The Synaptic Leap

BMC Systems Biology, Vol. 4, No. 1. (2010), 120.

BACKGROUND:Despite enormous efforts to combat malaria the disease still afflicts up to half a billion people each year of which more than one million die. Currently no approved vaccine is available and resistances to antimalarials are widely spread. Hence, new antimalarial drugs are urgently needed.RESULTS:Here, we present a computational analysis of the metabolism of Plasmodium falciparum, the deadliest malaria pathogen. We assembled a compartmentalized metabolic model and predicted life cycle stage specific metabolism with the help of a flux balance approach that integrates gene expression data. Predicted metabolite exchanges between parasite and host were found to be in good accordance with experimental findings when the parasite's metabolic network was embedded into that of its host (erythrocyte). Knock-out simulations identified 307 indispensable metabolic reactions within the parasite. 35 out of 57 experimentally demonstrated essential enzymes were recovered and another 16 enzymes, if additionally the assumption was made that nutrient uptake from the host cell is limited and all reactions catalyzed by the inhibited enzyme are blocked. This predicted set of putative drug targets, shown to be enriched with true targets by a factor of at least 2.75, was further analyzed with respect to homology to human enzymes, functional similarity to therapeutic targets in other organisms and their predicted potency for prophylaxis and disease treatment.CONCLUSIONS:The results suggest that the set of essential enzymes predicted by our flux balance approach represents a promising starting point for further drug development.
Carola Huthmacher, Andreas Hoppe, Sascha Bulik, Hermann Holzhutter

In Parassitologia, Vol. 41 (1999), 69-75.

An international consortium has been formed to sequence the entire genome of the human malaria parasite Plasmodium falciparum. We sequenced chromosome 2 of clone 3D7 using a shotgun sequencing strategy. Chromosome 2 is 947 kb in length, has a base composition of 80.2% A + T, and contains 210 predicted genes. In comparison to the Saccharomyces cerevisiae genome, chromosome 2 has a lower gene density, a greater proportion of genes containing introns, and nearly twice as many proteins containing predicted non-globular domains. A group of putative surface proteins was identified, rifins, which are encoded by a gene family comprising up to 7% of the protein-encoding gene in the genome. The rifins exhibit considerable sequence diversity and may play an important role in antigenic variation. Sixteen genes encoded on chromosome 2 showed signs of a plastid or mitochondrial origin, including several genes involved in fatty acid biosynthesis. Completion of the chromosome 2 sequence demonstrated that the A + T-rich genome of P. falciparum can be sequenced by the shotgun approach. Within 2-3 years, the sequence of almost all P. falciparum genes will have been determined, paving the way for genetic, biochemical, and immunological research aimed at developing new drugs and vaccines against malaria.
MJ Gardner, H Tettelin, DJ Carucci, LM Cummings, HO Smith, CM Fraser, JC Venter, SL Hoffman

In Nature, Vol. 419 (2002), 498-511.

The parasite Plasmodium falciparum is responsible for hundreds of millions of cases of malaria, and kills more than one million African children annually. Here we report an analysis of the genome sequence of P. falciparum clone 3D7. The 23-megabase nuclear genome consists of 14 chromosomes, encodes about 5,300 genes, and is the most (A + T)-rich genome sequenced to date. Genes involved in antigenic variation are concentrated in the subtelomeric regions of the chromosomes. Compared to the genomes of free-living eukaryotic microbes, the genome of this intracellular parasite encodes fewer enzymes and transporters, but a large proportion of genes are devoted to immune evasion and host-parasite interactions. Many nuclear-encoded proteins are targeted to the apicoplast, an organelle involved in fatty-acid and isoprenoid metabolism. The genome sequence provides the foundation for future studies of this organism, and is being exploited in the search for new drugs and vaccines to fight malaria.
MJ Gardner, N Hall, E Fung, O White, M Berriman, RW Hyman, JM Carlton, A Pain, KE Nelson, S Bowman, IT Paulsen, K James, JA Eisen, K Rutherford, SL Salzberg, A Craig, S Kyes, MS Chan, V Nene, SJ Shallom, B Suh, J Peterson, S Angiuoli, M Pertea, J Allen, J Selengut, D Haft, MW Mather, AB Vaidya, DM Martin, AH Fairlamb, MJ Fraunholz, DS Roos, SA Ralph, GI McFadden, LM Cummings, GM Subramanian, C Mungall, JC Venter, DJ Carucci, SL Hoffman, C Newbold, RW Davis, CM Fraser, B Barrell

Proceedings of the National Academy of Sciences, Vol. 107, No. 34. (24 August 2010), pp. 15135-15139.

