Malaria 2012: Drugs, Vaccines, and Pathogenesis
Tuesday, April 17, 2012
Approximately one half of the world population is at risk in contracting malaria, and it afflicts a disproportionally large number of people in the resource-constrained regions of the world. In recent years there has been a renewed effort in trying to control this disease at different levels, such as basic research of the causative Plasmodium species, new vaccine and drug development programs, efforts to control its vector, mosquito, and improving the public hygiene and the economic status. On the vaccine side, due to the complexity of the parasite physiology and the human immune system, there are many challenges in developing effective vaccines but there are several promising vaccines currently in clinical trials. On the drug side, there are signs of drug-resistance to the current artemisinin-based treatments but there are candidate drugs to address this problem. This symposium will focus on the latest development in our understanding of the parasite, in developing new vaccines, and in discovering potentially novel anti-malarial drugs.
Networking Reception to Follow.
Registration Pricing
| Member | $25 |
| Student / Postdoc / Fellow Member | $10 |
| Nonmember Academia | $60 |
| Nonmember Corporate | $80 |
| Nonmember Not for Profit | $60 |
| Student / Postdoc / Fellow Nonmember | $40 |
Agenda
* Presentation times are subject to change.
Tuesday, April 17, 2012 | |
8:30 AM | Registration and Continental Breakfast |
9:00 AM | Welcome and Opening Remarks |
Session I. Pathogenesis and intervention | |
9:15 AM | Pathophysiology, Host and Parasite Transcriptomics |
9:45 AM | Plasmodium-Induced Inflammation and Cerebral Malaria: Therapeutic Approaches |
10:15 AM | The Interrelated Roles of RNA Polymerase II and Histone Modifiers in Regulating Antigenic Variation by Malaria Parasites |
10:45 AM | Characterization of the Parasite Metabolome and Implications for Pathogenesis |
11:15 AM | Coffee Break |
Session II. Anti-malarial vaccines and other drugs under development | |
11:45 AM | A Malaria Vaccine: How Close are We? |
12:15 PM | The Achilles' Heel of the Malaria Parasite |
12:45 PM | Lunch Break and Poster Session |
Session II. (continued) | |
2:00 PM | Keynote presentation: Evolution of Malaria Parasites |
2:45 PM | Keynote presentation: New Medicines for the Control and Elimination of Malaria |
3:30 PM | Coffee Break |
4:00 PM | Identification of Methylene Blue as a Potent Inhibitor of P. falciparum Gametocyte Transmission and Development of Zinc-Finger Technology to Rapidly and Precisely Edit the Parasite Genome |
4:30 PM | Transition State Analogues Block Purine Salvage in Plasmodium falciparum |
5:00 PM | Networking Reception |
6:00 PM | Close |
Speakers
Organizers
Johanna P. Daily, MD
Albert Einstein College of Medicine
Dr. Daily is an Infectious Disease trained physician-scientist who has been carrying out field studies of malaria for over ten years. She received her MD at SUNY Upstate, completed an Internal Medicine residency at Tufts Medical Center and an Infectious Disease fellowship at the Brigham and Women’s Hospital. She is presently an associate professor in the Departments of Medicine (Infectious Disease) and Microbiology and Immunology at Albert Einstein College of Medicine. Her laboratory research interest is in the epidemiology and pathogenesis of the malaria parasite Plasmodium falciparum. The goal of the research has been to define the molecular mechanisms that underlie the variation of disease outcomes in P. falciparum. They have identified novel parasite biology when it resides in the human host; this biology has not been reported under in vitro cultivation and may play a role in enhanced virulence and/or transmission capacity. To further understand the implications of these novel in vivo states they study the parasite under in vitro conditions that mimic host blood stream conditions. They are also studying host response to infection using whole genome approaches to identify host factors that associate with severe disease outcomes. Using a complementary approach of high throughput small molecule analysis they have begun to identify parasite specific small molecules in vivo and in vitro. The long term goal is to refine the model of pathogenesis to identify parasite and host processes involved in disease to serve as targets for vaccine or chemotherapeutic development.
