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Malaria 2014: Advances in Pathophysiology, Biology and Drug Development

Malaria 2014: Advances in Pathophysiology, Biology and Drug Development

Friday, April 25, 2014

The New York Academy of Sciences

With approximately 3.3 billion people (one half of the world’s population) still at risk of contracting malaria, and over 650,000 malaria deaths annually, there is still much work to be done before this disease can be controlled and possibly eradicated. Increased prevention and control measures have led to a 25% worldwide reduction in malaria mortality rates since 2000. However, those living in the poorest countries remain the most vulnerable to malaria, and nearly 90% of all malaria deaths worldwide occur in the sub-Saharan Africa, mostly among children under five years of age infected with the malaria parasite Plasmodium falciparum. This one-day symposium examines the latest developments in understanding disease processes and the biology of the parasite, and developing antimalarial drugs and candidate vaccines. We will present recent research findings including the pathophysiology and neuropathology of cerebral malaria, the molecular mechanisms of sporozoite invasion in the liver, and the development of novel antimalarial therapies. We will also explore drug resistance to the artemisinin derivatives that are the core components of current drug combination therapies. Join us and our outstanding panel of speakers on World Malaria Day for a very exciting symposium.

Reception to follow.

Registration and Webinar Pricing

Student/Postdoc Member$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45


The Microbiology & Infectious Diseases Discussion Group is proudly supported by


Mission Partner support for the Frontiers of Science program provided by Pfizer


* Presentation titles and times are subject to change.

April 25, 2014

8:00 AM

Registration and Continental Breakfast

8:30 AM

Welcome and Opening Remarks
Jennifer Henry, PhD, The New York Academy of Sciences
Johanna Daily, MD, MS, Albert Einstein College of Medicine

Session I. Pathophysiology

8:45 AM

Keynote presentation: The Pathogenesis of Fatal Cerebral Malaria: A Few More Pieces of the Puzzle
Terrie E. Taylor, DO, Michigan State University

9:30 AM

Neuropathology of Experimental Cerebral Malaria
Mahalia S. Desruisseaux, MD, Albert Einstein College of Medicine

10:00 AM

Coffee Break

Session II. Pre-erythrocytic/Liver Stage Biology

10:30 AM

Keynote presentation: The Biology of P. vivax as Explored through Genomics
Jane M. Carlton, PhD, New York University

11:15 AM

Translational Regulation during Stage Transition in the Malaria Parasites
Liwang Cui, PhD, Pennsylvania State University

11:45 PM

The Plasmodium Sporozoite's Journey and Beyond
Photini Sinnis, MD, Johns Hopkins University

12:15 PM

Sporozoite Stages in the Liver: Development of Novel Therapies against Malaria
Purnima Bhanot, PhD, UMDNJ

12:45 PM

Lunch Break and Poster Session

Session III. Drug Resistance and Drug Development

1:45 PM

Keynote presentation: Artemisinin-Resistant Malaria in Southeast Asia: A Tale of Patients, Parasites and a "Propeller"
Rick M. Fairhurst, MD, PhD, National Institute of Allergy and Infectious Disease, NIH

2:30 PM

Targeting New Pathways in Plasmodium to Eliminate Malaria
Marcus Lee, PhD, Columbia University Medical Center

3:00 PM

The Molecular Basis of Antifolate Resistance
Laura Kirkman, MD, Weill Cornell Medical College

3:30 PM

Coffee Break

4:00 PM

Antimalarial Drug Resistance in Africa
Miriam Laufer, MD, MPH, University of Maryland School of Medicine

4:30 PM

Malaria Equilibrative Nucleoside Transporters: A Potential Path to Novel Anti-Malarial Drugs
Myles Akabas, MD, PhD, Albert Einstein College of Medicine

5:00 PM

Generation of Humanized Mouse Models for Malaria
Alex Ploss, PhD, Princeton University

5:30 PM

Presentation of ‘Best Poster’ Awards and Closing Remarks
David Fidock, PhD, Columbia University Medical Center

Networking Reception

6:30 PM




Johanna P. Daily, MD, MS

Albert Einstein College of Medicine

Johanna P. Daily, MD, MS is an Associate Professor of Medicine at Albert Einstein College of Medicine and an infectious disease trained physician who conducts field and laboratory based studies of Plasmodium falciparum to understand pathogenesis. She attended SUNY-Syracuse Medical College and trained at NEMC and BWH in Boston and was an Assistant Professor of Medicine at Harvard Medical School prior to Einstein. Her laboratory studies parasite and host biology associated with malarial disease outcomes using transcriptomic and metabolomic approaches to provide novel insights into disease mechanisms. Long term goals are to characterize host/pathogen factors related to parasite virulence and transmission as targets of intervention.

