Malaria
Manager: Dolores González Pacanowska IPBLN-B
Malaria (or paludism) is the most important parasitic disease in the world in terms of morbidity-mortality, since it causes a higher number of deaths than any other transmissible disease. In addition, it has an enormous socio-economic impact: malaria is a public health problem in over 90 countries, inhabited by a total of 2,400 million people, more than 40% of the world's population.
The annual prevalence of the disease is estimated at 300-500 million clinical cases, with over 90% of malaria cases found in sub-Saharan Africa, and mortality stands at approximately 1-2 million deaths per annum. Most deaths occur among young children, especially in remote rural areas with little access to health care. In many developing countries, particularly in Africa, the cost -both material and in the form of human lives- is enormous, even though it is a disease that is curable if diagnosed early and treated properly.
The parasites are transmitted by mosquitoes of the genus Anopheles, whose bite is followed by asymptomatic infection in hepatic cells. After an incubation period of approximately one week, the blood forms of the parasites are released, and these then develop and multiply in the interior of erythrocytes. The parasite produces proteins that are transported and placed at the red blood cell membrane. These proteins cause the erythrocyte to adhere to the walls of the blood vessels, thus obstructing them. There are four species of Plasmodium, namely, Plasmodium ovale, Plasmodium vivax, Plasmodium falciparum and Plasmodium malariae, which cause malaria in humans. Cerebral malaria is a severe complication of malaria caused by P. falciparum: the sequestration of infected red blood cells in blood vessels is associated with the onset of coma, and the condition can prove lethal if not treated. The parasites of the species P. vivax and P. ovale are characterised by presenting with the hypnozoite phase, which, if not treated appropriately, can persist for years in the liver and cause periodic malarial relapses.
Subprogram: Diagnostic Tools, Reference, Molecular Epidemiology and Control
Manager: Agustín Benito LLanes. ISCIII-A
One of the present shortfalls in research devoted to this goal is the lack of investment in diagnostic techniques, whether in the form of rapid diagnostic tests (RDTs), confirmation tests (real-time PCR, direct PCR, etc.) or molecular markers, which would enable malaria epidemiology to come up with answers in the context of endemic countries.
The projects earmarked for implementation in this field are based on developing parasite-antigen detection. These are tests that are extremely easy to perform, rapid and sensitive, and do not require the use of a microscope. The commercial systems (dipstick, cassette) are stable at ambient temperature, something that allows for transport to the tropics, and are a major aid for diagnosis of malaria at laboratories with little experience in microscopy.
To this end, the goal (within the context of RICET's projects) is to design prototypes of rapid tests based on various targets (dUTPase, other recombinant antigens drawn from expression libraries possessed by some groups) which are being evaluated in terms of sensitivity and specificity, and which will form part of the development work to be done over the next four years.
Furthermore, further research is to be conducted into the parasite's various genes in order to simplify diagnosis of confirmation by direct and real time PCR techniques, which would simplify the diagnosis currently being performed in this country, with the ultimate aim of transferring this task to the National Health System.
Moreover, the molecular marker, gen kdr , related to anophelinae resistance to pyrethroids, now makes it possible for us to target a given geographical area and assess the scheme to be followed in insectide-based malaria control, whether such insectides are present via impregnation of mosquito nets for beds or intramural spraying.
Finally, assessing the degree of transmission due to malaria in a given area (using population-based molecular markers, infective bite/person/year rates, percentage of infected and infective mosquitoes, etc.) will enable us to form a detailed picture of the degree of malaria transmission and the best strategy to be used to control the disease.
Search for and identification of targets for the improvement of malaria diagnosis.
Head Researcher: Agustín Benito, ISCIII-A
There is an ever-growing number of diagnostic tools that could help in the performance of rapid, confirmatory diagnosis of malarial infection, though some of these are somewhat complicated for use in developing countries, owing to their high technological level and cost. The lack and high cost of existing tests means that one of the Network's goals is research applied to improving current diagnostics.
Goal
To develop molecular (direct and real time PCR) and rapid antigen-capture diagnostic techniques for diagnosis of the two main species responsible for malaria in humans (P.falciparum and P.vivax)
Subprogram: Vector, Transmission and Control Studies
Manager: María Dolores Bargues Castelló DPUV
From the standpoint of the Network's participation in the context of neglected tropical diseases, there is a means whereby action can be taken in tropical countries, mainly Equatorial Guinea and Mozambique, where active collaboration among different research groups is already in place.
Hence, the aim is to undertake projects that are linked to control, characterisation of primary and secondary vector species, molecular vector insecticide-resistance studies, vector population genetics (anophelinae, glossinae, etc.), infection burden studies, etc. An important component are the reservoirs, which are of great importance in some tropical infections. Specific studies will therefore be conducted involving these, in view of their importance when it comes to diagnosis, molecular epidemiology and control. On the one hand, the study of native vectors related with imported pathology will be assessed in this programme, as will the introduction of imported vectors that might settle within our territory as a result of mobilisation and climate change, among other things.