David A. Fidock, PhD
Columbia University Medical Center
Dr. Fidock is an Associate Professor at the Columbia University Medical Center, with joint appointments in the Departments of Microbiology & Immunology and of Medicine. Previously, he was a faculty member at the Albert EInstein College of Medicine and was a postdoctoral researcher at UC Irvine and the NIH. His graduate training was at the Pasteur Institute in Paris. Dr. Fidock heads a malaria research lab focused primarily on defining the genetic and molecular basis of drug resistance and the mode of action of antimalarial drugs, as well as investigations into lipid metabolism in blood and liver stage parasites.
Takushi Kaneko, PhD
TB Alliance
Dr. Takushi Kaneko is Senior Project Leader at TB Alliance (Global Alliance for TB Drug Development), a New York based not-for-profit organization dedicated to the discovery and development of better, faster-acting, and affordable tuberculosis drugs. After obtaining a degree at the University of Michigan and conducting post-doctoral work at Harvard University, he spent most of his time in drug discovery research in Bristol-Myers Squibb and Pfizer in the areas of cancer chemotherapy, natural product discovery, and antibacterial agents.
Jennifer Henry, PhD
The New York Academy of Sciences
Speakers
Johanna P. Daily, MD
Albert Einstein College of Medicine
Kirk W. Deitsch, PhD
Weill Cornell Medical College
Dr. Kirk W. Deitsch is a Professor of Microbiology and Immunology at Weill Medical College of Cornell University. His primary research interests are centered on the molecular and biochemical aspects of malaria parasites including such cellular processes as antigenic variation, transcriptional gene regulation, DNA repair and nuclear organization. He spent five years as a research fellow in the Malaria Genetics Section of the Laboratory of Parasitic Diseases at the National Institutes of Health prior to his arrival at Weill Medical College in 2001. He is a recipient of a New Scholar Award in Global Infectious Diseases from the Ellison Medical Foundation as well as a Presidential Early Career Award in Science and Engineering. In addition to his research interests, he is also the co-director of the Molecular and Cell Biology PhD Program at Weill Cornell, the co-director of the Biology of Parasitism Summer course taught at the marine biological laboratory in Woods Hole MA, and the organizer of a 2-week summer course in advanced cell biology offered in Accra, Ghana that is sponsored by the American Society for Cell Biology. He also serves on several editorial boards and NIH study sections.
David A. Fidock, PhD
Columbia University Medical Center
Manuel Llinás, PhD
Princeton University
Dr. Manuel Llinás is an Associate Professor of Molecular Biology and a member of the Lewis-Sigler Institute for Integrative Genomics at Princeton University. Dr. Llinás earned a PhD in molecular and cell biology from the University of California-Berkeley and did postdoctoral work in the lab of Joseph DeRisi at the University of California-San Francisco. He joined the Princeton faculty in 2005. Dr. Llinás’ laboratory studies the deadliest of the four human Plasmodium parasites, Plasmodium falciparum. His research combines tools from functional genomics, molecular biology, computational biology, biochemistry, and metabolomics to understand the fundamental molecular mechanisms underlying the development of this parasite. The focus is predominantly on the red blood cell stage of development, which is the stage in which all of the clinical manifestations of the malaria disease occur. His research has focused on two major areas: the role of transcriptional regulation in orchestrating parasite development, and an in-depth characterization of the malaria parasite’s unique metabolic network. On the transcription side, Dr. Llinás’ lab works on the characterization of the first family of DNA binding proteins to be identified in the Plasmodium falciparum genome, the Apicomplexan AP2 (ApiAP2) proteins. The metabolomics work has begun to identify unique biochemical pathway architectures in the parasite. These two approaches explore relatively virgin areas in the malaria field with the goal of identifying novel strategies for therapeutic intervention.
Victor Nussenzweig, MD, PhD
New York University Langone Medical Center
Victor Nussenzweig was born in Sao Paulo, Brazil. He completed his MD/PhD degrees at the School of Medicine of the University of Sao Paulo. The post doctoral training in Immunology was at the Institute Pasteur (1958–1960). From 1963 to 1965 he worked with Dr. Baruch Benacerraf in the Department of Pathology at New York University School of Medicine. He was appointed Assistant Professor at NYU in 1966 and Hermann M. Biggs Professor of Pathology in 1987. He published more that 300 papers on the control of complement activation, on malaria biology and vaccine development. He has received many honors including membership in the National Academy of Arts and Sciences.
