Insights into the immunopathogenesis of malaria using mouse models

Malaria kills approximately 1-2 million people every year, mostly in sub-Saharan Africa and in Asia. These deaths are at the most severe end of a scale of pathologies affecting approximately 500 million people per year. Much of the pathogenesis of malaria is caused by inappropriate or excessive immune responses mounted by the body to eliminate malaria parasites. In this review, we examine the evidence that immunopathology is responsible for malaria disease in the context of what we have learnt from animal models of malaria. In particular, we look in detail at the processes involved in endothelial cell damage leading to syndromes such as cerebral malaria, as well as generalised systemic manifestations such as anaemia, cachexia and problems with thermoregulation of the body. We also consider malaria in light of the variation of the severity of disease observed among people, and discuss the contribution from animal models to our understanding of this variation. Finally, we discuss some of the implications of immunopathology, and of host and parasite genetic variation, for the design and implementation of anti-malarial vaccines.     

Cryptic erythrocytic infections in Plasmodium vivax,another challenge to its elimination

Human malaria caused by Plasmodium vivax infection (vivax malaria) is a major global health issue. It is the most geographically widespread form of the disease, accounting for 7 million annual clinical cases, the majority of cases in America and Asia and an estimation of over 2.5 billion people living under risk of infection. The general perception towards vivax malaria has shifted recently, following a series of reports, from being viewed as a benign infection to the recognition of its potential for more severe manifestations including fatal cases. However, the underlying pathogenic mechanisms of vivax malaria remain largely unresolved. Asymptomatic carriers of malaria parasites are a major challenge for malaria elimination. In the case of P. vivax, it has been widely accepted that the only source of cryptic parasites is hypnozoite dormant stages. Here, we will review new evidence indicating that cryptic erythrocytic niches outside the liver, in particular in the spleen and bone marrow, can represent a major source of asymptomatic infections. The origin of such parasites is being controversial and many key gaps in the knowledge of such infections remain unanswered. Yet, as parasites in these niches seem to be sheltered from immune response and antimalarial drugs, research on this area should be reinforced if elimination of malaria is to be achieved. Last, we will glimpse into the role of reticulocyte-derived exosomes, extracellular vesicles of endocytic origin, as intercellular communicators likely involved in the formation of such cryptic erythrocytic infections.     

Anopheles gambiae genome: perspectives for malaria control

Malaria, a disease that infects 300 million people throughout the world and kills more than a million people, mostly children in sub-Saharan Africa, involves three organisms. The human host where the disease is seen, the protozoan Plasmodium parasite and the mosquito. The parasite is transmitted to humans only by the mosquito vector, which in sub-Saharan regions is generally Anopheles gambiae. Malaria along with AIDS and tuberculosis are killing large numbers of people and crippling the economies of the affected African countries. Though an enormous effort has been made during the past twenty years to develop vaccines to block malaria in humans, the incidence of the disease is increasing in Africa. The reasons for this development include a breakdown in mosquito control related to increased insecticide resistance, as well as increased parasite resistance to antimalarial drugs. It is clear that new methods of Anopheles mosquito control are needed to ameliorate the medical and economic situation in sub-Saharan Africa. As a step toward new malaria control methods, the international Plasmodium falciparum and Anopheles gambiae consortia have carried out the full genome sequencing of the most deadly malaria parasite and the most efficient vector. These, combined with the human genome sequence, provide the genomic infrastructure for a better understanding of the complex interactions within the malaria triad. This essay discusses possible strategies as to how the Anopheles genome can contribute to malaria control.     

Malaria in the whole world and in Romania

Malaria is the world's most important tropical parasitic disease. Malaria is a public health problem today in more than 90 countries. Worldwide prevalence of the disease is estimated to be in the order of 300-500 million clinical cases each year. Malaria is endemic in a total of 101 countries and territories. In Romania, malaria does not represent an important public health problem. In 1999, there were reported a total number of 32 malaria cases in Romanian people. 78% from these recognized as etiological agent Pl. falciparum. The malaria cases imported from Turkey (5) have had as etiological agent Pl. vivax. The most affected age group is between 21-50 years and a distribution by profession shows that sailor personnel accounts for 65.6% of all cases. Africa remains the most important endemic region from where the malaria cases in Romanian people are imported. An adequate chemoprophylaxis is not, yet, easy to obtain for Romanian people who are travelling abroad in endemic countries because of the lack of specific drugs (especially for resistant forms of Pl. falciparum). Even if the Romanian Ministry of Health had elaborated orders regarding malaria and Cloroquine is the usual drug administered, as chemoprophylaxis, to Romanian people who travel abroad, in each year in our country appears around 30-60 imported malaria cases. That is the cause why Romanian Ministry of Health wants to solve this problem which is the major cause of the malaria cases in Romanian people.     

