Vascular dysfunction as a target for adjuvant therapy in cerebral malaria

Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum malaria that continues to be a major global health problem. Brain vascular dysfunction is a main factor underlying the pathogenesis of CM and can be a target for the development of adjuvant therapies for the disease. Vascular occlusion by parasitised red blood cells and vasoconstriction/vascular dysfunction results in impaired cerebral blood flow, ischaemia, hypoxia, acidosis and death. In this review, we discuss the mechanisms of vascular dysfunction in CM and the roles of low nitric oxide bioavailability, high levels of endothelin-1 and dysfunction of the angiopoietin-Tie2 axis. We also discuss the usefulness and relevance of the murine experimental model of CM by Plasmodium berghei ANKA to identify mechanisms of disease and to screen potential therapeutic interventions.

Metabolomics in the fight against malaria

Metabolomics uses high-resolution mass spectrometry to provide a chemical fingerprint of thousands of metabolites present in cells, tissues or body fluids. Such metabolic phenotyping has been successfully used to study various biologic processes and disease states. High-resolution metabolomics can shed new light on the intricacies of host-parasite interactions in each stage of the Plasmodium life cycle and the downstream ramifications on the host’s metabolism, pathogenesis and disease. Such data can become integrated with other large datasets generated using top-down systems biology approaches and be utilised by computational biologists to develop and enhance models of malaria pathogenesis relevant for identifying new drug targets or intervention strategies. Here, we focus on the promise of metabolomics to complement systems biology approaches in the quest for novel interventions in the fight against malaria. We introduce the Malaria Host-Pathogen Interaction Center (MaHPIC), a new systems biology research coalition. A primary goal of the MaHPIC is to generate systems biology datasets relating to human and non-human primate (NHP) malaria parasites and their hosts making these openly available from an online relational database. Metabolomic data from NHP infections and clinical malaria infections from around the world will comprise a unique global resource.

Malaria in Brazil: what happens outside the Amazonian endemic region

Brazil, a country of continental proportions, presents three profiles of malaria transmission. The first and most important numerically, occurs inside the Amazon. The Amazon accounts for approximately 60% of the nation’s territory and approximately 13% of the Brazilian population. This region hosts 99.5% of the nation’s malaria cases, which are predominantly caused by Plasmodium vivax (i.e., 82% of cases in 2013). The second involves imported malaria, which corresponds to malaria cases acquired outside the region where the individuals live or the diagnosis was made. These cases are imported from endemic regions of Brazil (i.e., the Amazon) or from other countries in South and Central America, Africa and Asia. Imported malaria comprised 89% of the cases found outside the area of active transmission in Brazil in 2013. These cases highlight an important question with respect to both therapeutic and epidemiological issues because patients, especially those with falciparum malaria, arriving in a region where the health professionals may not have experience with the clinical manifestations of malaria and its diagnosis could suffer dramatic consequences associated with a potential delay in treatment. Additionally, because the Anopheles vectors exist in most of the country, even a single case of malaria, if not diagnosed and treated immediately, may result in introduced cases, causing outbreaks and even introducing or reintroducing the disease to a non-endemic, receptive region. Cases introduced outside the Amazon usually occur in areas in which malaria was formerly endemic and are transmitted by competent vectors belonging to the subgenus Nyssorhynchus (i.e., Anopheles darlingi, Anopheles aquasalis and species of the Albitarsis complex). The third type of transmission accounts for only 0.05% of all cases and is caused by autochthonous malaria in the Atlantic Forest, located primarily along the southeastern Atlantic Coast. They are caused by parasites that seem to be (or to be very close to) P. vivax and, in a less extent, by Plasmodium malariae and it is transmitted by the bromeliad mosquito Anopheles (Kerteszia) cruzii. This paper deals mainly with the two profiles of malaria found outside the Amazon: the imported and ensuing introduced cases and the autochthonous cases. We also provide an update regarding the situation in Brazil and the Brazilian endemic Amazon.

Malaria in the state of Rio de Janeiro, Brazil, an Atlantic Forest area: an assessment using the health surveillance service

The lethality of malaria in the extra-Amazonian region is more than 70 times higher than in Amazonia itself. Recently, several studies have shown that autochthonous malaria is not a rare event in the Brazilian southeastern states in the Atlantic Forest biome. Information about autochthonous malaria in the state of Rio de Janeiro (RJ) is scarce. This study aims to assess malaria cases reported to the Health Surveillance System of the State of Rio de Janeiro between 2000-2010. An average of 90 cases per year had parasitological malaria confirmation by thick smear. The number of malaria notifications due to Plasmodium falciparum increased over time. Imported cases reported during the period studied were spread among 51% of the municipalities (counties) of the state. Only 35 cases (4.3%) were autochthonous, which represents an average of 3.8 new cases per year. Eleven municipalities reported autochthonous cases; within these, six could be characterised as areas of residual or new foci of malaria from the Atlantic Forest system. The other 28 municipalities could become receptive for transmission reintroduction. Cases occurred during all periods of the year, but 62.9% of cases were in the first semester of each year. Assessing vulnerability and receptivity conditions and vector ecology is imperative to establish the real risk of malaria reintroduction in RJ.