David A. Fidock, PhD

Columbia University Medical Center

Dr. Fidock is a Professor of Microbiology and Immunology and of Medical Sciences (in Medicine) in the Division of Infectious Diseases at the Columbia University Medical Center in northern Manhattan. He is also the Director of the Graduate Training Program in Microbiology, Immunology and Infection at Columbia University. Previously he was a faculty member at the Albert Einstein College of Medicine. Dr. Fidock completed his postdoctoral studies at the University of California at Irvine and in the Laboratory of Parasitic Diseases at the NIH. He obtained his PhD at the Pasteur Institute in Paris and his Bachelor of Sciences with Honors in Mathematics and Genetics at Adelaide University in South Australia. As of February 2014, Dr. Fidock has coauthored over 125 Pubmed-indexed papers on Plasmodium and written 6 book chapters. His laboratory specializes in the genetic and molecular analysis of mechanisms of drug resistance in the human malaria parasite Plasmodium falciparum and in elucidating antimalarial drug modes of action.

Jennifer S. Henry, PhD

The New York Academy of Sciences

Keynote Speakers

Jane M. Carlton, PhD

New York University

Dr. Carlton is Director of the Center for Genomics and Systems Biology, and Professor in the Department of Biology at New York University. She received her PhD in Genetics at the University of Edinburgh, Scotland, and has worked at several scientific institutions in the United States, including NCBI at the National Institutes of Health, and The Institute for Genomic Research (TIGR). Dr. Carlton is passionate about genomics and its power to revolutionize the study of parasites. Her research involves using the tools of comparative genomics (bioinformatics, genetics/genomics, evolution and molecular biology) to study the biology of the malaria parasite, as well as the sexually transmitted pathogen Trichomonas vaginalis. She has a keen interest in global public health through her collaborations with scientists in India, and is Program Director of a seven-year NIH International Center of Excellence in Malaria Research with Indian colleagues. She received the American Society of Parasitologists’ Stoll-Stunkard Memorial Award in 2010, was elected a Fellow of the American Association for the Advancement of Science in 2012, and has published more than 100 research articles and reviews. Professor Carlton’s ultimate goal is to cultivate and expand the science and use of genomics to study parasites.

Rick M. Fairhurst, MD, PhD

National Institute of Allergy and Infectious Disease, NIH

Dr Fairhurst received his MD and PhD (molecular biology) degrees from the University of California, Los Angeles (UCLA). Following an internal medicine residency and an infectious diseases fellowship at UCLA Medical Center, he joined the National Institute of Allergy and Infectious Diseases in 2001. As a clinical tenure-track investigator in the Laboratory of Malaria and Vector Research, Dr Fairhurst focuses his laboratory’s work on elucidating the mechanisms of genetic resistance and acquired immunity to malaria in Africa, and parasite resistance to artemisinin-based combination therapies in Southeast Asia. He travels frequently to malaria-endemic areas of Mali and Cambodia, where his trainees and colleagues enroll patients into clinical research protocols and use bio-specimens in on-site laboratory investigations. Dr Fairhurst is past president of the American Committee on Molecular, Cellular and Immunoparasitology, a subcommittee of the American Society of Tropical Medicine and Hygiene (ASTMH), and director of the National Institutes of Health MD–PhD Partnership Training Program. He has received the NIAID Outstanding Mentor of the Year Award (2011) and the ASTMH Bailey K. Ashford Medal for distinguished work in tropical medicine (2013).

Terrie E. Taylor, DO

Michigan State University

Dr. Terrie Taylor is a University Distinguished Professor in the College of Osteopathic Medicine at Michigan State University. She has been dividing her time between Michigan (July - December) and Malawi (January-June) since 1987. Together with Prof. Malcolm Molyneux, she has been involved in an ongoing research effort to understand the pathogenesis of fatal malaria in Malawian children. This effort has included bedside observations, autopsies and, most recently, neuro-imaging via MRI. Over 300 medical students from Michigan State have enjoyed clinical electives under Dr. Taylor's supervision in Malawi since 1987.


