World Malaria Day: Research Highlights from PLoS ONE and PLoS Pathogens

Today is World Malaria Day —a time to reflect upon and commemorate the global efforts to fight this deadly mosquito-born disease found throughout the tropical and subtropical regions of the world. Given the day, we thought it would be a good opportunity to highlight some of the recent malaria research published in PLoS ONE and PLoS Pathogens, as well as have the authors discuss their work.   Many thanks to the authors and academic editors who agreed to participate in this post.

PLoS ONE

Earlier this month, the Head of Malaria at the Foundation for Innovative New Diagnostics (FIND) in Geneva, Switzerland,  David Bell, and colleagues from the Ministry of Health of Senegal, FIND and WHO published a paper on the Major Reduction in Anti-Malarial Drug Consumption in Senegal after Nation-Wide Introduction of Malaria Rapid Diagnostic Tests.

According to Bell:

This paper demonstrates the tangible impact that can be achieved through the well-managed rollout of malaria rapid diagnostic tests (RDTs) nationwide. In particular, the article shows that:

  • rolling out a high quality nation-wide RDT programme is feasible even in low-income countries
  • a carefully planned and implemented rollout results in good adherence to diagnostic results by clinical staff
  • the widespread use of quality diagnostics can lead to a significant reduction in the number of anti-malarial drugs prescribed, which is both a public health gain and results in significant savings in ACT procurement (the Global Fund was able to retain €1.2 million from its Malaria grant to Senegal, available for use in other projects)
  • Senegal now has solid evidence of its “true” national malaria rates, allowing for more accurate targeting of malaria interventions and resources, essential if elimination is eventually to be achieved.

    Figure 2. Evolution of parasite based diagnosis of malaria in Senegal public health services 2007–2009.

While WHO recently recommended universal parasitological confirmation of suspected malaria prior to treatment, debate has continued as to whether wide-scale use of rapid diagnostic tests (RDTs) can achieve this goal. Adherence of health service personnel to RDT results has been poor in smaller-scale interventions some settings, with little impact on anti-malarial drug consumption. The experience in Senegal shows that this need not be the case, and that the well-managed use of quality diagnostics can have a dramatic positive impact on the management of malaria and febrile disease.

In the paper, Malaria Prevalence, Risk Factors and Spatial Distribution in a Hilly Forest Area of BangladeshUbydul Haque, a PhD student currently at  the Department of International Health, Institute of Tropical Medicine (NEKKEN) and the Global Center of Excellence Program in Nagasaki, Japan, along with colleagues from the International Center for Diarrhoeal Disease Research  in Bangladesh, and the  Johns Hopkins Bloomberg School of Public Health evaluate early stage malaria interventions in Bangladesh.

From the authors:

Figure 2. Land cover classification in Rajasthali

Malaria is a major public health concern in Bangladesh and it is endemic in the Chittagong Hill Tracts where prevalence was 11.7% in 2007. One sub-district, Rajasthali, had a prevalence of 36%. Several interventions were introduced in early 2007 to control malaria with the support of Global Fund. This study was undertaken to evaluate the impacts of these intensive early stage interventions on malaria in Bangladesh. The study result confirmed the malaria prevalence dropped to 11.5% in 2009. Sex, age, number of bed nets, forest cover, altitude and household density were potential risk factors. Statistically significant malaria clusters were identified. Significant differences among risk factors were observed between cluster and non-cluster areas. Malaria has significantly decreased within 2 years after onset of intervention program. Both aspects of the physical and social environment, as well as demographic characteristics are associated with spatial heterogeneity of risk. The ability to identify and locate these areas provides a strategy for targeting interventions during initial stages of intervention programs.

The findings are important since the prevalence rate sharply declined although malaria cluster effect still remains.

In another paper published this month called, Determinants of the Cost-Effectiveness of Intermittent Preventive Treatment for Malaria in Infants and Children, Amanda Ross a statistician at the Swiss Tropical and Public Health Institute and first author of the manuscript writes:

With finite resources, a rational basis is needed for choosing between malaria control strategies. The potential strategies, intermittent preventive treatment in children (IPTc) and infants (IPTi), are under consideration. IPT aims to deliver anti-malarial treatment to the target age group at specified time points whether or not they are known to be infected with the aim of reducing morbidity and mortality.