Christopher Plowe, MD, MPH
University of Maryland
Christopher Plowe is a Howard Hughes Medical Institute Investigator in Patient-Oriented Research, a Professor of Medicine, of Molecular Microbiology and Immunology, and of Epidemiology and Public Health, and Leader of the Malaria Group as well as Associate Director for Research Training at the University of Maryland School of Medicine's Center for Vaccine Development in Baltimore. He leads one of the country's largest and most productive malaria research groups, with team members working in the molecular parasitology and genomic epidemiology laboratories in Baltimore and at field sites in Mali, Malawi and Southeast Asia. Born and raised in South Dakota, he earned degrees in Philosophy and Medicine at Cornell and in Public Health and Tropical Medicine at Columbia, and completed fellowships in infectious diseases at Johns Hopkins, and in malaria research at the National Institutes of Health. Dr. Plowe has worked on many aspects of malaria but is best known for developing tools for the molecular surveillance of drug resistant malaria and for his work on malaria vaccines, including the first demonstration of strain-specific blood-stage vaccine efficacy against clinical malaria. His other current major interests are on mitigating the threat of emerging artemisinin resistance in Southeast Asia by conducting genome-wide association studies to identify molecular markers of resistance to help guide containment efforts, and training malaria researchers in Mali, West Africa and in Myanmar and other Southeast Asian countries.
Ana Rodriguez, PhD
New York University School of Medicine
Ana Rodriguez is an Associate Professor at New York University School of Medicine, Department of Microbiology, Division of Parasitology. Since 1999, a main interest of her laboratory is the study of malaria-induced inflammatory pathology. Through the study of Plasmodium pathogenesis they intend to open new approaches to control disease pathology and death. The laboratory also participates in efforts to develop effective drugs against Chagas Disease. In collaboration with the Broad Institute, they have performed high through put screenings of intracellular Trypanosoma cruzi, to find compounds with anti-trypanosomal activities. They currently collaborate with Sanofi-Aventis and GSK in the development of different candidate drugs originally identified in the high throughput screen.
Vern L. Schramm, PhD
Albert Einstein College of Medicine
Vern L. Schramm, PhD, was trained in chemistry, microbiology, nutrition and mechanistic enzymology with degrees from South Dakota State University, Harvard University and the Australian National University. Research in faculty positions at Temple University School of Medicine and Albert Einstein College of Medicine have focused on the analysis of enzymatic transition states. Transition state knowledge from this research has been used to generate stable chemical analogues of the transition state. These are some of the most powerful inhibitors known. The technology is now being developed for application to malaria, cancer, gout and bacterial antibiotics. Dr. Schramm is currently Ruth Merns Chair and Professor of Biochemistry at the Albert Einstein College of Medicine. Dr. Schramm has served as an Associate Editor of the Journal of the American Chemical Society and is a member of the National Academy of Sciences.
Timothy N.C. Wells, PhD
Medicines for Malaria Venture
Timothy N.C. Wells has been the Chief Scientific Officer of Medicines for Malaria Venture based in Geneva, Switzerland since 2007. He has a PhD in Chemistry from Imperial College London, and an ScD in Biology from Cambridge UK. Prior to this he was head of Research for the Swiss-headquartered biotech company Serono.
Elizabeth Winzeler, PhD
University of California, San Diego
Elizabeth Winzeler, PhD is a Professor in the Department of Pediatrics at University of California, School of Medicine. She received her Bachelor of Arts degree in Natural Sciences and Art from Lewis and Clark College in 1984. After a hiatus working as software developer she returned to academia and obtained a Ph. D. at Stanford in 1996 in the Department of Biochemistry, working with the development microbiologist, Lucy Shapiro. As a postdoctoral fellow in the Department of Biochemistry at Stanford from 1996-1999 she worked with the yeast geneticist, Ron Davis before moving to San Diego to take up a joint appointment at Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation in 1999. In 2004 she was awarded the New Scholar in Biomedical Research award from the Keck Foundation. In addition to being a Keck scholar she is also a former Ellison Medical Foundation Scholar and was a semifinalist in the 2008 Howard Hughes Competition. At the Genomics Institute of the Novartis Research Foundation she has led a malaria drug discovery effort that has resulted in the identification of several novel antimalarial chemotypes that are currently in clinical trials. Her group uses systematic, data intensive methods to solve problems at the interface of host pathogen biology typically utilizing large collections of chemical screening data, whole genome sequencing, or other “big data.” She recently moved to the University of California, San Diego, School of Medicine to join a group focused on Infection, Immunity and Inflammation.
