The Synaptic Leap

The American journal of tropical medicine and hygiene, Vol. 86, No. 2. (February 2012), pp. 194-198.

Abstract. We identified 480 persons with positive thick smears for asexual Plasmodium falciparum parasites, of whom 454 had positive rapid diagnostic tests (RDTs) for the histidine-rich protein 2 (HRP2) product of the hrp2 gene and 26 had negative tests. Polymerase chain reaction (PCR) amplification for the histidine-rich repeat region of that gene was negative in one-half (10/22) of false-negative specimens available, consistent with spontaneous deletion. False-negative RDTs were found only in persons with asymptomatic infections, and multiplicities of infection (MOIs) were lower in persons with false-negative RDTs (both P < 0.001). These results show that parasites that fail to produce HRP2 can cause patent bloodstream infections and false-negative RDT results. The importance of these observations is likely to increase as malaria control improves, because lower MOIs are associated with false-negative RDTs and false-negative RDTs are more frequent in persons with asymptomatic infections. These findings suggest that the use of HRP2-based RDTs should be reconsidered.
Ousmane Koita, Ogobara Doumbo, Amed Ouattara, Lalla Tall, Aoua Konaré, Mahamadou Diakité, Mouctar Diallo, Issaka Sagara, Godfred Masinde, Safiatou Doumbo, Amagana Dolo, Anatole Tounkara, Issa Traoré, Donald Krogstad

Malaria Journal, Vol. 11, No. 1. (2012), 33.

BACKGROUND:Cytoadherence of infected red blood cells to brain endothelium is causally implicated in malarial coma, one of the severe manifestations of falciparum malaria. Cytoadherence is mediated by specific binding of variant parasite antigens, expressed on the surface of infected erythrocytes, to endothelial receptors including, ICAM-1, VCAM and CD36. In fatal cases of severe falciparum malaria with coma, blood vessels in the brain are characteristically congested with infected erythrocytes. Brain sections from a fatal case of knowlesi malaria, but without coma, were similarly congested with infected erythrocytes. The objective of this study was to determine the binding phenotype of Plasmodium knowlesi infected human erythrocytes to recombinant human ICAM-1, VCAM and CD36.METHODS:Five patients with PCR-confirmed P. knowlesi malaria were recruited into the study with consent between April and August 2010. Pre-treatment venous blood was washed and cultured ex vivo to increase the proportion of schizont-infected erythrocytes. Cultured blood was seeded into Petri dishes with triplicate areas coated with ICAM-1, VCAM and CD36. Following incubation at 37degreesC for one hour the dishes were washed and the number of infected erythrocytes bound/mm2 to PBS control areas and to recombinant human ICAM-1 VCAM and CD36 coated areas were recorded. Each assay was performed in duplicate. Assay performance was monitored with the Plasmodium falciparum clone HB3.RESULTS:Blood samples were cultured ex vivo for up to 14.5 h (mean 11.3 +/- 1.9 h) to increase the relative proportion of mature trophozoite and schizont-infected red blood cells to at least 50 (mean 65.8 +/- 17.51%). Three (60%) isolates bound significantly to ICAM-1 and VCAM, one (20%) isolate bound to VCAM and none of the five bound significantly to CD36.CONCLUSIONS:Plasmodium knowlesi infected erythrocytes from human subjects bind in a specific but variable manner to the inducible endothelial receptors ICAM-1 and VCAM. Binding to the constitutively-expressed endothelial receptor CD36 was not detected. Further work will be required to define the pathological consequences of these interactions.
Farrah Fatih, Angela Siner, Atique Ahmed, Lu Woon, Alister Craig, Balbir Singh, Sanjeev Krishna, Janet Singh

Journal of ethnopharmacology, Vol. 112, No. 1. (30 May 2007), pp. 132-137.