The Plasmodium bottleneck: malaria parasite losses in the mosquito vector

Nearly one million people are killed every year by the malaria parasite Plasmodium. Although the disease-causing forms of the parasite exist only in the human blood, mosquitoes of the genus Anopheles are the obligate vector for transmission. Here, we review the parasite life cycle in the vector and highlight the human and mosquito contributions that limit malaria parasite development in the mosquito host. We address parasite killing in its mosquito host and bottlenecks in parasite numbers that might guide intervention strategies to prevent transmission.

The remarkable journey of adaptation of the Plasmodium falciparum malaria parasite to New World anopheline mosquitoes

Plasmodium falciparum originated in Africa, dispersed around the world as a result of human migration and had to adapt to several different indigenous anopheline mosquitoes. Anophelines from the New World are evolutionary distant form African ones and this probably resulted in a more stringent selection of Plasmodium as it adapted to these vectors. It is thought that Plasmodium has been genetically selected by some anopheline species through unknown mechanisms. The mosquito immune system can greatly limit infection and P. falciparum evolved a strategy to evade these responses, at least in part mediated by Pfs47, a highly polymorphic gene. We propose that adaptation of P. falciparum to new vectors may require evasion of their immune system. Parasites with a Pfs47 haplotype compatible with the indigenous mosquito vector would be able to survive and be transmitted. The mosquito antiplasmodial response could be an important determinant of P. falciparum population structure and could affect malaria transmission in the Americas.

Is there an efficient trap or collection method for sampling Anopheles darlingi and other malaria vectors that can describe the essential parameters affecting transmission dynamics as effectively as human landing catches? - A Review

Distribution, abundance, feeding behaviour, host preference, parity status and human-biting and infection rates are among the medical entomological parameters evaluated when determining the vector capacity of mosquito species. To evaluate these parameters, mosquitoes must be collected using an appropriate method. Malaria is primarily transmitted by anthropophilic and synanthropic anophelines. Thus, collection methods must result in the identification of the anthropophilic species and efficiently evaluate the parameters involved in malaria transmission dynamics. Consequently, human landing catches would be the most appropriate method if not for their inherent risk. The choice of alternative anopheline collection methods, such as traps, must consider their effectiveness in reproducing the efficiency of human attraction. Collection methods lure mosquitoes by using a mixture of olfactory, visual and thermal cues. Here, we reviewed, classified and compared the efficiency of anopheline collection methods, with an emphasis on Neotropical anthropophilic species, especially Anopheles darlingi, in distinct malaria epidemiological conditions in Brazil.

A decade of malaria during pregnancy in Brazil: what has been done concerning prevention and management

In Brazil, malaria remains a disease of major epidemiological importance because of the high number of cases in the Amazonian Region. Plasmodium spp infections during pregnancy are a significant public health problem with substantial risks for the pregnant woman, the foetus and the newborn child. In Brazil, the control of malaria during pregnancy is primarily achieved by prompt and effective treatment of the acute episodes. Thus, to assure rapid diagnosis and treatment for pregnant women with malaria, one of the recommended strategy for low transmission areas by World Health Organization and as part of a strategy by the Ministry of Health, the National Malaria Control Program has focused on integrative measures with woman and reproductive health. Here, we discuss the approach for the prevention and management of malaria during pregnancy in Brazil over the last 10 years (2003-2012) using morbidity data from Malaria Health Information System. Improving the efficiency and quality of healthcare and education and the consolidation of prevention programmes will be challenges in the control of malaria during pregnancy in the next decade.