10.1073/pnas.1006422107 Malaria transmission is strongly influenced by environmental temperature, but the biological drivers remain poorly quantified. Most studies analyzing malaria–temperature relations, including those investigating malaria risk and the possible impacts of climate change, are based solely on mean temperatures and extrapolate from functions determined under unrealistic laboratory conditions. Here, we present empirical evidence to show that, in addition to mean temperatures, daily fluctuations in temperature affect parasite infection, the rate of parasite development, and the essential elements of mosquito biology that combine to determine malaria transmission intensity. In general, we find that, compared with rates at equivalent constant mean temperatures, temperature fluctuation around low mean temperatures acts to speed up rate processes, whereas fluctuation around high mean temperatures acts to slow processes down. At the extremes (conditions representative of the fringes of malaria transmission, where range expansions or contractions will occur), fluctuation makes transmission possible at lower mean temperatures than currently predicted and can potentially block transmission at higher mean temperatures. If we are to optimize control efforts and develop appropriate adaptation or mitigation strategies for future climates, we need to incorporate into predictive models the effects of daily temperature variation and how that variation is altered by climate change.
Krijn Paaijmans, Simon Blanford, Andrew Bell, Justine Blanford, Andrew Read, Matthew Thomas

Mol Biol Evol, Vol. 24, No. 2. (1 February 2007), pp. 562-573.

When selection is strong and beneficial alleles have a single origin, local reductions in genetic diversity are expected. However, when beneficial alleles have multiple origins or were segregating in the population prior to a change in selection regime, the impact on genetic diversity may be less clear. We describe an example of such a "soft" selective sweep in the malaria parasite Plasmodium falciparum that involves adaptive genome rearrangements. Amplification in copy number of genome regions containing the pfmdr1 gene on chromosome 5 confer resistance to mefloquine and spread rapidly in the 1990s. Using flanking microsatellite data and real-time polymerase chain reaction determination of copy number, we show that 5-15 independent amplification events have occurred in parasites on the Thailand/Burma border. The amplified genome regions (amplicons) range in size from 14.7 to 49 kb and contain 2-11 genes, with 2-4 copies arranged in tandem. To examine the impact of drug selection on flanking variation, we genotyped 48 microsatellites on chromosome 5 in 326 parasites from a single Thai location. Diversity was reduced in a 170- to 250-kb (10-15 cM) region of chromosomes containing multiple copies of pfmdr1, consistent with hitchhiking resulting from the rapid recent spread of selected chromosomes. However, diversity immediately flanking pfmdr1 is reduced by only 42% on chromosomes bearing multiple amplicons relative to chromosomes carrying a single copy. We highlight 2 features of these results: 1) All amplicon break points occur in monomeric A/T tracts (9-45 bp). Given the abundance of these tracts in P. falciparum, we expect that duplications will occur frequently at multiple genomic locations and have been underestimated as drivers of phenotypic evolution in this pathogen. 2) The signature left by the spread of amplified genome segments is broad, but results in only limited reduction in diversity. If such "soft" sweeps are common in nature, statistical methods based on diversity reduction may be inefficient at detecting evidence for selection in genome-wide marker screens. This may be particularly likely when mutation rate is high, as appears to be the case for gene duplications, and in pathogen populations where effective population sizes are typically very large. 10.1093/molbev/msl185
Shalini Nair, Denae Nash, Daniel Sudimack, Anchalee Jaidee, Marion Barends, Anne-Catrin Uhlemann, Sanjeev Krishna, Francois Nosten, Tim Anderson