Stephania rotunda (Menispermaceae) is used in traditional medicine for the treatment of fever. Four major alkaloids: dehydroroemerine, tetrahydropalmatine, xylopinine, cepharanthine as well as aqueous extract (SA), dichloromethane extracts (SD1 and SD2) from this plant were tested against Plasmodium falciparum W2 in vitro. Dehydroroemerine, cepharanthine and SD1 were the most active against W2 with IC(50) of 0.36, 0.61microM and 0.7microg/mL, respectively. Their IC(50) on human monocytic THP1 cells were 10.8, 10.3microM and >250microg/mL, respectively. Cepharanthine, SD1 and SA were selected for in vivo antimalarial test against Plasmodium berghei in mice. The results of SD1 and SA at dose of 150mg/kg showed a decrease of 89 and 74% of parasitaemia by intra-peritoneal injection and 62.5 and 46.5% of parasitaemia by oral administration, respectively. The result of cepharanthine at dose of 10mg/kg showed a decrease of 47% of parasitaemia by intra-peritoneal injection and 50% of parasitaemia by oral administration. Drug interaction of chloroquine and major alkaloids indicates that cepharanthine-chloroquine and tetrahydropalmatine-xylopinine associations are synergistic. These results are in agreement with the use of this plant in the treatment of malaria. This is the first report on in vivo antimalarial investigation for Stephania rotunda.
Aun Chea, Sotheara Hout, Sok-Siya Bun, Nino Tabatadze, Monique Gasquet, Nadine Azas, Riad Elias, Guy Balansard

ChemMedChem (24 January 2012)

Malaria is one of the world's most devastating parasitic diseases, causing almost one million deaths each year. Growing resistance to classical antimalarial drugs, such as chloroquine, necessitates the discovery of new therapeutic agents for successful control of this global disease. Here, we report the synthesis of some 6-halo-β-carbolines as analogues of the potent antimalarial natural product, manzamine A, retaining its heteroaromatic core whilst providing compounds with much improved synthetic accessibility. Two compounds displayed superior activity to chloroquine itself against a resistant Plasmodium falciparum strain, identifying them as promising leads for future development. Furthermore, in line with previous reports of similarities in antimalarial and antiprion effects of aminoaryl-based antimalarial agents, the 1-amino-β-carboline libraries were also found to possess significant bioactivity against a prion-infected cell line. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Mark Thompson, Jennifer Louth, Susan Little, Matthew Jackson, Yohan Boursereau, Beining Chen, Iain Coldham

Evolution, Vol. 2, No. 1. (March 1948), 58.

A classification of ecological types within the Bromeliaceae is developed. It is pointed out that the principal cleavage within the family is between species that are dependent on their substratum for nutrients and water and those that are not. Nutritive independence has been possible due to the evolution of (a) the 'tank' habit of impounding water and humus between overlapping leaf bases, and (b) a system of epidermal absorbing trichomes on the leaves which exploit the water and humus of the tank. The habit of Bromelia humilis Jacq. is described. The plant has a 'tank' which it exploits by upgrowing interfoliar mycotrophic roots, a condition previously unknown in the family. An analysis of the distribution of epiphytic bromeliads in varying conditions of light and humidity leads to the conclusion that light is their prime ecoclimatic variable. All the ecological evidence is shown to be against Schimper's (1888) hypothesis, that epiphytes have evolved from the ground flora in wet forest, applying to the c...
Colin Pittendrigh

Cellular microbiology (22 December 2011)

The spleen is a complex organ that is perfectly adapted to selectively filtering and destroying senescent red blood cells (RBCs), infectious microorganisms and Plasmodium-parasitized RBCs (pRBCs). Infection by malaria is the most common cause of spleen rupture and splenomegaly, albeit variably, a landmark of malaria infection. Here, the role of the spleen in malaria is reviewed with special emphasis in lessons learned from human infections and mouse models. © 2011 Blackwell Publishing Ltd.
Hernando Del Portillo, Mireia Ferrer, Thibaut Brugat, Lorena Martin-Jaular, Jean Langhorne, Marcus Vg Lacerda

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Vol. 21, No. 3. (September 1995), pp. 577-587.