Myles Akabas, MD, PhD

Albert Einstein College of Medicine

Myles H. Akabas, M.D., Ph.D. is a Professor of Physiology and Biophysics, Neuroscience and Medicine and Director of the Medical Scientist Training Program at the Albert Einstein College of Medicine. He received his BA in Physics from Cornell University and his MD-PhD from the Albert Einstein College of Medicine. He completed an Internal Medicine residency and Nephrology fellowship at the Columbia-Presbyterian Medical Center. He was appointed Assistant Professor of Medicine at Columbia University College of Physicians and Surgeons. He received a Klingenstein Fellowship in Neuroscience, an Established Investigator Award from the New York City Affiliate of the American Heart Association and the Paul F. Cranefield Award of Scientific Merit from the Society of General Physiologists. In 2000 he was recruited back to the Albert Einstein College of Medicine and became MSTP Director in 2004. He is the recipient of the LaDonne Schulman Award for Excellence in Teaching from the graduate students of the Albert Einstein College of Medicine. Dr. Akabas’s research interests focus on the physiology of ion channels and membrane transporters. His recent work has focused on the structure and function of purine transporters in malaria parasites.

Purnima Bhanot, PhD

UMDNJ - New Jersey Medical School

Purnima Bhanot is an Associate Professor in Microbiology and Molecular Genetics at the Rutgers New Jersey Medical School. She received a Bachelor of Arts in biochemistry from Mount Holyoke College and a Ph.D in molecular biology and genetics from the Johns Hopkins School of Medicine. She continued her research training in malaria as a postdoctoral fellow at the New York University School of Medicine. She received postdoctoral fellowships from the Irvington Institute of Immunology and the Life Sciences Research Foundation. Her current research focuses on signalling pathways of Plasmodium’s pre-erythrocytic stages. She has identified the role of cGMP signalling in the parasite’s infection of the liver and its subsequent intra-hepatic development. Her research is supported by the National Science Foundation, the National Institutes of Health, the Department of Defense and the American Heart Association.

Liwang Cui, PhD

Pennsylvania State University

Liwang Cui is a Professor at the Department of Entomology, Pennsylvania State University. He received his BS degree in Plant Protection from Shenyang Agricultural University (1984), a PhD in microbial control from the Moldova Agricultural University (1991), a PhD in molecular virology from University of Kentucky (1996). He did his postdoctoral training at the Walter Reed Army Institute of Research in medical entomology and parasitology (1997-2000). He teaches courses in vector-borne diseases and parasitology. His research interests focus on malaria, including developmental biology, epigenetic regulation of gene expression and mechanisms of drug resistance in malaria parasites. Dr. Cui’s research is mostly funded by the National Institutes of Health and he has co-authored more than 130 papers in peer-reviewed scientific journals.  He is currently directing an International Center of Excellence in Malaria Research (ICEMR), funded by National Institute of Allergy and Infectious Diseases, NIH and conducts malaria research in three Southeast Asian countries.

Mahalia S. Desruisseaux, MD

Albert Einstein College of Medicine

Dr. Mahalia Desruisseaux is an Assistant Professor at the Albert Einstein College of Medicine. She received her MD degree at the Robert Wood Johnson Medical School in New Jersey, and completed an Internal Medicine residency at North Shore University Hospital in Manhasset, NY. She came to Einstein in 2003 as a clinical fellow in Infectious Diseases, and has been working on a murine model of cerebral malaria since. She was the first recipient of the IDSA ERF/NFID Colin L Powell Minority Postdoctoral Fellowship in Tropical Disease Research for her work during this fellowship. Dr. Desruisseaux was first to describe an increase in all the components of the endothelin pathway in the mouse model, associated with a decrease in cerebral blood flow. She also demonstrated that mice successfully treated with antimalarials sustain persistent cognitive deficits associated with abnormalities in the microtubule-associated protein tau, a protein which has been linked to the development of Alzheimer's disease. Currently her continuing program is focused on detailing the mechanisms leading to blood brain barrier dysfunction and to persistent cognitive deficits in the experimental cerebral malaria model.