Sponsors
Academy Friends
Corporate Alliance on Malaria in Africa (CAMA)
Promotional Partners
American Society for Microbiology
American Society of Parasitologists
Brazilian Society of Tropical Medicine
Chinese Society of Parasitology
Egyptian Parasitologists United/Parasitologists United Journal
European Federation of Parasitologists
Human Vaccines & Immunotherapeutics — Landes Bioscience
The Malaria Research and Reference Reagent Resource Center (MR4)
Abstracts
Pathophysiology, Host and Parasite Transcriptomics
Johanna Daily, Albert Einstein College of Medicine
Infection with the malaria parasite Plasmodium falciparum leads to widely different clinical conditions in the human host – ranging from asymptomatic, to mild flu-like symptoms to coma and death. Despite the immense medical implications, the genetic and molecular basis of this diversity remains largely unknown. We hypothesize that variation in both host and parasite biology culminate to mediate infection outcomes. This interaction is likely dynamic, and thus we have attempted to capture host and parasite biologic states during natural infection. We utilize whole genome analysis of both the parasite and host cells directly from blood samples. We identified previously unknown physiological diversity in the in vivo biology of the malaria parasite, not seen under standard laboratory in vitro cultivation methods. We now will present data derived from a cohort of children with severe disease and identify parasite biology associated with severe disease and mortality. In addition we have carried out a longitudinal study in children with severe malaria followed by an episode of mild malaria to identify host transcriptional responses associated with mild disease using a paired analysis. The long term goal is to identify parasite or host biology that can be targeted to reduce individual and global health burden of Plasmodium falciparum.
Plasmodium-Induced Inflammation and Cerebral Malaria: Therapeutic Approaches
Ana Rodriguez, New York Univerity School of Medicine
Malaria is characterized by cyclical fevers and high levels of inflammatory cytokines. While an early inflammatory response contributes to parasite clearance, excessive and persistent inflammation can lead to more severe disease pathology. We found that Plasmodium falciparum infected erythrocytes contain uric acid precipitates that are released upon rupture of the erythrocyte. Uric acid precipitates are highly inflammatory molecules considered a danger signal for innate immunity, and are the causative agent in gout. We found that P. falciparum uric acid precipitates activate human dendritic cells and are responsible for approximately half of the total stimulatory activity induced by P. falciparum lysates. Since uric acid precipitates were identified in P. falciparum and P. vivax infected erythrocytes freshly isolated from malaria patients, we propose that uric acid precipitates are an important cause of inflammation in malaria. We are also analyzing the role of uric acid precipitates during cerebral malaria. Release of these precipitates over brain endothelial cells during sequestration may induce blood brain barrier damage. Our preliminary results in vitro indicate that human brain endothelial cells disrupt cell to cell adhesions and enter into apoptosis as a response to P. falciparum lysates and of uric acid precipitates.We are also studying the role of drugs that modulate angiotensin receptors in the context of cerebral malaria. Preliminary results in vitro and in vivo indicate that they can modulate the integrity of endothelial cells adhesions and determine the outcome of experimental cerebral malaria.
