Signal transduction in Plasmodium-Red Blood Cells interactions and in cytoadherence

Malaria is responsible for more than 1.5 million deaths each year, especially among children (Snow et al. 2005). Despite of the severity of malaria situation and great effort to the development of new drug targets (Yuan et al. 2011) there is still a relative low investment toward antimalarial drugs. Briefly there are targets classes of antimalarial drugs currently being tested including: kinases, proteases, ion channel of GPCR, nuclear receptor, among others (Gamo et al. 2010). Here we review malaria signal transduction pathways in Red Blood Cells (RBC) as well as infected RBCs and endothelial cells interactions, namely cytoadherence. The last process is thought to play an important role in the pathogenesis of severe malaria. The molecules displayed on the surface of both infected erythrocytes (IE) and vascular endothelial cells (EC) exert themselves as important mediators in cytoadherence, in that they not only induce structural and metabolic changes on both sides, but also trigger multiple signal transduction processes, leading to alteration of gene expression, with the balance between positive and negative regulation determining endothelial pathology during a malaria infection.

IFN-γ-induced priming maintains long-term strain-transcending immunity against blood-stage Plasmodium chabaudi malaria

The mechanism by which protective immunity to Plasmodium is lost in the absence of continued exposure to this parasite has yet to be fully elucidated. It has been recently shown that IFN-γ produced during human and murine acute malaria primes the immune response to TLR agonists. In this study, we investigated whether IFN-γ-induced priming is important to maintain long-term protective immunity against Plasmodium chabaudi AS malaria. On day 60 postinfection, C57BL/6 mice still had chronic parasitemia and efficiently controlled homologous and heterologous (AJ strain) challenge. The spleens of chronic mice showed augmented numbers of effector/effector memory (TEM) CD4(+) cells, which is associated with increased levels of IFN-γ-induced priming (i.e., high expression of IFN-inducible genes and TLR hyperresponsiveness). After parasite elimination, IFN-γ-induced priming was no longer detected and protective immunity to heterologous challenge was mostly lost with >70% mortality. Spontaneously cured mice had high serum levels of parasite-specific IgG, but effector T/TEM cell numbers, parasite-driven CD4(+) T cell proliferation, and IFN-γ production were similar to noninfected controls. Remarkably, the priming of cured mice with low doses of IFN-γ rescued TLR hyperresponsiveness and the capacity to control heterologous challenge, increasing the TEM cell population and restoring the CD4(+) T cell responses to parasites. Contribution of TLR signaling to the CD4(+) T cell responses in chronic mice was supported by data obtained in mice lacking the MyD88 adaptor. These results indicate that IFN-γ-induced priming is required to maintain protective immunity against P. chabaudi and aid in establishing the molecular basis of strain-transcending immunity in human malaria.

Liver accumulation of Plasmodium chabaudi-infected red blood cells and modulation of regulatory T Cell and dendritic cell responses

It is postulated that accumulation of malaria-infected Red Blood Cells (iRBCs) in the liver could be a parasitic escape mechanism against full destruction by the host immune system. Therefore, we evaluated the in vivo mechanism of this accumulation and its potential immunological consequences. A massive liver accumulation of P. c. chabaudi AS-iRBCs (PciRBCs) was observed by intravital microscopy along with an over expression of ICAM-1 on day 7 of the infection, as measured by qRT-PCR. Phenotypic changes were also observed in regulatory T cells (Tregs) and dendritic cells (DCs) that were isolated from infected livers, which indicate a functional role for Tregs in the regulation of the liver inflammatory immune response. In fact, the suppressive function of liver-Tregs was in vitro tested, which demonstrated the capacity of these cells to suppress naive T cell activation to the same extent as that observed for spleen-Tregs. On the other hand, it is already known that CD4+ T cells isolated from spleens of protozoan parasite-infected mice are refractory to proliferate in vivo. In our experiments, we observed a similar lack of in vitro proliferative capacity in liver CD4+ T cells that were isolated on day 7 of infection. It is also known that nitric oxide and IL-10 are partially involved in acute phase immunosuppression; we found high expression levels of IL-10 and iNOS mRNA in day 7-infected livers, which indicates a possible role for these molecules in the observed immune suppression. Taken together, these results indicate that malaria parasite accumulation within the liver could be an escape mechanism to avoid sterile immunity sponsored by a tolerogenic environment.