J. Virol., Vol. 84, No. 15. (1 August 2010), pp. 7726-7729.

"Evolution-proof" or "late-life-acting" insecticides (LLAIs) preferentially kill older adult mosquitoes and are of extreme interest to control vector-borne diseases such as malaria. We used quantitative PCR to assess whether the Anopheles gambiae densonucleosis virus (AgDNV) had potential as an LLAI. After infection, AgDNV titers increased modestly during larval development but replicated slower than the host cells, resulting in a significant decrease in the normalized virus titer during larval and pupal development. Normalized virus titers dramatically increased after adult emergence, peaking in 7- to 10-day-old adults. Unlike other DNVs, AgDNV does not significantly replicate in preadult mosquitoes but rather preferentially replicates in older adults. The natural dynamics of AgDNV make it ideal for expression of insect-specific toxin genes as a biological LLAI. 10.1128/JVI.00631-10
Xiaoxia Ren, Jason Rasgon

FEBS Journal, Vol. 274, No. 18. (September 2007), pp. 4688-4698.

Despite intensive research extending back to the 1930s, when the first synthetic antimalarial drugs made their appearance, the repertoire of clinically licensed formulations remains very limited. Moreover, widespread and increasing resistance to these drugs contributes enormously to the difficulties in controlling malaria, posing considerable intellectual, technical and humanitarian challenges. A detailed understanding of the molecular mechanisms underlying resistance to these agents is emerging that should permit new drugs to be rationally developed and older ones to be engineered to regain their efficacy. This review summarizes recent progress in analysing the causes of resistance to the major antimalarial drugs and its spread.
JE Hyde

Nature, Vol. 466, No. 7307. (04 August 2010), pp. 702-703.

One of the hallmarks of cellular biochemistry is the ability to extract energy efficiently from available substrates. The malaria parasite, however, deviates from the norm, and has come up with its own solution. All living organisms require energy for growth, maintenance and reproduction. At the cellular level, chemical reactions transform energy from one type to another: the energy stored in chemical bonds is turned into ATP — the cell's energy currency — when certain complex molecules are broken down to simpler ones.
Hagai Ginsburg

Nature, Vol. 466, No. 7307. (04 August 2010), pp. 702-703.

One of the hallmarks of cellular biochemistry is the ability to extract energy efficiently from available substrates. The malaria parasite, however, deviates from the norm, and has come up with its own solution. All living organisms require energy for growth, maintenance and reproduction. At the cellular level, chemical reactions transform energy from one type to another: the energy stored in chemical bonds is turned into ATP — the cell's energy currency — when certain complex molecules are broken down to simpler ones.
Hagai Ginsburg

Nature, Vol. 465, No. 7296. (20 May 2010), pp. 342-345.

The current and potential future impact of climate change on malaria is of major public health interest1, 2. The proposed effects of rising global temperatures on the future spread and intensification of the disease3, 4, 5, and on existing malaria morbidity and mortality rates3, substantively influence global health policy6, 7. The contemporary spatial limits of Plasmodium falciparum malaria and its endemicity within this range8, when compared with comparable historical maps, offer unique insights into the changing global epidemiology of malaria over the last century. It has long been known that the range of malaria has contracted through a century of economic development and disease control9. Here, for the first time, we quantify this contraction and the global decreases in malaria endemicity since approximately 1900. We compare the magnitude of these changes to the size of effects on malaria endemicity proposed under future climate scenarios and associated with widely used public health interventions. Our findings have two key and often ignored implications with respect to climate change and malaria. First, widespread claims that rising mean temperatures have already led to increases in worldwide malaria morbidity and mortality are largely at odds with observed decreasing global trends in both its endemicity and geographic extent. Second, the proposed future effects of rising temperatures on endemicity are at least one order of magnitude smaller than changes observed since about 1900 and up to two orders of magnitude smaller than those that can be achieved by the effective scale-up of key control measures. Predictions of an intensification of malaria in a warmer world, based on extrapolated empirical relationships or biological mechanisms, must be set against a context of a century of warming that has seen marked global declines in the disease and a substantial weakening of the global correlation between malaria endemicity and climate.
Peter Gething, David Smith, Anand Patil, Andrew Tatem, Robert Snow, Simon Hay