Recent molecular demostration of different genotypes, chromosomal forms, introgressive hybridisation, adaptive inversions, or recent reproductive isolation in Anophelinae, apart from enabling their structure and population movements to be characterised, is directly linked to their capacity to transmit malaria as well as other infectious diseases, thereby explaining the possible increase in their transmission capacity and geographical spread. At present, the application of different molecular markers enables us to understand genetic flows among Culicidae, as well as their genetic and ecological barriers, of vital importance for appreciation of their transmission capacity and for knowledge of control measures against the diseases that they transmit. The various genotypes appear to be linked to characteristics that influence their behaviour and transmission capacity. Moreover, there is an increasing body of evidence to show that genetic variation among the Anophelinae is linked to the mosquito's adaptation to its environment.
In the face of such a sharp increase in cases of malaria imported into Spain from endemic countries, it is of vital importance to study the geographical distribution of potential malaria vectors in this country, and of Culicidae vectors of other infectious diseases, such as Dirofilariasis (Heartworm Disease), in order to assess their importance in the appearance or non-appearance of home-grown outbreaks. Similarly, the population dynamic and estimation of the transmission capacity of these vectors, as well as the effectiveness of and resistance to new insecticide products, are fundamental focal points of research for Spain in a situation of climate and global change and the introduction of infectious-contagious transmission agents by mosquitoes from other latitudes. Among these, malaria is a priority, in view of the incessant inflow of immigration from endemic countries, basically Africa but also Latin America and Asia, the fact that Spain was endemic up until the early 1950s, and that potential-vector Anophelinae species continue to be distributed throughout the Iberian Peninsula.
Goal
The geographical distribution, vectorial capacity, behaviour and basic entomological indices of potential malaria vectors in Spain must be studied, to assess their importance in terms of risk of appearance of homegrown outbreaks. To this end, we plan to apply Geographical Information Systems (GIS) and molecular characterisation techniques to the task of assessing the receptivity/vulnerability, not only of malaria in Spain as "re-emerging" in former risk areas (Guadalquivir salt marshes (marismas), Ebro River Delta, Extremadura, etc.) where paludism and vectors interacted, or areas bordering international airports (Madrid Autonomous Region), but also of other infectious diseases transmitted by Culicidae.
Evaluation of anophelinae resistance/susceptibility to insecticides in the urban area of Manhiça, Mozambique
Head Researcher Jorge Cano ISCIII-A
Mozambique's National Malaria Control Programme has drawn up a Plan of Action on the use of residual insecticides in the control of malaria country-wide. To date, nothing is known of the possible degree of sensitivity possessed by the insecticides earmarked for use in the different areas targeted for action.
Goal
Implementation of a surveillance system in the Manhiça district for detection of malaria vector populations' resistance to insecticides commonly used in the control campaigns (pyrethroids, organophosphates, organochlorines and carbamates).
Malaria transmission study in Ilha Josina and Taninga, Manhiça District , Mozambique
Head Researcher Jorge Cano ISCIII-A
The control campaigns launched by Mozambique's National Fight Against Malaria Control Programme have led to a substantial reduction in virgin areas for RTS,S/AS02 vaccine trials.
Goal
To describe the malaria transmission pattern in two places where RTS,S/AS02D vaccine trials are being conducted, i.e., Ilha Josina and Taninga (Manhiça District).
Subprogram: Malaria Treatment
Manager: Dolores González Pacanowska IPBLN-B
Malaria is one of the leading infectious diseases world-wide. Mortality is put at approximately 1.5 million deaths/year, with 300 to 400 million new cases per annum. The situation with respect to treatment and control has worsened enormously due to the appearance of insecticide-resistant vectors and multi-drug-resistant parasites. New therapeutic strategies for treating the disease must be urgently developed. Furthermore, many of the compounds usually used in treatment and prophylaxis have adverse effects. Thus, since 1992 many neuropsychiatric effects associated with taking mefloquine have been described.
In addition, it has been suggested that these effects can be assumed to affect women more frequently than men. More recently, the appearance of adverse effects have been linked to gender, low body weight and first time of administration. An experimental animal study reveals that mefloquine induces neurological effects which can be of clinical relevance and could result in permanent injury to the central nervous system. In-depth study of the factors associated with the adverse effects of prophylactic therapy will help define the recommended dosage.
The Network has a series of lead compounds with proven in vitro and in vivo antimalarial activity against the parasite. Specifically, efforts have focused on two types of compounds, i.e., quinones and imidazoisoindole derivatives. The aim is to explore the potential of these compounds, by designing, synthesising and evaluating new analogues, structurally optimising the new series by topological analysis and characterising their mechanism of action. Whereas the mechanism of action of the former appears to be at the e-mitochondrial transport chain and glutathione metabolism level, the mode of action of the latter class of compunds remains unknown. Likewise, their efficacy in both in vitro and in vivo disease models will be analysed. The information obtained wil be used in the design and optimisation of new compounds.