Malaria in pregnant women living in areas of low transmission on the southeast Brazilian Coast: molecular diagnosis and humoural immunity profile

Studies on autochthonous malaria in low-transmission areas in Brazil have acquired epidemiological relevance because they suggest continued transmission in what remains of the Atlantic Forest. In the southeastern portion of the state of São Paulo, outbreaks in the municipality of Juquitiba have been the focus of studies on the prevalence of Plasmodium, including asymptomatic cases. Data on the occurrence of the disease or the presence of antiplasmodial antibodies in pregnant women from this region have not previously been described. Although Plasmodium falciparum in pregnant women has been widely addressed in the literature, the interaction of Plasmodium vivax and Plasmodium malariae with this cohort has been poorly explored to date. We monitored the circulation of Plasmodium in pregnant women in health facilities located in Juquitiba using thick blood film and molecular protocols, as well as immunological assays, to evaluate humoural immune parameters. Through real-time and nested polymerase chain reaction, P. vivax and P. malariae were detected for the first time in pregnant women, with a positivity of 5.6%. Immunoassays revealed the presence of IgG antibodies: 44% for ELISA-Pv, 38.4% for SD-Bioline-Pv and 18.4% for indirect immunofluorescence assay-Pm. The high prevalence of antibodies showed significant exposure of this population to Plasmodium. In regions with similar profiles, testing for a malaria diagnosis might be indicated in prenatal care.

An overview of malaria transmission from the perspective of Amazon Anopheles vectors

In the Americas, areas with a high risk of malaria transmission are mainly located in the Amazon Forest, which extends across nine countries. One keystone step to understanding the Plasmodium life cycle in Anopheles species from the Amazon Region is to obtain experimentally infected mosquito vectors. Several attempts to colonise Ano- pheles species have been conducted, but with only short-lived success or no success at all. In this review, we review the literature on malaria transmission from the perspective of its Amazon vectors. Currently, it is possible to develop experimental Plasmodium vivax infection of the colonised and field-captured vectors in laboratories located close to Amazonian endemic areas. We are also reviewing studies related to the immune response to P. vivax infection of Anopheles aquasalis, a coastal mosquito species. Finally, we discuss the importance of the modulation of Plasmodium infection by the vector microbiota and also consider the anopheline genomes. The establishment of experimental mosquito infections with Plasmodium falciparum, Plasmodium yoelii and Plasmodium berghei parasites that could provide interesting models for studying malaria in the Amazonian scenario is important. Understanding the molecular mechanisms involved in the development of the parasites in New World vectors is crucial in order to better determine the interaction process and vectorial competence.

A historical perspective on malaria control in Brazil

Malaria has always been an important public health problem in Brazil. The early history of Brazilian malaria and its control was powered by colonisation by Europeans and the forced relocation of Africans as slaves. Internal migration brought malaria to many regions in Brazil where, given suitableAnopheles mosquito vectors, it thrived. Almost from the start, officials recognised the problem malaria presented to economic development, but early control efforts were hampered by still developing public health control and ignorance of the underlying biology and ecology of malaria. Multiple regional and national malaria control efforts have been attempted with varying success. At present, the Amazon Basin accounts for 99% of Brazil’s reported malaria cases with regional increases in incidence often associated with large scale public works or migration. Here, we provide an exhaustive summary of primary literature in English, Spanish and Portuguese regarding Brazilian malaria control. Our goal was not to interpret the history of Brazilian malaria control from a particular political or theoretical perspective, but rather to provide a straightforward, chronological narrative of the events that have transpired in Brazil over the past 200 years and identify common themes.

Aspidosperma (Apocynaceae) plant cytotoxicity and activity towards malaria parasites. Part II: experimental studies withAspidosperma ramiflorum in vivo and in vitro

Several species of Aspidosperma plants are used to treat diseases in the tropics, including Aspidosperma ramiflorum, which acts against leishmaniasis, an activity that is experimentally confirmed. The species, known as guatambu-yellow, yellowperoba, coffee-peroba andmatiambu, grows in the Atlantic Forest of Brazil in the South to the Southeast regions. Through a guided biofractionation of A. ramiflorum extracts, the plant activity against Plasmodium falciparum was evaluated in vitro for toxicity towards human hepatoma G2 cells, normal monkey kidney cells and nonimmortalised human monocytes isolated from peripheral blood. Six of the seven extracts tested were active at low doses (half-maximal drug inhibitory concentration < 3.8 µg/mL); the aqueous extract was inactive. Overall, the plant extracts and the purified compounds displayed low toxicity in vitro. A nonsoluble extract fraction and one purified alkaloid isositsirikine (compound 5) displayed high selectivity indexes (SI) (= 56 and 113, respectively), whereas compounds 2 and 3 were toxic (SI < 10). The structure, activity and low toxicity of isositsirikine in vitro are described here for the first time in A. ramiflorum, but only the neutral and precipitate plant fractions were tested for activity, which caused up to 53% parasitaemia inhibition of Plasmodium bergheiin mice with blood-induced malaria. This plant species is likely to be useful in the further development of an antimalarial drug, but its pharmacological evaluation is still required.