The clinical and laboratory features of severe falciparum malaria in 180 Gambian children were studied between 1985 and 1989. Of the 180 children, 118 (66%) presented with seizures, 77 (43%) had cerebral malaria, 35 (20%) had witnessed seizures after admission, 29 (16%) were hypoglycemic, and 27 (15%) died. Respiratory distress was a common harbinger of a fatal outcome. The differences in admission parasite counts in the blood, hematocrit, and opening cerebrospinal pressures for patients who died and survivors were not significant. A multiple logistic regression model identified neurological status (coma, particularly if associated with extensor posturing), stage of parasite development on the peripheral blood film, pulse rate of > 150 or respiratory rate of > 50, hypoglycemia, and hyperlactatemia (plasma lactate level, > 5 mmol/L) as independent indicators of a fatal outcome. Biochemical evidence of hepatic and renal dysfunction was an additional marker of a poor prognosis, but, in contrast to severe malaria in adults, none of these children with severe malaria had acute renal failure.
D Waller, S Krishna, J Crawley, K Miller, F Nosten, D Chapman, FO ter Kuile, C Craddock, C Berry, PA Holloway

PLoS Comput Biol, Vol. 7, No. 12. (22 December 2011), e1002320.

Genes underlying important phenotypic differences between Plasmodium species, the causative agents of malaria, are frequently found in only a subset of species and cluster at dynamically evolving subtelomeric regions of chromosomes. We hypothesized that chromosome-internal regions of Plasmodium genomes harbour additional species subset-specific genes that underlie differences in human pathogenicity, human-to-human transmissibility, and human virulence. We combined sequence similarity searches with synteny block analyses to identify species subset-specific genes in chromosome-internal regions of six published Plasmodium genomes, including Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi, Plasmodium yoelii, Plasmodium berghei, and Plasmodium chabaudi. To improve comparative analysis, we first revised incorrectly annotated gene models using homology-based gene finders and examined putative subset-specific genes within syntenic contexts. Confirmed subset-specific genes were then analyzed for their role in biological pathways and examined for molecular functions using publicly available databases. We identified 16 genes that are well conserved in the three primate parasites but not found in rodent parasites, including three key enzymes of the thiamine (vitamin B1) biosynthesis pathway. Thirteen genes were found to be present in both human parasites but absent in the monkey parasite P. knowlesi, including genes specifically upregulated in sporozoites or gametocytes that could be linked to parasite transmission success between humans. Furthermore, we propose 15 chromosome-internal P. falciparum-specific genes as new candidate genes underlying increased human virulence and detected a currently uncharacterized cluster of P. vivax-specific genes on chromosome 6 likely involved in erythrocyte invasion. In conclusion, Plasmodium species harbour many chromosome-internal differences in the form of protein-coding genes, some of which are potentially linked to human disease and thus promising leads for future laboratory research. With more than 250 million infections and over a million deaths each year, malaria remains one of the most devastating infectious diseases worldwide. With the availability of complete genome sequences of both human and non-human Plasmodium parasites, the causative agents of malaria, it is now possible to use comparative genomics as a tool to look for genes that are present in some but not all Plasmodium species. Such species subset-specific genes possibly underlie important phenotypic differences between malaria parasites and could provide important clues for the development of new strategies to prevent and treat malaria in humans. In this study, we performed a comprehensive computational comparison of the published genomes of six Plasmodium species, including two human (P. falciparum and P. vivax), one monkey (P. knowlesi), and three rodent malaria parasites (P. berghei, P. yoelii, and P. chabaudi). This comparison revealed many species subset-specific genes that are potentially linked to human pathogenicity, human-to-human transmissibility, and human virulence. These genes can now be examined further by targeted experimental analyses to test predicted phenotypic associations and to elucidate gene function.
Christian Frech, Nansheng Chen

Malaria Journal, Vol. 11, No. 1. (2012), 11.

