Malaria cerebral / Cerebral malaria

RESUMEN La malaria sigue siendo un problema de salud pública que afecta especialmente a las regiones tropicales y los países en vía de desarrollo, y Latinoamérica es una región endémica para la enfermedad. A pesar de que se ha demostrado una disminución de los casos de malaria en general, los casos de malaria complicada se mantienen estables. Entre las complicaciones graves de esta infección parasitaria está la malaria cerebral, que si bien se considera infrecuente, está asociada con una mortalidad de hasta el 20 %, especialmente en niños, y además produce altas tasas de discapacidad: alrededor del 11 % de los niños y el 25 % de los adultos que la padecen. De ahí la relevancia de conocerla y hacer la detección temprana de esta complicación. En este escrito se presenta la definición de malaria cerebral y su mecanismos fisiopatológicos, desde la obstrucción microvascular, la tormenta de citoquinas, hasta la alteración endotelial. Se llama la atención sobre el cuadro de signos y síntomas, la importancia de mantener esta sospecha clínica y la necesidad de considerar los principales diagnósticos diferenciales; se menciona la utilidad de cada una de las ayudas diagnósticas y la limitación por su poca disponibilidad en muchas áreas geográficas. Se deja el mensaje a todo el equipo de salud de estar atentos a detectar oportunamente las complicaciones sistémicas. Se presentan las bases del tratamiento actual y hacia dónde va la investigación en vacunas. Esta revisión es también una invitación a reflexionar sobre el enfoque de esta patología y la necesaria inclusión de otros factores que considerar, como las condiciones culturales, socioeconómicas y de educación que inciden en el comportamiento de la enfermedad en las comunidades afectadas.

SUMMARY Malaria continues to be a public health problem that particularly affects the tropical regions and developing countries, whereas Latin America is an endemic region for the disease. Despite the fact that a decrease in malaria cases has been shown, in general, cases of complicated malaria remain stable and within the severe complications of this parasitic infection is cerebral malaria, which, although considered uncommon, is associated with a mortality of up to 20 %, especially in children and also produces high disability rates: about 11 % of children and 25 % of adults who suffer from it. Of hence the relevance of knowing it and making early detection of this complication. We present the definition of cerebral malaria, the pathophysiological mechanisms from the microvascular obstruction, cytokine storm to endothelial alteration. We call the attention to the picture of signs and symptoms, the importance of maintaining this clinical suspicion and the need to consider the main differential diagnoses; we mention the usefulness of each of the diagnostic aids and the limitation due to the limited availability of them in many geographic areas. We leave a message for the entire health team to be attentive to detect timely systemic complications. The bases of the current treatment and where is vaccine research going. This review is also an invitation to reflect on the approach to this pathology and the necessary inclusion of other factors to consider such as cultural conditions, socioeconomic and educational conditions that affect the behavior of the disease in affected communities.

Melatonin activates FIS1, DYN1, and DYN2 Plasmodium falciparum related-genes for mitochondria fission: Mitoemerald-GFP as a tool to visualize mitochondria structure.

Malaria causes millions of deaths worldwide and is considered a huge burden to underdeveloped countries. The number of cases with resistance to all antimalarials is continuously increasing, making the identification of novel drugs a very urgent necessity. A potentially very interesting target for novel therapeutic intervention is the parasite mitochondrion. In this work, we studied in Plasmodium falciparum 3 genes coding for proteins homologues of the mammalian FIS1 (Mitochondrial Fission Protein 1) and DRP1 (Dynamin Related Protein 1) involved in mitochondrial fission. We studied the expression of P. falciparum genes that show ample sequence and structural homologies with the mammalian counterparts, namely FIS1, DYN1, and DYN2. The encoded proteins are characterized by a distinct pattern of expression throughout the erythrocytic cycle of P. falciparum, and their mRNAs are modulated by treating the parasite with the host hormone melatonin. We have previously reported that the knockout of the Plasmodium gene that codes for protein kinase 7 is essential for melatonin sensing. We here show that PfPk7 knockout results in major alterations of mitochondrial fission genes expression when compared to wild-type parasites, and no change in fission proteins expression upon treatment with the host hormone. Finally, we have compared the morphological characteristics (using MitoTracker Red CMX Ros) and oxygen consumption properties of P. falciparum mitochondria in wild-type parasites and PfPk7 Knockout strains. A novel GFP construct targeted to the mitochondrial matrix to wild-type parasites was also developed to visualize P. falciparum mitochondria. We here show that, the functional characteristics of P. falciparum are profoundly altered in cells lacking protein kinase 7, suggesting that this enzyme plays a major role in the control of mitochondrial morphogenesis and maturation during the intra-erythrocyte cell cycle progression.