Immunoregulation in human malaria: the challenge of understanding asymptomatic infection

Asymptomatic Plasmodium infection carriers represent a major threat to malaria control worldwide as they are silent natural reservoirs and do not seek medical care. There are no standard criteria for asymptomaticPlasmodium infection; therefore, its diagnosis relies on the presence of the parasite during a specific period of symptomless infection. The antiparasitic immune response can result in reducedPlasmodium sp. load with control of disease manifestations, which leads to asymptomatic infection. Both the innate and adaptive immune responses seem to play major roles in asymptomatic Plasmodiuminfection; T regulatory cell activity (through the production of interleukin-10 and transforming growth factor-β) and B-cells (with a broad antibody response) both play prominent roles. Furthermore, molecules involved in the haem detoxification pathway (such as haptoglobin and haeme oxygenase-1) and iron metabolism (ferritin and activated c-Jun N-terminal kinase) have emerged in recent years as potential biomarkers and thus are helping to unravel the immune response underlying asymptomatic Plasmodium infection. The acquisition of large data sets and the use of robust statistical tools, including network analysis, associated with well-designed malaria studies will likely help elucidate the immune mechanisms responsible for asymptomatic infection.

Malaria in gold-mining areas in Colombia

Gold-mining may play an important role in the maintenance of malaria worldwide. Gold-mining, mostly illegal, has significantly expanded in Colombia during the last decade in areas with limited health care and disease prevention. We report a descriptive study that was carried out to determine the malaria prevalence in gold-mining areas of Colombia, using data from the public health surveillance system (National Health Institute) during the period 2010-2013. Gold-mining was more prevalent in the departments of Antioquia, Córdoba, Bolívar, Chocó, Nariño, Cauca, and Valle, which contributed 89.3% (270,753 cases) of the national malaria incidence from 2010-2013 and 31.6% of malaria cases were from mining areas. Mining regions, such as El Bagre, Zaragoza, and Segovia, in Antioquia, Puerto Libertador and Montelíbano, in Córdoba, and Buenaventura, in Valle del Cauca, were the most endemic areas. The annual parasite index (API) correlated with gold production (R2 0.82, p < 0.0001); for every 100 kg of gold produced, the API increased by 0.54 cases per 1,000 inhabitants. Lack of malaria control activities, together with high migration and proliferation of mosquito breeding sites, contribute to malaria in gold-mining regions. Specific control activities must be introduced to control this significant source of malaria in Colombia.

Genesis and classification of Oxisols in a highland toposequence of the upper Jequitinhonha Valley (MG)

The Brazilian System of Soil Classification (SiBCS) is a taxonomic system, open and in permanent construction, as new knowledge on Brazilian soils is obtained. The objective of this study was to characterize the chemical, physical, morphological, micro-morphological and mineralogical properties of four pedons of Oxisols in a highland toposequence in the upper Jequitinhonha Valley, emphasizing aspects of their genesis, classification and landscape development. The pedons occupy the following slope positions: summit - Red Oxisol (LV), mid slope (upper third) - Yellow-Red Oxisol (LVA), lower slope (middle third)- Yellow Oxisol (LA) and bottom of the valley (lowest third) - "Gray Oxisol" ("LAC"). These pedons were described and sampled for characterization in chemical and physical routine analyses. The total Fe, Al and Mn contents were determined by sulfuric attack and the Fe, Al and Mn oxides in dithionite-citrate-bicarbonate and oxalate extraction. The mineralogy of silicate clays was identified by X ray diffraction and the Fe oxides were detected by differential X ray diffraction. Total Ti, Ga and Zr contents were determined by X ray fluorescence spectrometry. The "LAC" is gray-colored and contains significant fragments of structure units in the form of a dense paste, characteristic of a gleysoil, in the horizons A and BA. All pedons are very clayey, dystrophic and have low contents of available P and a pH of around 5. The soil color was related to the Fe oxide content, which decreased along the slope. The decrease of crystalline and low- crystalline Fe along the slope confirmed the loss of Fe from the "LAC". Total Si increased along the slope and total Al remained constant. The clay fraction in all pedons was dominated by kaolinite and gibbsite. Hematite and goethite were identified in LV, low-intensity hematite and goethite in LVA, goethite in LA. In the "LAC", no hematite peaks and goethite were detected by differential X ray diffraction. The micro-morphology indicated prevalence of granular microstructure and porosity with complex stacking patterns.. The soil properties in the toposequence converged to a single soil class, the Oxisols, derived from the same source material. The landscape evolution and genesis of Oxisols of the highlands in the upper Jequitinhonha Valley are related to the evolution of the drainage system and the activity of excavating fauna.