MyD88 signaling is directly involved in the development of murine placental Malaria

Malaria is a widespread infectious disease caused by the parasite Plasmodium. During pregnancy, malaria infection leads to a range of complications that can affect both the mother and fetus, including stillbirth, infant mortality, and low birth weight. In this study, we utilized a mouse model of placental malaria (PM) infection to determine the importance of the protein MyD88 in the host immune response to Plasmodium during pregnancy. Initially, we demonstrated that Plasmodium berghei NK65GFP adhered to placental tissue via chondroitin sulfate A and induced PM in mice with a C57BL/6 genetic background. To evaluate the involvement of MyD88 in the pathology of PM, we performed a histopathological analysis of placentas obtained from MyD88(-/-) and wild-type (WT) mice following infection on the 19th gestational day. Our data demonstrated that the detrimental placental alterations observed in the infected mice were correlated with the expression of MyD88. Moreover, in the absence of this protein, production of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) was significantly reduced in the infected mice. More importantly, in contrast to fetuses from infected WT mice, which exhibited a reduction in body weight, the fetuses from infected MyD88(-/-) mice did not display significant weight loss compared to their noninfected littermates. In addition, we observed a decrement of maternal care associated with malaria infection, which was attenuated in the MyD88-deficient mice. Collectively, the results of this study illustrate the pivotal importance of the MyD88 signaling pathway in the pathogenesis of placental malaria, thus presenting new possibilities for targeting MyD88 in therapeutic interventions.

Viagem sem volta. [Depoimento a Rodrigo de Oliveira Andrade]

Fêmeas de pinguins-de-magalhães morrem mais que machos durante migração anual.

A study of the anti-plasmodium activity of angiotensin II analogs

Controlling the dissemination of malaria requires the development of new drugs against its etiological agent, a protozoan of the Plasmodium genus. Angiotensin II and its analog peptides exhibit activity against the development of immature and mature sporozoites of Plasmodium gallinaceum. In this study, we report the synthesis and characterization of angiotensin II linear and cyclic analogs with anti-plasmodium activity. The peptides were synthesized by a conventional solid-phase method on Merrifield's resin using the t-Boc strategy, purified by RP-HPLC and characterized by liquid chromatography/ESI (+) MS (LC-ESI(+)/MS), amino acid analysis, and capillary electrophoresis. Anti-plasmodium activity was measured in vitro by fluorescence microscopy using propidium iodine uptake as an indicator of cellular damage. The activities of the linear and cyclic peptides are not significantly different (p < 0.05). Kinetics studies indicate that the effects of these peptides on plasmodium viability overtime exhibit a sigmoidal profile and that the system stabilizes after a period of 1 h for all peptides examined. The results were rationalized by partial least-square analysis, assessing the position-wise contribution of each amino acid. The highest contribution of polar amino acids and a Lys residue proximal to the C-terminus, as well as that of hydrophobic amino acids in the N-terminus, suggests that the mechanism underlying the anti-malarial activity of these peptides is attributed to its amphiphilic character.