Fas and perforin contribute to the pathogenesis of murine cerebral malaria

Abstract

Malaria is a serious health, social and economic problem for over 40% of the world's population living in endemic regions. Of the half-billion people infected with malaria each year, some 2.5 million will develop cerebral complications. Even with expedient treatment with anti-malarials, the prognosis for an individual displaying symptoms of cerebral malaria remains poor, with an estimated 25%of cases resulting in death. There is, as yet, no direct treatment for cerebral malaria, and the exact mechanism by which it causes death is still undetermined.     

Introduction: International Symposium on Modern Trends in Malaria

Malaria continues to kill some two million people a year, half of whom are young children. We have no vaccine, the parasite has become resistant to the most effective drugs, and elimination of the mosquito vector through spraying with insecticide is being questioned. Yet research on malaria is — at last — being funded reasonably well. What has been achieved? Scientists gathered at the All India Institute of Medical Sciences (AIIMS) in New Delhi from 13-15 February 2003 to discuss these issues. Because many antima-larial strategies work at the cell surface (see the abstract on Membranes as future therapeutic targets) it seems appropriate to give readers of Bioscience Reports: Molecular and Cellular Biology of the Cell Surface an opportunity to catch a glimpse of the current situation through the (unedited) abstracts of the invited speakers.     

Malaria and urbanization in sub-Saharan Africa

There are already 40 cities in Africa with over 1 million inhabitants and the United Nations Environmental Programme estimates that by 2025 over 800 million people will live in urban areas. Recognizing that malaria control can improve the health of the vulnerable and remove a major obstacle to their economic development, the Malaria Knowledge Programme of the Liverpool School of Tropical Medicine and the Systemwide Initiative on Malaria and Agriculture convened a multi-sectoral technical consultation on urban malaria in Pretoria, South Africa from 2nd to 4th December, 2004. The aim of the meeting was to identify strategies for the assessment and control of urban malaria. This commentary reflects the discussions held during the meeting and aims to inform researchers and policy makers of the potential for containing and reversing the emerging problem of urban malaria.     

Malaria Diagnosis: A Brief Review

Malaria is a major cause of death in tropical and sub-tropical countries, killing each year over 1 million people globally; 90% of fatalities occur in African children. Although effective ways to manage malaria now exist, the number of malaria cases is still increasing, due to several factors. In this emergency situation, prompt and effective diagnostic methods are essential for the management and control of malaria. Traditional methods for diagnosing malaria remain problematic; therefore, new technologies have been developed and introduced to overcome the limitations. This review details the currently available diagnostic methods for malaria.     

Innate immunity against malaria parasites in Anopheles gambiae

Malaria continues to exert a huge toll in the world today, causing approximately 400 million cases and killing between 1-2 million people annually. Most of the malaria burden is borne by countries in Africa. For this reason, the major vector for malaria in this continent, Anopheles gambiae, is under intense study. With the completion of the draft sequence of this important vector, efforts are underway to develop novel control strategies. One promising area is to harness the power of the innate immunity of this mosquito species to block the transmission of the malaria parasites. Recent studies have demonstrated that Toll and Imd signaling pathways and other immunity-related genes （encoding proteins possibly function in recognition or as effector molecules） play significant roles in two different arms of innate immunity： level of infection intensity and melanization of Plasmodium oocysts. The challenges in the future are to understand how the functions of these different genes are coordinated in defense against malaria parasites, and if different arms of innate immunity are cross-regulated or coordinated.     

Malaria control priorities and constraints

Each year, there are still between 300-500 million clinical cases of malaria and over one million deaths due to the disease, 90% of which occur in Africa south of the Sahara. In all continents, malaria risk is highest in remote rural areas where poverty abounds, population densities are low and the quality and coverage of the health services are poor or in existent. A sustained impact on the malaria burden can only be achieved through the cost-effective use of current tools, by including malaria in health sector development and inter-sectorial action, by mobilizing malaria control within communities and by investing in new and more effective tools. This paper highlights some of the constraints faced by countries in controlling malaria and outlines the priority activities that are being carried out to address these constraints within both communities and the health services. It aims to be set the scene for the papers of this Centenary book which address some of these issues in more detail.     