Laura Kirkman, MD

Weill Cornell Medical College

Laura Kirkman is currently an Assistant Professor of Medicine in the Division of Infectious Diseases at Weill Cornell Medical College and with a secondary appointment in the Department of Microbiology and Immunology. After graduating from Swarthmore College, she became interested in parasitology while working in the laboratory of Thomas Wellems. There she was introduced to molecular parasitology and fieldwork on P. falciparum working both at NIAID and in Bamako, Mali. She attended Medical School at Albert Einstein College of Medicine where she spent a year as a HHMI student fellow studying T. gondii in the labs of Drs. Kami Kim and Louis Weiss. She completed her medical training at Yale New Haven Hospital and Infectious Disease Fellowship at NYP/Weill Cornell Medical College. After fellowship, she was a postdoctoral fellow in the laboratory of Kirk Deitsch investigating DNA repair in the malaria parasite. Now as a member of the faculty, Dr. Kirkman focuses her laboratory studies on malaria and the tick born pathogen Babesia. In addition, she continues her clinical work and serves as the Associate Program Director of the Infectious Diseases fellowship. She is funded by the NIH, a 2013 WCMC CTSC seed award, and the William Randolph Hearst Foundation.

Miriam K. Laufer, MD, MPH

University of Maryland School of Medicine

Dr. Laufer is a pediatric infectious disease specialist, with a primary research interest in malaria. She has conducted research, clinical care and professional education in several developing countries, but has dedicated the past decade to working in Malawi. She currently serves as Principal Investigator for two NIAID-funded clinical trials being conducted in Blantyre, Malawi as well as the project leader for the clinical epidemiology portion of Malawi’s International Center for Excellence in Malaria Research. Her research studies focus on malaria epidemiology in various transmission settings throughout Malawi, malaria during pregnancy and its impact on infants, and the interaction between HIV and malaria. Her laboratory at the University of Maryland explores the application of molecular epidemiology tools to address critical issues related to malaria pathogenesis, disease burden and drug resistance.

Marcus Lee, PhD

Columbia University

My graduate research, in the laboratory of Dr. Marilyn Anderson at the University of Melbourne, Australia, focused on the folding and evolutionary history of a complex multi-domain proteinase inhibitor that functions as a plant defense protein. My thesis work led me to think more about the fundamental problem of protein folding and traffic within the eukaryotic secretory pathway. In my first postdoctoral training period, with Dr. Randy Schekman at the University of California Berkeley, I probed the molecular basis of vesicle formation from the endoplasmic reticulum, the first step in protein secretion. During this time, I became interested in the fascinating cell biology of the malaria parasite, and joined the lab of Dr. David Fidock, at Columbia University, as an NIH-funded NRSA fellow. My current research has been focused on two areas: to develop a deeper understanding of the basic biology of the parasite, in particular the organization of membrane-trafficking pathways, and to uncover mechanisms of resistance to novel antimalarial compounds that may have uncharacterized targets.

Alexander Ploss, PhD

Princeton University

Alexander Ploss completed his PhD in Immunology at Memorial Sloan-Kettering Cancer Center in 2005 and postdoctoral training at the Rockefeller University in New York in 2009. He was a research assistant and later research associate professor at the Center for the Study of Hepatitis C at the Rockefeller University. In 2013 Dr. Ploss moved his lab to Princeton University where he is an Assistant Professor in the Department of Molecular Biology and a Faculty Affiliated in the Program in Global Health and Health Policy. He is also a member of the Cancer Institute of New Jersey. His research focuses on immune responses and pathogenesis to human infectious diseases, including hepatitis B (HBV) and C viruses (HCV), yellow fever virus, dengue virus and malaria. His group combines tissue engineering, molecular virology/pathogenesis, and animal construction, to create and apply innovative technologies including humanized mouse models for the study and intervention of human hepatotropic infections. In support and recognition of his work he received a Kimberly Lawrence Cancer Research Discovery Fund Award, the Astellas Young Investigator Award of the Infectious Diseases Society of America and the Liver Scholar Award of the American Liver Foundation.