The Interrelated Roles of RNA Polymerase II and Histone Modifiers in Regulating Antigenic Variation by Malaria Parasites
Kirk W. Deitsch, Weill Medical College of Cornell University
Both virulence and antigenic variation of the human malaria parasite Plasmodium falciparum are linked to expression of the variant surface protein PfEMP1, different forms of which are encoded by the multicopy var gene family. var gene expression is mutually exclusive and regulated at the level of transcription, and specific histone modifications are associated with either the active or silent state of the genes. We previously showed that active transcription is necessary for the maintenance of proper regulation of var gene expression through multiple asexual divisions. Our current work is focused on a surprising polymorphism within the C-terminal domain of RNA polymerase II of P. falciparum that has been implicated in the recruitment of histone modifiers to actively transcribed regions of the genome. We have found a specific putative histone methyltransferase and its cognate demethylase that are predicted to be recruited by RNA polymerase II during transcription, thus potentially reinforcing the epigenetic marks found at active var genes and providing a possible mechanism for cellular memory. We have now shown that this histone methyltransferase directly binds to RNA polymerase II via its C-terminal domain, and that inhibition of this interaction disrupts var gene regulation, thus identifying a potential novel target for drug development.
Characterization of the Parasite Metabolome and Implications for Pathogenesis
Manuel Llinás, Princeton University
The genome of Plasmodium falciparum indicates that the metabolic pathways utilized by this organism are highly unique. Recent efforts to comprehensively examine the biology of P. falciparum have focused on transcriptome and proteome analysis to gain insight into Plasmodium-specific pathways. The third crucial component that remains to be established is the metabolome: the complement of small-molecule metabolites and their relative levels. Our lab has begun to characterize various aspects of parasite metabolism using high accuracy mass-spectrometry to simultaneously measure metabolites from complex cellular extracts from parasite-infected cells. The approaches we are using allow us to assay various aspects of the P. falciparum metabolome. One approach has been to examine the interaction of Plasmodium with the host red blood cell using targeted measurements of specific metabolites shared with the host erythrocyte. We are also using 13C and 15N isotopic labeling experiments to directly trace carbon flux through known biochemical pathways. Finally, we are using metabolite measurements to map genetic control of metabolism by assaying global metabolite patterns in the parents and progeny of a Plasmodium falciparum genetic cross. Results from these studies are beginning to unravel the divergence of metabolism in P. falciparum and promise to provide unique avenues for future drug intervention strategies.
A Malaria Vaccine: How Close are We?
Christopher Plowe, University of Maryland
Vaccines are the most powerful public health tools mankind has created, but malaria parasites are bigger, more complicated, and wilier than the viruses and bacteria that have been conquered or controlled with vaccines. Despite decades of research toward a vaccine for malaria, this goal has remained elusive, in part because of extreme genetic diversity in leading vaccine antigens. Nevertheless, recent advances justify optimism that a licensed malaria vaccine is within reach. A subunit recombinant protein vaccine that affords in the neighborhood of 50% protective efficacy against clinical malaria is in the late stages of clinical evaluation in Africa. Incremental improvements on this successful vaccine are possible and worth pursuing. However, the best hope for a highly efficacious malaria vaccine that would improve prospects for malaria eradication may lie with the use of attenuated whole parasites, which were tested unsuccessfully in humans in New York in 1945, forgotten, then tested successfully in Baltimore and Chicago in the early 1970s, but abandoned in favor of recombinant DNA approaches until finally becoming a leading strategy in the new era of malaria elimination and eradication.
The Achilles' Heel of the Malaria Parasite
Victor Nussenzweig, New York University Langone Medical Center
In response to environmental stresses, the mammalian serine threonine kinases PERK, GCN2, HRI, and PKR phosphorylate the regulatory serine 51 of the eukaryotic initiation factor 2α (eIF2α) of translation to inhibit global protein synthesis. Plasmodium, the protozoan that causes malaria, expresses three eIF2α kinases IK1, IK2, and PK4. Like GCN2, IK1 regulates stress response to amino acid starvation. IK2 inhibits development of malaria sporozoites present in the mosquito salivary glands. Here we show that the phosphorylation by PK4 of the regulatory serine 59 of Plasmodium eIF2α is essential for the completion of the parasite’s erythrocytic cycle that causes disease in humans. PK4 activity leads to the arrest of global protein synthesis in schizonts, where ontogeny of daughter merozoites takes place, and in gametocytes that infect Anopheles mosquitoes. The implication of these findings is that drugs that reduce PK4 activity should alleviate disease and inhibit malaria transmission. High throughput screening of small molecule libraries in search for inhibitors is ongoing.