Malaria: burden of disease

Despite more than 100 years since Laveran described plasmodium species and Ross confirmed that they were transmitted by female anopheline mosquitoes, malaria remains a leading cause of morbidity and mortality worldwide. Although the areas where transmission takes place have reduced, and they are by now confined to the inter tropical areas, the number of people living at risk has grown to about 3 billion, and is expected to go on increasing. Not only does malaria cause around 500 million cases every year, and between 1 and 3 million deaths, but it also carries a huge burden that impairs the economic and social development of large parts of the planet. The failed attempt to eradicate malaria gave way to the control policy that was followed by a huge resurgence of malaria during the late 70s and 80s. Together with the emergence and spread of resistance to chloroquine and the weak health infrastructure in many of the endemic countries, particularly in Africa, the malaria situation worsened worldwide. The last decade of the 20th century was witness to the international community becoming increasingly aware of the unacceptable situation that the burden of malaria represented to large parts of the world. Renewed efforts to describe the problem, design and evaluate new control strategies, design and develop new drugs, better understand the biology of the parasite and the immunity it induces in the human host, develop candidate vaccines, together with new financial support constitute renewed hope that may lead to new trends in global health.     

The origin of malaria: mixed messages from genetic diversity

Over the past 35 years, the incidence of malaria has increased 2-3-fold. At present, it affects 300-500 million people and causes about 1 million deaths, primarily in Africa. The continuing upsurge has come from a coincidence of drug-resistant parasites, insecticide-resistant mosquitoes, global climate change and continuing poverty and political instability. An analogous rapid increase in malaria might have taken place about 10,000 years ago. Patterns of genetic variation in mitochondrial DNA support this model, but variation in nuclear genes gives an ambiguous message. Resolving these discrepancies has implications for the evolution of drug resistance and vaccine evasion.     

Does malaria epidemiology project Cameroon as ‘Africa in miniature’?

Cameroon, a west-central African country with a ~20 million population, is commonly regarded as ‘Africa in miniature’ due to the extensive biological and cultural diversities of whole Africa being present in a single-country setting. This country is inhabited by ancestral human lineages in unique eco-climatic conditions and diverse topography. Over 90% Cameroonians are at risk of malaria infection, and ~41% have at least one episode of malaria each year. Historically, the rate of malaria infection in Cameroon has fluctuated over the years; the number of cases was about 2 million in 2010 and 2011. The Cameroonian malaria control programme faces an uphill task due to high prevalence of multidrug-resistant parasites and insecticide-resistant malaria vectors. Above all, continued human migration from the rural to urban areas as well as population exchange with adjoining countries, high rate of ecological instabilities caused by deforestation, poor housing, lack of proper sanitation and drainage system might have resulted in the recent increase in incidences of malaria and other vector-borne diseases in Cameroon. The available data on eco-environmental variability and intricate malaria epidemiology in Cameroon reflect the situation in the whole of Africa, and warrant the need for in-depth study by using modern surveillance tools for meaningful basic understanding of the malaria triangle (host-parasite-vector-environment).     

Innovative techniques to discover novel antimalarials

Malaria a global pandemic has engulfed nearly 0.63 million people globally. It is high time that a cure for malaria is required to stop its ever increasing menace. Our commentary discusses the advent and contribution of genetic algorithm (GA) in the drug discovery efforts towards developing cure for malaria. GAs are computational models of Darwinian evolution, ideally capture and mimic the principles of genetic variation and natural selection to evolve good solutions through multiple iterations on the space of all possible candidate solutions, called the search space, to a given optimization problem. Herein we will discuss the applications, advantages, disadvantages and future directions of GA with respect to malaria.     

Diversity oriented synthesis for novel anti-malarials

Malaria a global pandemic has engulfed nearly 0.63 million people globally. It is high time that a cure for malaria is required to stop its ever increasing menace. Our commentary discusses the advent and contribution of diversity oriented synthesis (DOS) in the drug discovery efforts towards developing cure for malaria. DOS based on chemical genetics focusses on design and synthesis of molecular libraries which covers large tracts of biologically relevant chemical space. Herein we will discuss the applications, advantages, disadvantages and future directions of DOS with respect to malaria.     