Revisão taxonômica e filogenia da Seção Myzorhynchella de Anopheles (Nyssorhynchus) (Diptera: Culicidae)

Anopheles é o gênero da família Culicidae mais estudado devido sua importância médica. Atualmente o gênero Anopheles compreende 472 espécies válidas que estão divididas em sete subgêneros. Os principais vetores de plasmódio da Malária no Brasil pertencem ao subgênero Nyssorhynchus, que inclui 39 espécies oficialmente reconhecidas e um número crescente de complexos de espécies crípticas que estão distribuídas em três Seções: Myzorhynchella, Albimanus e Argyritarsis. Atualmente a Seção Myzorhynchella é formada por seis espécies: An. lutzii, An. parvus, An. nigritarsis, An. guarani, An. antunesi e An. pristinus. Para o desenvolvimento da análise morfológica, observou-se material-tipo depositado em diferentes coleções, espécimes depositados na coleção entomológica da FSP/USP, além de outros obtidos em coletas realizadas durante o presente estudo em diferentes localidades do Brasil. As análises moleculares foram desenvolvidas a partir de espécimes obtidos nas coletas. Revisão taxonômica da Seção Myzorhynchella é apresentada, incluindo-se descrições de quatro novas espécies e redescrições das demais, informações sobre bionomia, importância médica, caracterização molecular, distribuição geográfica, estado de preservação do material-tipo, além de chaves de identificação de adultos, larva de quarto estádio e genitália masculina. Os resultados das análises filogenéticas utilizando sequências de ITS2, COI e Catalase indicam a existência de pelo menos doze espécies dentro da Seção Myzorhynchella, os espécimes que vêm sendo identificados como An. antunesi constitui um complexo formado por possíveis cinco espécies e aqueles de An. parvus e An. pristinus também podem representar complexos de espécies. As sequências de ITS2 podem ser utilizadas como marcador diagnóstico para espécies da Seção Myzorhynchella. Contudo, o estudo ainda demonstra que pouco se conhece sobre a diversidade de espécies de Anopheles que ocorrem em ambientes onde a malária ocorre em baixa endemicidade. Pelo número de espécies novas encontradas e pela escassez de trabalhos com espécies da Seção, fica evidente a necessidade de mais estudos.

Can iron be used to treat malaria?

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Studies on Brazilian anophelines from the northeast and Amazon regions ...

"References" at end of each study.

Új vektoriális betegségek megjelenésének lehetősége, és a már őshonos betegségek jelentőségének növekedése a klímaváltozás következtében. A XXI. század egészségügyi és hadászati biztonságát fenyegető hazardok

Az ízeltlábúak által terjesztett fertőző betegségek egyre emelkedő mértékben jelentenek majd veszélyt Európa mérsékelt övi lakosságának egészségi állapotára nézve. A klímaváltozás következtében meghosszabbodó vegetációs időszak, és az emelkedő átlaghőmérséklet a már jelen lévő betegség (Pl. Lyme), és számos, a lakosság számára új, meleg égövi betegség megtelepedését, vagy újra megjelenését okozhatja, mint amilyen például a leishmaniasis vagy a malária. A jövőben nem csak a civil lakosság egészségi állapotát, de a hadsereg személyi állományának egészségét és a hadműveletek biztonságát is veszélyeztethetik a vektoriális megbetegedések. _____ Emerging vectorial diseases threaten the population of the temperate areas of Europe. Due to climate change the increasing seasonal mean temperatures and the prolongation of the potential activity period of arthropod vectorial organisms will enhance the importance of the tick-borne diseases (eg. Lyme disease) and will facilitate the expansion of new or re-emerging vectorial diseases, such as leishmaniasis or malaria. These serious vectorial diseases can cause notable hazard not only for citizens but for the personnels and may endanger the safety of the operations, too.