Development and Phase 3 testing of the most advanced malaria vaccine, RTS,S/AS01, indicates that malaria vaccine R&D is moving into a new phase. Field trials of several research malaria vaccines have also confirmed that it is possible to impact the host-parasite relationship through vaccine-induced immune responses to multiple antigenic targets using different platforms. Other approaches have been appropriately tested but turned out to be disappointing after clinical evaluation. As the malaria community considers the potential role of a first-generation malaria vaccine in malaria control efforts, it is an apposite time to carefully document terminated and ongoing malaria vaccine research projects so that lessons learned can be applied to increase the chances of success for second-generation malaria vaccines over the next 10 years. The most comprehensive resource of malaria vaccine projects is a spreadsheet compiled by WHO thanks to the input from funding agencies, sponsors and investigators worldwide. This spreadsheet, available from WHO's website, is known as "the rainbow table". By summarizing the published and some unpublished information available for each project on the rainbow table, the most comprehensive review of malaria vaccine projects to be published in the last several years is provided below.
Lauren Schwartz, Graham Brown, Blaise Genton, Vasee Moorthy

Eur. J. Immunol., Vol. 36, No. 5. (2006), pp. 1179-1186.

Protective immune responses against malaria are induced by immunization with radiation-attenuated Plasmodium sporozoites. In contrast, non-viable, heat-killed sporozoites do not induce protection, emphasizing the requirement for live parasites to achieve effective immune responses. Using an experimental system with CD8+ T cells from T cell receptor-transgenic mice, we analyzed the primary CD8+ T cell responses elicited by heat-killed inactivated sporozoites. We found that the numbers of specific CD8+ T cells induced were much lower compared to when immunizing with attenuated sporozoites; however, the kinetics of activation and the phenotype of these T cells were similar in both groups. Despite their low frequency after priming, high numbers of specific CD8+ T cells were observed after boosting with a recombinant vaccinia virus. Upon induction of the recall response, the same level of protection was observed when either heat-killed or attenuated sporozoites were used for priming. We propose that live parasites are not critical for the induction of memory T cell populations against the malaria liver stages.
Julius C Hafalla, Urvashi Rai, Alexandre Morrot, Dabeiba Bernal-Rubio, Fidel Zavala, Ana Rodriguez

Human vaccines, Vol. 7 Suppl (b 2011), pp. 16-21.

Eukaryotic pathogens typically follow a complex life cycle, including host switch and morphologically distinct forms. Parasite stage conversion offers exceptional opportunities for whole organism vaccine development. In case of Plasmodium, the causative agent of malaria, disease is exclusively caused by asexual blood stages that invade and replicate within erythrocytes. Pathogenic blood stage infections are preceded by a silent parasite growth phase inside the liver. Two alternative experimental whole organisms vaccine strategies that lead to arrested Plasmodium liver stages elicit potent, lasting immunity against re-infection. Live irradiation- or genetically arrested parasites are metabolically active and correspond to classical attenuated vaccines. Specific antimalarial treatment during experimental natural sporozoite infections prevents a febrile malaria episode and, simultaneously, induces effective anti-liver stage immunity. Translation of these strategies into a safe, affordable, and accessible pediatric anti-malaria vaccine requires major bioengineering and pharmaceutical improvements, respectively, but holds promise for a truly effective immunization scheme against the most prevalent and fatal vector-borne disease.
Kai Matuschewski, Julius Clemence Hafalla, Steffen Borrmann, Johannes Friesen

Annals of tropical medicine and parasitology, Vol. 79, No. 6. (December 1985), pp. 549-562.

One hundred and ninety-eight Nigerian children who received weekly chemoprophylaxis with chloroquine from shortly after birth until the age of one year or two years and 185 age-matched controls were studied. Chemoprophylaxis with chloroquine was partially, but not completely, effective in controlling malaria. Clinical malaria was documented significantly less frequently in protected children than in control children, and only 9% of random blood films obtained from protected children were positive for Plasmodium falciparum while 41% of random blood films from control children were positive for this parasite. Mean malaria antibody levels were lower in protected than in control children; for ELISA and precipitin antibodies the difference between the two groups was less marked at two years than at one year. Mortality was similar among protected and among control children. No rebound mortality or morbidity was observed after chemoprophylaxis was stopped.
AM Bradley-Moore, BM Greenwood, AK Bradley, A Bartlett, DE Bidwell, A Voller, BR Kirkwood, HM Gilles