Malaria journal, Vol. 9, No. 1. (10 August 2010)

ABSTRACT: BACKGROUND: Ontologies are rapidly becoming a necessity for the design of efficient information technology tools, especially databases, because they permit the organization of stored data using logical rules and defined terms that are understood by both humans and machines. This has as consequence both an enhanced usage and interoperability of databases and related resources. It is hoped that IDOMAL, the ontology of malaria will prove a valuable instrument when implemented in both malaria research and control measures. METHODS: The OBOEdit2 software was used for the construction of the ontology. IDOMAL is based on the Basic Formal Ontology (BFO) and follows the rules set by the OBO Foundry consortium. RESULTS: The first version of the malaria ontology covers both clinical and epidemiological aspects of the disease, as well as disease and vector biology. IDOMAL is meant to later become the nucleation site for a much larger ontology of vector borne diseases, which will itself be an extension of a large ontology of infectious diseases (IDO). The latter is currently being developed in the frame of a large international collaborative effort. CONCLUSIONS: IDOMAL, already freely available in its first version, will form part of a suite of ontologies that will be used to drive IT tools and databases specifically constructed to help control malaria and, later, other vector-borne diseases. This suite already consists of the ontology described here as well as the one on insecticide resistance that has been available for some time. Additional components are being developed and introduced into IDOMAL.
Pantelis Topalis, Elvira Mitraka, Ioana Bujila, Elena Deligianni, Emmanuel Dialynas, Inga Siden-Kiamos, Marita Troye-Blomberg, Christos Louis

Proceedings of the National Academy of Sciences, Vol. 104, No. 40. (2 October 2007), pp. 15835-15840.

10.1073/pnas.0610485104 An infection with Plasmodium falciparum may lead to severe malaria as a result of excessive binding of infected erythrocytes in the microvasculature. Vascular adhesion is mediated by P. falciparum erythrocyte membrane protein-1 (PfEMP1), which is encoded for by highly polymorphic members of the var-gene family. Here, we profile var gene transcription in fresh P. falciparum trophozoites from Ugandan children with malaria through var-specific DBL1α-PCR amplification and sequencing. A method for subsectioning region alignments into homology areas (MOTIFF) was developed to examine collected sequences. Specific PfEMP1-DBL1α amino acid motifs correlated with rosetting and severe malaria, with motif location corresponding to distinct regions of receptor interaction. The method is potentially applicable to other families of variant proteins and may be useful in identifying sequence-phenotype relationships. The results suggest that certain PfEMP1 sequences are predisposed to inducing severe malaria.
Johan Normark, Daniel Nilsson, Ulf Ribacke, Gerhard Winter, Kirsten Moll, Craig Wheelock, Justus Bayarugaba, Fred Kironde, Thomas Egwang, Qijun Chen, Björn Andersson, Mats Wahlgren

Integrated Assessment, Vol. 2, No. 4. (2001), pp. 173-181.

Vector-borne diseases are feared to extend their range in a future where global warming has occurred. There is considerable concern about scourges such as malaria re-invading currently temperate regions and reaching into higher altitudes in Africa. In this paper we examine the various factors thought to determine potential infectivity of malaria, and its actual outbreak in the context of a dynamic integrated assessment model. We quantify: (i) the role of demographics in placing a larger population in harms way; (ii) the role of climate change in increasing the potential geographic range and severity of the risk of infection; and (iii) the role of economic and social development in limiting the occurrence of malaria. We then explore the climate and economic implications of various climate policies in their effectiveness to limit potential infectivity of malaria. In illustration of these issues we present the climate-related and economics-related impacts of unilateral CO2 control by OECD on incidence of malaria in non-OECD nations. The model presented here, although highly stylized in its representation of socio-economic factors, provides strong evidence of the role of socio-economic factors in determination of malaria incidence. The case study offers insights into unintended adverse consequences of well-meaning climate policies.
RSJ Tol, H Dowlatabadi