Photini Sinnis, MD

Johns Hopkins University

Photini Sinnis is an Associate Professor in the Department of Microbiology & Immunology at Johns Hopkins University. She received her M.D. from Dartmouth Medical School during which time she became interested in medical parasitology. She began her parasitology training in the Woods Hole Biology of Parasitism course and subsequently obtained a Howard Hughes fellowship to work in the laboratory of Dr. Thomas Wellems on malaria genetics.  After her medical residency at Columbia-Presbyterian Hospital, she was a postdoctoral fellow with Dr. Victor Nussenzweig, studying the pre-erythrocytic stages of Plasmodium. She started her independent group in the Department of Medical Parasitology at NYU in 1998 and moved to Johns Hopkins in August 2011. Photini’s research focuses on the biology of sporozoites and the liver stages into which they develop. Dr. Sinnis’s work is funded by the National Institutes of Health, the Bill & Melinda Gates Foundation and the Malaria Vaccine Initiative. She has authored more than 50 papers, has served on NIH scientific review boards, is a Deputy Editor of PLoS Neglected Tropical Diseases and on the editorial board of PLoS ONE and Parasitology International. In her free time she likes to teach science to elementary and middle school children.


Promotional Partners

Global Health Technologies Coalition

Malaria Nexus


The PATH Malaria Vaccine Initiative

Roll Back Malaria

The Microbiology & Infectious Diseases Discussion Group is proudly supported by

Mission Partner support for the Frontiers of Science program provided by Pfizer


Keynote Presentation:

The Pathogenesis of Fatal Cerebral Malaria: A Few More Pieces of the Puzzle
Terrie E. Taylor, Michigan State University

Malaria control and prevention efforts have not yet had a sustained impact in the epicenter of the disease, sub-Saharan Africa. Even now, more than half a million lives are lost each year. Cerebral malaria (CM) is a severe complication clinically characterized by coma and seizures. The case fatality rate is 15-25% and the annual incidence ranges from 1-12 cases per 1,000 children in malaria-endemic region. Most (85%) of the morbidity and mortality occur in young African children. In an autopsy-based investigation of clinicopathological correlates, we described the pathologies of fatal CM, but could not identify a pathologic cause of death. We learned that the standard clinical case definition misclassifies ~25% of patients, and we characterized a constellation of ophthalmologic findings, collectively termed “malarial retinopathy”. Including these eye findings greatly improves the specificity of the clinical diagnosis of CM. In 2009, we added magnetic resonance imaging (MRI) to our characterization of CM patients and learned that marked acute increases in BV are the single most important prognostic feature. Importantly, the brain volumes decrease over 24-48 hours in survivors, suggesting that any interventions targeting this phenomenon would only need to diminish, and not entirely normalize, the volume - - an important consideration in terms of the timing of a trial targeting children with CM. The next step will be to identify the mechanisms responsible for the markedly increased brain volumes seen in fatal CM. These findings will inform the design of a pivotal clinical trial of potentially life-saving interventions.

Neuropathology of Experimental Cerebral Malaria
Mahalia S. Desruisseaux, Albert Einstein College of Medicine

Infection with P. falciparum can result in significant morbidity, including adverse long-term neurological sequelae despite successful anti-parasitic treatment. Using a mouse model of experimental cerebral malaria, we previously demonstrated that cerebral vasculopathy was associated with neuronal damage and subsequent neuro-cognitive deficits. The vasoactive peptide, endothelin-1 (ET-1), has been shown to regulate blood-brain barrier (BBB) permeability, inflammation, and vascular tone, and we have demonstrated, in our experimental model, that this peptide may be important in the pathogenesis of cerebral malaria. We also previously reported that experimental CM is associated with abnormal regulation of the microtubule- associated protein, tau, and that dysregulated tau may be involved in the mediation of long-term neuro-cognitive deficits. Here we present data demonstrating that not only is ET-1 important in the regulation of cerebral blood flow, blood-brain barrier integrity and inflammation, but that it is also intimately involved in the development of disease severity and mortality; likely via its regulations of several cellular signaling pathways, including mitogen-activated protein kinase and protein kinase B (or Akt) signaling, pathways which have been implicated in the abnormal regulation of tau. We propose that both long-term morbidity in CM survivors and mortality during acute disease result, in part, from ET-1-mediated disruption of the BBB, its role in the cerebral inflammatory process, and its regulation of cellular signaling pathways, particularly in neural cells, leading to gliosis, neuronal degeneration, and subsequent adverse neuro-cognitive sequelae. The peptide and its downstream substrates may present potential therapeutic targets for adjunctive therapy in cases of cerebral malaria.