Malaria epidemic expected in Mozambique

Health experts fear epidemics of several infectious diseases in Mozambique as floods recede and mosquitoes begin breeding. According to Pierre Kahozi of WHO, malaria is already endemic in the region but there are fears that a much greater outbreak might occur. Scores of suspected cases of cholera were reported and more are expected, along with cases of other diarrheal conditions. Neil Cameron, chief director of communicable diseases at the health department in South Africa, said that more cases are expected within a month when the breeding cycle of mosquitoes is renewed. He reported that the number of malaria cases in South Africa increased from 12,000 in 1995 to 50,000 in 1999, and a number of people had been dying from this disease. The increase could be attributed partly to climatic changes and resistance to certain drugs. DDT had been used in the past to control mosquitoes, and it?s possible that it will be used again in Mozambique. The issues involved in tackling malaria are now being considered as part of a special development initiative on infectious diseases that is being undertaken jointly by the health departments of three countries: South Africa, Mozambique, and Swaziland.     

The molecular basis of glucose-6-phosphate dehydrogenase deficiency.

With more than 300 different variants reported, the human enzyme glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49) is one of the most polymorphic proteins known. An estimated 400 million people throughout the world are deficient in G6PD; numerous lines of evidence indicate that this is because female heterozygotes have a selective advantage in malaria infections. The cloning of the G6PD gene has made it possible to clarify the molecular basis underlying this enzyme deficiency and polymorphism.     

Modelling of malaria risk,rates, and trends: A spatiotemporal approach for identifying and targeting sub-national areas of high and low burden

While mortality from malaria continues to decline globally, incidence rates in many countries are rising. Within countries, spatial and temporal patterns of malaria vary across communities due to many different physical and social environmental factors. To identify those areas most suitable for malaria elimination or targeted control interventions, we used Bayesian models to estimate the spatiotemporal variation of malaria risk, rates, and trends to determine areas of high or low malaria burden compared to their geographical neighbours. We present a methodology using Bayesian hierarchical models with a Markov Chain Monte Carlo (MCMC) based inference to fit a generalised linear mixed model with a conditional autoregressive structure. We modelled clusters of similar spatiotemporal trends in malaria risk, using trend functions with constrained shapes and visualised high and low burden districts using a multi-criterion index derived by combining spatiotemporal risk, rates and trends of districts in Zambia. Our results indicate that over 3 million people in Zambia live in high-burden districts with either high mortality burden or high incidence burden coupled with an increasing trend over 16 years (2000 to 2015) for all age, under-five and over-five cohorts. Approximately 1.6 million people live in high-incidence burden areas alone. Using our method, we have developed a platform that can enable malaria programs in countries like Zambia to target those high-burden areas with intensive control measures while at the same time pursue malaria elimination efforts in all other areas. Our method enhances conventional approaches and measures to identify those districts which had higher rates and increasing trends and risk. This study provides a method and a means that can help policy makers evaluate intervention impact over time and adopt appropriate geographically targeted strategies that address the issues of both high-burden areas, through intensive control approaches, and low-burden areas, via specific elimination programs.     

Experimental human challenge infections can accelerate clinical malaria vaccine development

Malaria is one of the most frequently occurring infectious diseases worldwide, with almost 1 million deaths and an estimated 243 million clinical cases annually. Several candidate malaria vaccines have reached Phase IIb clinical trials, but results have often been disappointing. As an alternative to these Phase IIb field trials, the efficacy of candidate malaria vaccines can first be assessed through the deliberate exposure of participants to the bites of infectious mosquitoes (sporozoite challenge) or to an inoculum of blood-stage parasites (blood-stage challenge). With an increasing number of malaria vaccine candidates being developed, should human malaria challenge models be more widely used to reduce cost and time investments? This article reviews previous experience with both the sporozoite and blood-stage human malaria challenge models and provides future perspectives for these models in malaria vaccine development.     

Mosquito midgut barriers to malaria parasite development

Malaria is one of the deadliest infectious diseases and kills more than one million people every year. For transmission to occur, the malaria parasite has to complete an elaborate developmental program in hostile mosquito environment. Thus, understanding the molecular mechanisms by which mosquitoes limit the parasite development may lead to new methods for controlling malaria. There has been considerable progress during the last decade in this research area. This review focuses on the mosquito response to midgut invasion of the malaria parasite and examines the role of mosquito digestive enzymes, peritrophic matrix and microvillar proteins as barriers to parasite development.