Proc. Natl. Acad. Sci. USA (2004)

Malaria is a major human parasitic disease caused by four species of Plasmodium protozoa. Plasmodium vivax, the most widespread, affects millions of people across Africa, Asia, the Middle East, and Central and South America. We have studied the genetic variability of 13 microsatellite loci in 108 samples from 8 localities in Asia, Africa, South America, and New Guinea. Only one locus is polymorphic; nine are completely monomorphic, and the remaining three are monomorphic in all but one or two populations, which have a rare second allele. In contrast, Plasmodium falciparum displays extensive microsatellite polymorphism within and among populations. We further have analyzed, in 96 samples from the same 8 localities, 8 tandem repeats (TRs) located on a 100-kb contiguous chromosome segment described as highly polymorphic. Each locus exhibits 2-10 alleles in the whole sample but little intrapopulation polymorphism (1-5 alleles with a prevailing allele in most cases). Eight microsatellite loci monomorphic in P. vivax are polymorphic in three of five Plasmodium species related to P. vivax (two to seven individuals sampled). Plasmodium simium, a parasite of New World monkeys, is genetically indistinguishable from P. vivax. At 13 microsatellite loci and at 7 of the 8 TRs, both species share the same (or most common) allele. Scarce microsatellite polymorphism may reflect selective sweeps or population bottlenecks in recent evolutionary history of P. vivax; the differential variability of the TRs may reflect selective processes acting on particular regions of the genome. We infer that the world expansion of P. vivax as a human parasite occurred recently, perhaps <10,000 years ago.
MC Leclerc, P Durand, C Gauthier, S Patot, N Billotte, M Menegon, C Severini, FJ Ayala, F Renaud

Am J Trop Med Hyg., Vol. 71, No. 2. (2004), pp. 128-135.

The role of epidemic malaria as a distinct epidemiologic entity posing unique intervention challenges is reviewed from a global perspective. Epidemic malaria derives from particular interactions of vectors, parasites, and various environmental and anthropogenic determinants. Malaria epidemics generally afflict immunologically vulnerable populations, and their explosiveness can strain the capacity of health facilities, causing case fatality rates to increase five-fold or more during outbreaks. People of all ages remain susceptible to the full range of clinical effects. This flatter demographic profile may translate into larger economic consequences, although the full economic impact of epidemic malaria remains undefined. Specialized intervention approaches are recommended for epidemic-prone areas, including enhanced surveillance activities and intensified antivector interventions. Such considerations are particularly critical during a time when malaria epidemics are occurring more frequently in Africa and throughout the world.
AE Kiszewski, AW Teklehaimanot

The American Journal of the Medical Sciences, Vol. 332, No. 2., pp. 97-99.

Brugada syndrome is an arrhythmic syndrome characterized by a pattern of right bundle branch block and an ST-segment elevation in the right precordial leads on the electrocardiogram. This type of electrocardiographic change is predominantly documented in Asian and white persons and almost never present in persons of African ancestry. Despite the well-known risk of sudden death in patients with Brugada syndrome, controversy exists concerning the management of asymptomatic patients with Brugada-type electrocardiographic patterns. The present report describes the case of a patient with a Brugada-type electrocardiographic pattern induced by his febrile condition. A favorable outcome was achieved with a conservative approach.
Takeki Suzuki, Shun Kohsaka

The American Journal of the Medical Sciences, Vol. 332, No. 2., pp. 97-99.

Brugada syndrome is an arrhythmic syndrome characterized by a pattern of right bundle branch block and an ST-segment elevation in the right precordial leads on the electrocardiogram. This type of electrocardiographic change is predominantly documented in Asian and white persons and almost never present in persons of African ancestry. Despite the well-known risk of sudden death in patients with Brugada syndrome, controversy exists concerning the management of asymptomatic patients with Brugada-type electrocardiographic patterns. The present report describes the case of a patient with a Brugada-type electrocardiographic pattern induced by his febrile condition. A favorable outcome was achieved with a conservative approach.
Takeki Suzuki, Shun Kohsaka