Keynote Presentation:

The Biology of P. vivax Explored through Genomics
Jane M. Carlton, New York University

Vivax malaria is a serious global health issue, and yet studies on the parasite are fewer and more limited in scope compared to Plasmodium falciparum. The first P. vivax genome, published in 2008, revealed a wealth of information that significantly propelled our understanding of the unique biology and pathology of the species. What has been achieved in the six years since? Here I present a comparative analysis of P. vivax genomes from Brazil, Mauritania, India and North Korea with the previously published El Salvador strain. Approximately twice as much genetic diversity is observed among these isolates as among a comparable collection of isolates of P. falciparum. This diversity, as well as gene family variability, suggests the capacity for greater functional variation within the global population of P. vivax, and serves as a warning that P. vivax could present a qualitatively different eradication task. I will also present preliminary analysis of ~150 global P. vivax isolates collected as part of the International Centers of Excellence in Malaria Research. Finally, we have sequenced several strains of Plasmodium cynomolgi, a simian malaria parasite and the close taxon to P. vivax. A map of genetic variation provides a resource for identifying P. cynomolgi traits and studying parasite populations. We show that genomes of the monkey malaria clade can be characterized almost exclusively by CNVs in multigene families involved in evasion of the human immune system and invasion of host erythrocytes. Together these new datasets drive our knowledge of P. vivax biology significantly forward.

Translational Regulation during Stage Transition in the Malaria Parasites
Liwang Cui, PhD, The Pennsylvania State University

Plasmodium falciparum is the causative agent of the deadliest malaria, which causes nearly one million deaths each year. The malaria parasite completes its life cycle in two hosts, a mosquito and a human. Gametocyte, a specialized form of the malaria parasite, mediates transmission from human to mosquito. In malaria parasites, translational regulation is critical during the development of specialized transition stages between the vertebrate host and mosquito vector. Many genes including two transmission-blocking vaccine candidates pfs25 and pfs28 are translationally regulated during gametocyte formation and transmission. Our study of the Pumilio/FBF (Puf) family RNA-binding protein family in malaria parasites revealed they serves as master translation regulators of a large number of genes during the transition stage between human host and mosquito vector. The two Puf members display different yet related functions during gametocyte development. The molecular mechanism is conserved, supporting the paradigm of Puf-mediated translation regulation through 3' untranslated regions (UTRs) of target mRNAs. Furthermore, our study provides first evidence for a functional Puf-binding element in the 5' UTR of a target gene. This study provides a renewed view of Pufs as versatile translation regulators and sheds lights on their functions in the development of lower branches of eukaryotes.

The Plasmodium Sporozoite’s Journey and Beyond
Photini Sinnis, MD, Johns Hopkins University

Plasmodium sporozoites are inoculated by infected mosquitoes into the dermis of the mammalian host. Using the rodent malaria model, we have elucidated how the major surface protein of the sporozoite functions in the parasite’s journey from mosquito to mammalian host. More recently we have found that exit from the skin is a bottleneck for the parasite and possibly one of our best opportunities to intervene. I will discuss our data as to how two abundant surface proteins function in sporozoite exit from the dermis. These studies utilize the rodent malaria model and combine cell biology studies with intravital imaging of mutant parasites in a variety of transgenic mice.

Sporozoite Stages in the Liver: Development of Novel Therapies against Malaria
Purnima Bhanot, UMDNJ - New Jersey Medical School

The first obligatory developmental step in Plasmodium’s human cycle is the infection of the liver by sporozoites. Within the hepatocyte, sporozoites differentiate and divide to form liver stages. Liver stages eventually enter the bloodstream and infect erythrocytes causing disease. Therefore, inhibiting sporozoite infection and liver stage development (together termed pre-erythrocytic stages) would block malaria at an early step. However, most current drugs do not target pre-erythrocytic stages. We seek to fill this gap by providing mechanistic insights into sporozoite infection of hepatocytes and intrahepatic development. This will help identify novel drug targets and drugs for malaria prevention. We have demonstrated that a tri-substituted pyrolle (Tsp) molecule is a potent inhibitor of both sporozoite infection of hepatocytes and liver stage development. Tsp blocks sporozoite invasion, including that of P. falciparum, and has a partial effect on sporozoite motility. Treatment of sporozoites with Tsp significantly reduces the number of liver stages that develop both in tissue culture and in mice. In addition, Tsp arrests liver stage development prior to the parasite’s exit from the hepatocyte. Importantly, the Tsp-mediated block in liver stage infection leads to a significant decrease in blood stage parasitemia. A major target of Tsp is the parasite’s cGMP dependent protein kinase (PKG). Transgenic sporozoites expressing a Tsp-resistant allele of PKG have reduced sensitivity to Tsp and develop into liver stages even in the presence of Tsp. PKG conditional ‘knockout’ sporozoites become developmentally arrested in the liver. Our work provides proof-of-principle that inhibition of the Plasmodium PKG in pre-erythrocytic stages significantly reduces liver and blood-stage infection.

