January 5, 2018: Cellular Microbiology
https://www.readbyqxmd.com/read/29311293/pfcdpk1-is-critical-for-malaria-parasite-gametogenesis-and-mosquito-infection
#10
Abhisheka Bansal, Alvaro Molina-Cruz, Joseph Brzostowski, Poching Liu, Yan Luo, Karthigayan Gunalan, Yuesheng Li, José M C Ribeiro, Louis H Miller
Efforts to knock out Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) from asexual erythrocytic stage have not been successful, indicating an indispensable role of the enzyme in asexual growth. We recently reported generation of a transgenic parasite with mutant CDPK1 [Bansal A, et al. (2016) MBio 7:e02011-16]. The mutant CDPK1 (T145M) had reduced activity of transphosphorylation. We reasoned that CDPK1 could be disrupted in the mutant parasites. Consistent with this assumption, CDPK1 was successfully disrupted in the mutant parasites using CRISPR/Cas9...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29310655/methylene-blue-induced-morphological-deformations-in-plasmodium-falciparum-gametocytes-implications-for-transmission-blocking
#11
Ishan Wadi, C Radhakrishna Pillai, Anupkumar R Anvikar, Abhinav Sinha, Mahendra Nath, Neena Valecha
BACKGROUND: Malaria remains a global health problem despite availability of effective tools. For malaria elimination, drugs targeting sexual stages of Plasmodium falciparum need to be incorporated in treatment regimen along with schizonticidal drugs to interrupt transmission. Primaquine is recommended as a transmission blocking drug for its effect on mature gametocytes but is not extensively utilized because of associated safety concerns among glucose-6-phosphate dehydrogenase (G6PD) deficient patients...
January 8, 2018: Malaria Journal
https://www.readbyqxmd.com/read/29305880/distinct-effects-of-hiv-protease-inhibitors-and-erad-inhibitors-on-zygote-to-ookinete-transition-of-the-malaria-parasite
#12
Evi Goulielmaki, Sofia Kaforou, Kannan Venugopal, Thanasis G Loukeris, Inga Siden-Kiamos, Konstantinos Koussis
In an effort to eradicate malaria, new interventions are proposed to include compound/vaccine development against pre-erythrocytic, erythrocytic and mosquito stages of Plasmodium. Drug repurposing might be an alternative approach to new antimalarials reducing the cost and the time required for drug development. Previous in vitro studies have examined the effects of protease inhibitors on different stages of the Plasmodium parasite, although the clinical relevance of this remains unclear. In this study we tested the putative effect of three HIV protease inhibitors, two general aspartyl protease inhibitors and three AAA-p97 ATPase inhibitors on the zygote to ookinete transition of the Plasmodium parasite...
January 3, 2018: Molecular and Biochemical Parasitology
https://www.readbyqxmd.com/read/29304870/dynamics-of-anti-msp3-and-pfs230-antibody-responses-and-multiplicity-of-infection-in-asymptomatic-children-from-southern-ghana
#13
Linda E Amoah, Festus K Acquah, Ruth Ayanful-Torgby, Akua Oppong, Joana Abankwa, Evans K Obboh, Susheel K Singh, Michael Theisen
BACKGROUND: During a Plasmodium infection, exposure of human host immune cells to both the asexual and the sexual stages of the parasite elicit immune responses. These responses may be protective and prevent the development of high parasitaemia and its associated clinical symptoms, or block the transmission of malaria to an uninfected person. This study aimed at examining the dynamics of naturally acquired immune responses against the asexual and sexual forms of Plasmodium falciparum as well as assessing differences in the multiplicity of infection (MOI) in asymptomatic Ghanaian children living in two communities with varying malaria transmission intensities...
January 5, 2018: Parasites & Vectors
https://www.readbyqxmd.com/read/29300748/functional-interrogation-of-plasmodium-genus-metabolism-identifies-species-and-stage-specific-differences-in-nutrient-essentiality-and-drug-targeting
#14
Alyaa M Abdel-Haleem, Hooman Hefzi, Katsuhiko Mineta, Xin Gao, Takashi Gojobori, Bernhard O Palsson, Nathan E Lewis, Neema Jamshidi
Several antimalarial drugs exist, but differences between life cycle stages among malaria species pose challenges for developing more effective therapies. To understand the diversity among stages and species, we reconstructed genome-scale models (GEMs) of metabolism for five life cycle stages and five species of Plasmodium spanning the blood, transmission, and mosquito stages. The stage-specific models of Plasmodium falciparum uncovered stage-dependent changes in central carbon metabolism and predicted potential targets that could affect several life cycle stages...