Gestão de resíduos sólidos domiciliares na cidade de Chibuto, província de Gaza Moçambique

This study analyzes the process of generation and management of solid waste in the Municipality of the City of Chibuto-Mozambique, drawing on the different approaches towards allocation and the socio-environmental implications resulting from this process and waste spatial distribution. To answer these objectives a questionnaire was administered to 367 households distributed in 14 neighborhoods of the city to elicit information on how solid waste is treated and what could be its impact on public health of the residents. From this perspective, the questionnaire gasp information from immigrant residents regarding both their origin, and socio economic condition. Apart from the questionnaire, semi-structured interviews were conducted to staff working on the Sanitation Sector, Urbanization Sector of the Chibuto Municipality, including the Health Service, and Women and Social Affairs. In addition to these data collection methods, for further discussion on the subject, the researcher draw a theoretical framework grounded through literature review, as well as systematic observation of the phenomenon. Research findings revealed that the solid waste collection services provided by the Chibuto Municipality do not follow the procedures laid down in the Regulation on Solid Waste Management, which advocates environmentally safe, sustainable, and complete management of waste. First, the services use open dumps for waste management. Secondly, waste collection does not cover all citizens living in the neighborhoods governed by the municipality, due to financial, technical, and organizational reasons. More importantly, the study found that due to this failure, more than 90% of households surveyed continue to use the traditional methods on waste management which include burning, or the burial techniques. On the other hand, some citizens throw waste on the streets, a method that threatens public health because it increases cases of diseases related to sanitation problems such as (diarrhea and malaria), especially in suburban and peripheral urban areas. Concerning with the above mentioned problems which constitute a real threat to the public health, some ways are proposed for more sustainable and spatially appropriate solid waste management through recycling, waste sorting, composting, reuse, and reduction of solid waste generation.

A organização da educação no território federal do Amapá: do "ideal" ao real, do liberal ao conservador (1943-1958)

The present study on “organization education on Amapá’s Federal Territory (1943-1958)”, looked forward to answering the following questions: Was there an educational policy, in a systemic way, on the former Amapá’s federal territory? On the other hand, what were the main initiatives of the first intervenors for the education dissemination? After facing these questions, we established, as hypothesis, that the developed actions in the education’s scope on that territory back in the 40’s and 50’s were not able to implant an educational project in Amapá, since there was no preoccupation to understanding the sociocultural reality of Amapá’s population. Given this hypothesis, we analyzed the relation between the political practices developed by the first intervenor on the territory and the brazilian political scenario, from the legal-administrative nature of the federal entities and political conjuncture of the “New State” (1937-1945). To achieve that, we sought some similarities between Janary Gentil Nunes’s ways of governing and Getúlio Vargas’s political actions. To make this happen, it was necessary to check official documents out, as well as unofficial ones, especially the old articles published by “Amapá”, the local newspaper, official press tool back then, which disseminated the beliefs and values of the constituted authorities, with the purpose of “strengthen” the “modernization” ideal on the people. Such practice was based on the attempt of breaking off sociocultural economic backwardness of the territory, hiding out the reality of the Amapá’s population, marked by poverty, a high illiteracy rate and the typical tropical diseases from Amazon (Malaria). During the rupture’s process between the old and the modern, the education takes on a major role in the official speech, being used as political advertisement and as essential element to the modernization and to the development of a “new man”: now “civilized”. However, the investigation on the expansion of the elementary education in Amapá, showed us the presence of a significant number of rural schools, in contradiction to the disseminated urban modernization promise around there. In this sense, we can affirm that educational policy on Amapá’s territory failed by reasons of being based on the “transplantation” of the Federal District’s educational project, and it is important to recall that, back then, the brazilian Federal District was Rio de Janeiro. Despite the public agents had established uncountable schools on rural areas, these were not carried out from a more systemic process, this is, considering the reality of the Amazon’s "cabloco". So, we observed the existence of the separation between the modern speech and the maintenance of old oligarchic practices by that time.

Entre Nós : Instituto Gulbenkian de Ciência

Emissões - Entre Nós

Alterações à fisiologia e infeção por Plasmodium berghei do mosquito Anopheles gambiae mediadas pela ativação de recetores GPCR

Dissertação de Mestrado, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2015

Design and synthesis of novel quinolones directed to the Plasmodium falciparum bc1 protein complex

Tese de Doutoramento, Química, Especialização em Química Orgânica, Faculdade de Ciências e Tecnologia, Universidade do Algarve, 2016