Keynote Presentation:

Artemisinin-Resistant Malaria in Southeast Asia: A Tale of Patients, Parasites and a "Propeller"
Rick M. Fairhurst, MD, PhD, National Institute of Allergy and Infectious Disease, NIH

Plasmodium falciparum resistance to frontline antimalarial drugs has emerged repeatedly in Southeast Asia and spread to Africa, prompting the World Health Organization to recommend the worldwide use of artemisinin (ART)-based combination therapies (ACTs) for falciparum malaria in 2005. ART and its derivatives are highly potent, short-acting antimalarial drugs that must be used in combination with less potent, long-acting partner drugs (e.g., lumefantrine, piperaquine) to completely eliminate parasites from patients. ART resistance in P. falciparum was first reported in 2009 from Pailin Province, Western Cambodia, where it manifested as delayed parasite clearance in patients treated with an ART derivative or ACT. ART-resistant parasites have since become entrenched throughout Western Cambodia, have emerged elsewhere in Southeast Asia, and are now threatening the efficacy of all ACTs worldwide. In a highly collaborative international effort, a series of in-vitro, genomic, epidemiological and clinical studies have rapidly increased our knowledge of ART resistance. These collaborations have (i) defined clinical ART resistance as a long parasite clearance half-life in patients, (ii) mapped the emergence and spread of ART resistance across Southeast Asia, (iii) developed an in-vitro assay for the study of ART resistance in the laboratory, and (iv) associated mutations in a parasite kelch protein "propeller" with ART resistance in Cambodia. Efforts are now underway to elucidate the molecular mechanism of ART resistance, to map the geographic distribution of "propeller" mutations, and to eliminate ART-resistant parasites from Southeast Asia and prevent their global spread.

Targeting New Pathways in Plasmodium to Eliminate Malaria
Marcus Lee, PhD, Columbia University Medical Center

To eliminate malaria, medicines must be developed that are not only curative against the pathogenic asexual blood stage but that also prevent the preceding liver stage infection from causing relapses and block transmission to the mosquito host, which occurs via sexual forms known as gametocytes. There are currently no known universal, drug-able and chemically validated targets for these multiple malarial life-stages. We have identified a parasite phosphatidylinositol-4 kinase, a conserved eukaryotic enzyme that modifies cellular lipids to regulate intracellular signaling and trafficking, as a key Plasmodium vulnerability that is the target of imidazopyrazines, a novel class of compound that act across all lifecycle stages. Evolved resistance, full genome-scanning, and genome editing experiments in intra-erythrocytic stages, as well as biochemical data, show that imidazopyrazines exert their potent antimalarial activity through interaction with the ATP-binding pocket of this lipid kinase. In asexual blood stages, imidazopyrazines block a late step in parasite development by disrupting the formation of new membranes around developing daughter parasites, a likely result of perturbed phosphatidylinositol 4-phosphate (PI4P) pools and disrupted vesicular trafficking. Our findings validate PfPI4K as the first drug target that appears to be required across all Plasmodium lifecycle stages.

The Molecular Basis of Antifolate Resistance
Laura Kirkman, MD, Weill Cornell Medical College

Drugs targeting the folate biosynthesis pathway were a crucial part of malaria control until widespread resistance undermined the use of these agents. The correlation between point mutations in target enzymes and anti-folate resistance has been well described. We investigated the additional contribution of the first and rate-limiting enzyme of the folate biosynthesis pathway, GTP-cyclohydrolase (GCH1). Plasmodium is able to both synthesize folate de novo as well as scavenge from its environment and we propose that the parasite strives to maintain a balanced flux through the folate pathway. I will present our work investigating the role of gene amplification of gch1, first identified in field isolates that are highly resistant to anti-folates, as well as the contribution of regulation of the protein itself by the extended N terminal region to anti-folate resistance. We propose that modifications in GCH1 copy number and activity potentially facilitate fixation of downstream resistant alleles in the parasite population.