Keynote Presentation: Evolution of Malaria Parasites
Elizabeth Winzeler, University of California, San Diego
The ability of the P. falciparum parasites to acquire drug resistance through single nucleotide polymorphisms and copy number amplifications as well as to evade the host immune response makes it difficult to control the global malaria burden. My group has been using long term in vitro evolution of cloned parasites, grown in the presence and absence of drugs and full genome sequencing of patient isolates to determine how quickly the parasite will acquire evasive genetic changes that may allow parasites to escape drugs and vaccines. Sequencing and microarray analysis shows that single nucleotide polymorphisms arising in core chromosomal regions are relatively common and that the core genome is very stable. In contrast, large-scale deletions and rearrangements of subtelomeric regions containing members of gene families involved in immune evasion are more frequent during mitotic growth. Our findings predict rapid evolution and diversification in a clonal parasite population and predict the rapid appearance of multiple haplotypes even in a single human malaria infection.
Keynote Presentation: New Medicines for the Control and Elimination of Malaria
Timothy N.C. Wells, Medicines for Malaria Venture, Geneva, Switzerland
Malaria is a disease which used to be characterized by market failure. The disease effects primarily children, and children in poor countries, meaning that the financial case for the development of new medicines has been difficult within the pharmaceutical industry. MMV was set up 12 years ago to catalyse the discover development and delivery of new medicines against malaria: in partnership with academia, industry, government and foundations. To date four products have been launched, which are having a major impact on the lives of children. The decision by WHO to move forward on a strategy for malaria eradication in 2007 led to the need for new medicines, not just to cure patients, but to block transmission, prevent relapses, and protect children from reinfection. There has been a renaissance of new molecules coming into the pipeline, from a balance of target based, and whole cell screening – some of which are now being validated in patients. The implications of this success for malaria, and for other therapeutic areas will be discussed.
Identification of Methylene Blue as a Potent Inhibitor of P. falciparum Gametocyte Transmission and Development of Zinc-Finger Technology to Rapidly and Precisely Edit the Parasite Genome
David Fidock, Columbia Univeristy Medical Center
The recent expansion of the malaria control agenda has highlighted the need to develop new drugs that can be used to block transmission Plasmodium falciparum parasites to the mosquito vector. We report the development of a luciferase-based assay that enables precise assessment of the transmission-blocking activity of antimalarial compounds. This assay uses reporter lines that express GFP-luciferase fusions under the control of promoters active at different stages of gametocyte maturation. The data reveal that most first-line antimalarials are effective only against early-stage gametocytes. Encouragingly, methylene blue was found to exert potent activity against early and mature gametocytes and to block transmission to mosquitoes. We also present recent work illustrating that zinc-finger nuclease technology can be harnessed to generate gene knockouts and gene editing events with unprecedented speed and precision. We propose that this new approach will substantially improve the ability to rapidly and efficiently manipulate the P. falciparum genome for experimental investigations including the study of antimalarial drug resistance.
Transition State Analogues Block Purine Salvage in Plasmodium falciparum
Vern L. Schramm, Albert Einstein College of Medicine
Purine metabolism in P. falciparum relies on hypoxanthine salvage and can be disrupted with transition-state analogue inhibitors effective against both human and Plasmodium purine nucleoside phosphorylases (PNPs). Transition state analogue inhibitors of human and Plasmodium PNPs are lethal for P. falciparum cultured in vitro. PNPs are present both in parasites and human erythrocytes and PfPNP is critical for in vitro growth. P. falciparum genetically disrupted in PNP have increased purine requirements and are unable to thrive in vitro at physiological concentrations of hypoxanthine. P. falciparum is the most lethal of malaria parasites in humans and it has narrow host specificity. Aotus monkeys provide a non-human primate model for testing the efficacy of PNP transition-state analogues against this parasite. Inhibition of PNP by orally administrated DADMe-Immucillin-G (here named BCX4945), clears the blood of P. falciparum in Aotus monkeys followed by recrudescence when treatment is stopped. BCX4945 causes depletion of hypoxanthine from Aotus blood, demonstrating inhibition of both hPNP and PfPNP in vivo.
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