Efficient expression systems for cysteine proteases of malaria parasites: too good to be true?

Papain-like cysteine proteases of malaria parasites are considered important chemotherapeutic targets or valuable models for the evaluation of drug candidates. Consequently, many of these enzymes have been cloned and expressed in Escherichia coli for their biochemical characterization. However, their expression has been problematic, showing low yield and leading to the formation of insoluble aggregates. Given that highly-productive expression systems are required for the high-throughput evaluation of inhibitors, we analyzed the existing expression systems to identify the causes of such apparent issues. We found that significant divergences in codon and nucleotide composition from host genes are the most probable cause of expression failure, and propose several strategies to overcome these limitations. Finally we predict that yeast hosts Saccharomyces cerevisiae and Pichia pastoris may be better suited than E. coli for the efficient expression of plasmodial genes, presumably leading to soluble and active products reproducing structural and functional characteristics of the natural enzymes.

The emerging of the fifth malaria parasite (Plasmodium knowlesi): a public health concern?

After examining the most recent scientific evidences, which assessed the role of some malaria plasmodia that have monkeys as natural reservoirs, the authors focus their attention on Plasmodium knowlesi. The infective foci attributable to this last Plasmodium species have been identified during the last decade in Malaysia, in particular in the states of Sarawak and Sabah (Malaysian Borneo), and in the Pahang region (peninsular Malaysia). The significant relevance of molecular biology assays (polymerase chain reaction, or PCR, performed with specific primers for P. knowlesi), is underlined, since the traditional microscopic examination does not offer distinguishing features, especially when the differential diagnosis with Plasmodium malariae is of concern. Furthermore, Plasmodium knowlesi disease may be responsible of fatal cases, since its clinical presentation and course is more severe compared with those caused by P. malariae, paralleling a more elevated parasitemia. The most effective mosquito vector is represented by Anopheles latens; this mosquito is a parasite of both humans and monkeys. Among primates, the natural hosts are Macaca fascicularis, M. nemestina, M. inus, and Saimiri scirea. When remarking the possible severe evolution of P. knowlesi malaria, we underline the importance of an early recognition and a timely management, especially in patients who have their first onset in Western Hospitals, after journeys in Southeast Asian countries, and eventually participated in trekking excursions in the tropical forest. When malaria-like signs and symptoms are present, a timely diagnosis and treatment become crucial. In the light of its emerging epidemiological features, P. knowlesi may be added to the reknown human malaria parasites, whith includes P. vivax, P. ovale, P. malariae, and P. falciparum, as the fifth potential ethiologic agent of human malaria. Over the next few years, it will be mandatory to support an adequate surveillance and epidemiological network. In parallel with epidemiological and health care policy studies, also an accurate appraisal of the clinical features of P. knowlesi-affected patients will be strongly needed, since some preliminary experiences seem to show an increased disease severity, associated with increased parasitemia, in parallel with the progressive increase of inter-human infectious passages of this emerging Plasmodium.

La Malaria en el Nuevo Mundo: de los Origenes al Siglo XXI / Malaria in the New World: From its Origin to the XXI Century

A partir de una revisión histórico-epidemiológica de la información disponible sobre el Paludismo en nuestro continente, después de la llegada de los Conquistadores, se comentan las relaciones parásito-vectores y hospederos naturales, dejando abierta la gran incógnita del origen de los parásitos maláricos en el Nuevo Mundo. Se traza una visión de salud y enfermedad como producto de la conquista y de la limitada experiencia de nuestros aborígenes frente a las patologías importadas de Eurasia. Un resumen sobre la lucha antipalúdica organizada permite algunas consideraciones sobre su presente y futuro. Se concluye sugiriendo un esfuerzo multidisciplinario y pluriinstitucional basado en una estrategia de participación comunitaria para superar el estancamiento o los retrocesos presentes en los inicios del Siglo XXI.

Starting from a historic-epidemiological review of the available information concerning malaria in our continent after the arrival of the "conquistadores", the authors discuss the relations between parasites, vectors and natural hosts, leaving unsolved the question concerning the origin of malaria parasites in the New World. An outlook of health-disease process as a product of the conquest and the limited experience of our ancestors in front of exotic pathologies arrived from Eurasia is given. A summary of the organized struggle against malaria allows some considerations on its present and future perspectives. Finally, a suggestion for a joint professional and institutional effort with a community based strategy is made, aimed to overcome the blockage and setbacks recorded at the beginning of the XXI century.