Antimalarial Drug Resistance in Africa
Miriam K. Laufer, University of Maryland School of Medicine

Although resistance to antimalarial drugs has historically emerged in Southeast Asia and then spread to Africa, the burden of antimalarial drug resistance is the greatest in high transmission settings in Africa where it leads to increased disease severity and death. There are unique human, vector and parasite factors that contribute to the emergence, spread and disappearance of antimalarial drug resistance in Africa. I will describe our studies of the molecular epidemiology, genetics and clinical implications of drug resistance in Malawi, one of the high transmission regions in Africa, where we have found surprising differences between chloroquine and sulfadoxine-pyrimethamine resistance. I will discuss our results in light of current concerns about artemisinin-resistant malaria in Southeast Asia. Our findings may help to predict the behavior of resistance to new anti-malarial medications and inform strategies to prevent the spread of drug-resistant malaria in Africa the future.

Malaria Equilibrative Nucleoside Transporters: A Potential Path to Novel Anti-Malarial Drugs
Myles Akabas, MD, Phd, Albert Einstein College of Medicine

Malaria remains a major public health illness. The development of resistance to current antimalarial medications makes it essential to identify new antimalarial drug targets and therapies. Plasmodium parasites are purine auxotrophs. Thus, purine import is essential for growth. Genetic, biochemical, and physiologic evidence suggests that the Plasmodium falciparum Equilibrative Nucleoside Transporter 1 (PfENT1) is the primary purine transporter. PfENT1 inhibitors might serve as novel antimalarial drugs but no PfENT1 inhibitors have been identified. We developed a novel yeast-based high throughput screen that relies on the 5-fluoruridine sensitivity of PfENT1-expressing fui1Δ yeast to provide a powerful positive selection for inhibitors of PfENT1. We screened ~64,000 compounds in 384 well plates and identified 171 small molecule inhibitors of PfENT1 (0.26% hit rate). We have further characterized nine of the highest activity compounds that constitute five distinct chemotypes in a series of secondary assays. All nine compounds were positive in an orthogonal assay based on the adenosine dependence of growth of PfENT1-expressing purine auxotrophic yeast. All nine also blocked [3H]adenosine uptake into PfENT1-expressing yeast and into RBC-free trophozoite-stage parasites. None of the nine compounds kill yeast but all kill P. falciparum in culture. Compound efficacy is similar for chloroquine sensitive and resistant strains. Twenty-four hour treatment with a 10xIC50 concentration of compound is sufficient to kill parasites. All nine compounds inhibit the homologous P. vivax transporter with similar efficacy. Our data support the hypothesis that blocking purine import through PfENT1 is a compelling approach for the development of novel antimalarial drugs.

Generation of Humanized Mouse Models for Malaria
Alexander Ploss, Princeton University

Malaria is a life-threatening parasitic disease for which approximately half the world's population is at risk. Although progress has been made in preventing and treating malaria, more effective, tolerable, and affordable therapies and vaccines are needed. A small animal model would dramatically speed the development of anti-malarial drugs and vaccines. Although plasmodial parasites species exist which efficiently infect rodent they are genetically distinct from parasites that cause malaria in human, which limits their predictive value. Plasmodium falciparum and P. vivax, which contribute most substantially to disease in humans exhibit a mechanistically undefined human tropism and animal models that recapitulate the parasitic life cycle are scarce. To address this challenge we humanize the relevant tissue compartments, i.e. liver and blood in mice. Specifically, transplantation of human hepatocytes into specially conditioned xeno-recipients leads to a robust human hepatic chimerism. Resulting human liver chimeric mice are susceptible to infection with P. falciparum sporozoite and support faithful development of parasitic liver stages. Efforts are ongoing to extent this work to P. vivax. Introduction of human erythrocytes into human liver chimeric mice allows for transition for liver to blood stages. Humanized mice will be useful for studies of malaria pathogenesis and transmission to arthropod hosts. These animals will be immediately applicable for safety and efficacy assessments of genetically attenuated parasites, anti-malarial drugs, and passive immune protection strategies.

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