January 4, 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/29281708/protein-protein-conjugate-nanoparticles-for-malaria-antigen-delivery-and-enhanced-immunogenicity
#15
Puthupparampil V Scaria, Beth Chen, Christopher G Rowe, David S Jones, Emma Barnafo, Elizabeth R Fischer, Charles Anderson, Nicholas J MacDonald, Lynn Lambert, Kelly M Rausch, David L Narum, Patrick E Duffy
Chemical conjugation of polysaccharide to carrier proteins has been a successful strategy to generate potent vaccines against bacterial pathogens. We developed a similar approach for poorly immunogenic malaria protein antigens. Our lead candidates in clinical trials are the malaria transmission blocking vaccine antigens, Pfs25 and Pfs230D1, individually conjugated to the carrier protein Exoprotein A (EPA) through thioether chemistry. These conjugates form nanoparticles that show enhanced immunogenicity compared to unconjugated antigens...
2017: PloS One
https://www.readbyqxmd.com/read/29247222/modelling-mosquito-infection-at-natural-parasite-densities-identifies-drugs-targeting-ef2-pi4k-or-atp4-as-key-candidates-for-interrupting-malaria-transmission
#16
Koen J Dechering, Hans-Peter Duerr, Karin M J Koolen, Geert-Jan van Gemert, Teun Bousema, Jeremy Burrows, Didier Leroy, Robert W Sauerwein
Eradication of malaria requires a novel type of drug that blocks transmission from the human to the mosquito host, but selection of such a drug is hampered by a lack of translational models. Experimental mosquito infections yield infection intensities that are substantially higher than observed in natural infections and, as a consequence, underestimate the drug effect on the proportion of mosquitoes that become infected. Here we introduce a novel experimental and computational method to adequately describe drug efficacy at natural parasite densities...
December 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29219249/activities-of-11-azaartemisinin-and-n-sulfonyl-derivatives-against-asexual-and-transmissible-malaria-parasites
#17
Rozanne Harmse, Dina Coertzen, Ho Ning Wong, Frans J Smit, Mariette E van der Watt, Janette Reader, Sindiswe H Nondaba, Lyn-Marie Birkholtz, Richard K Haynes, David D N'Da
Dihydroartemisinin (DHA), either used in its own right or as the active drug generated in vivo from the other artemisinins in current clinical use-artemether and artesunate-induces quiescence in ring-stage parasites of Plasmodium falciparum (Pf). This induction of quiescence is linked to artemisinin resistance. Thus, we have turned to structurally disparate artemisinins that are incapable of providing DHA on metabolism. Accordingly, 11-azaartemisinin 5 and selected N-sulfonyl derivatives were screened against intraerythrocytic asexual stages of drug-sensitive Pf NF54 and drug-resistant K1 and W2 parasites...
December 8, 2017: ChemMedChem
https://www.readbyqxmd.com/read/29190291/malera-an-updated-research-agenda-for-diagnostics-drugs-vaccines-and-vector-control-in-malaria-elimination-and-eradication
#18
(no author information available yet)
Since the turn of the century, a remarkable expansion has been achieved in the range and effectiveness of products and strategies available to prevent, treat, and control malaria, including advances in diagnostics, drugs, vaccines, and vector control. These advances have once again put malaria elimination on the agenda. However, it is clear that even with the means available today, malaria control and elimination pose a formidable challenge in many settings. Thus, currently available resources must be used more effectively, and new products and approaches likely to achieve these goals must be developed...
November 2017: PLoS Medicine
https://www.readbyqxmd.com/read/29162427/disulfide-bond-mapping-of-pfs25-a-recombinant-malaria-transmission-blocking-vaccine-candidate
#19
Shwu-Maan Lee, Jordan Plieskatt, C Richter King
A liquid chromatography tandem-mass spectrometry method was developed to map the eleven disulfide bonds in Pfs25, a malaria transmission-blocking vaccine candidate. The compact and complex nature of Pfs25 has led to difficulties in prior peptide mapping efforts. Here, we report confirmation of proper disulfide pairing of a recombinant Pfs25, by optimizing denaturation and digestion with trypsin/Lys-C. The digested peptides were separated by reversed phase HPLC to obtain the peptide map and elucidate the disulfide linkages...
November 18, 2017: Analytical Biochemistry
https://www.readbyqxmd.com/read/29161848/complex-wolbachia-infection-dynamics-in-mosquitoes-with-imperfect-maternal-transmission
#20
Bo Zheng, Wenliang Guo, Linchao Hu, Mugen Huang, Jianshe Yu
Dengue, malaria, and Zika are dangerous diseases primarily transmitted by Aedes aegypti, Aedes albopictus, and Anopheles stephensi. In the last few years, a new disease control method, besides pesticide spraying to kill mosquitoes, has been developed by releasing mosquitoes carrying bacterium Wolbachia into the natural areas to infect the wild population of mosquitoes and block disease transmission. The bacterium is transmitted by infected mothers and the maternal transmission was assumed to be perfect in virtually all previous models...
April 1, 2018: Mathematical Biosciences and Engineering: MBE
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