Field trials have provided information on the effectiveness of IPT on clinical episodes in a number of settings. It is not practical, however, for the trials to include the very large numbers of children required to estimate the effectiveness on the less frequent but important outcomes of severe malaria (requiring hospitalisation) and death, neither is it feasible to carry out large numbers of trials for many different setting nor implementation characteristics.

Figure 5. Predicted effects and cost-effectiveness of IPT depending on timing of first dose in seasonal settings.

This paper uses a comprehensive model of malaria epidemiology together with economic data to provide predictions of the impact and cost-effectiveness of IPTc for different settings, drugs and implementation characteristics, and to investigate the limits where IPT is no longer cost-effective. These predictions contribute to a growing database of the likely effectiveness, including cost, of different malaria control strategies generated using this common simulation platform. These predictions, taken together with other considerations, can aid decision-makers.

Our final PLoS ONE malaria highlight comes from Francesco Dieli, a Professor of Immunology and Director of the Division of Immunology and Immunogenetics at the University of Palermo, Italy.  As the Academic Editor for the recently published paper, Interethnic Differences in Antigen-Presenting Cell Activation and TLR Responses in Malian Children during Plasmodium falciparum Malaria, by Charles Arama et al., he writes:

Half of the world’s population remains at risk of contracting malaria. During 2008, malaria was estimated to be responsible for 767,000 deaths in Africa alone, mostly in children below the age of 5 years. There is substantial evidence that host genetic factors play a major role in determining the outcome of infection with Plasmodium falciparum (P. falciparum), the ethiologic agent of malaria, but in humans, this genetic trait is complex. Several epidemiological approaches can be applied in the study of the genetic susceptibility to malaria, amongst which is inter-ethnic comparative analyses among populations with different genetic backgrounds, exposed to the same epidemiological context and showing different susceptibility to the disease.  The combination of such epidemiological studies, together with linkage analyses in a rural area in Mali have clearly shown different genetic innate susceptibility to P. falciparum between two ethnic groups, the Fulani and the Dogon. These populations live under similar social, cultural and geographic conditions and are exposed to identical malaria pressure. However, the Fulani are better protected against Plasmodium falciparum malaria as compared to the Dogon and this has been associated to the development of robust anti-malarial immunity.

Nevertheless, little is known about the functionality of innate immunity in Fulani and sympatric ethnic groups and how this branch of immunity influences susceptibility to malaria infection. This aspect is of crucial importance to fully understand the immunological mechanisms of susceptibility/resistance to malaria, as innate immunity both rapidly inhibits parasite growth, thereby limiting the onset of disease, and instructs specific adaptive immunity

The paper by Arama and colleagues clearly demonstrates that important differences exist between the Fulani and Dogon groups at the level of innate immune response, which involve the function of dendritic cells (DCs): P. falciparum infection impairs the phenotype of DCs and alters their responses  to TLR agonists in Dogon, but not in Fulani children, and this has an important consequence on the outcome of subsequent adaptive immunity to P. falciparum, as documented by differential IFN-γ release in the two ethnic groups.

While evaluation of a larger cohort of patients is required to confirm these results and to analyze the potential occurrence of distinct TLR polymorphisms in these two ethnic groups, this paper clearly indicate that understanding of innate immune responses to P. falciparum in naturally exposed children may yield important insights in the development of immunity to malaria, with particular regard to the definition of robust correlates of susceptibility/resistance to infection, and to the development of novel vaccination strategies.

PLoS Pathogens

Dr. Anthony James, a Distinguished Professor of Microbiology & Molecular Genetics at the University of California, Irvine School of Medicine, writes about his recently published article, Engineered Resistance to Plasmodium falciparum Development in Transgenic Anopheles stephensi.

Figure 1. A model of the modified scFv transgenes.

Malaria eradication will require vector-control strategies that are both self-sustaining and not affected by migration of infected humans and mosquitoes. Replacement of wild malaria- susceptible mosquito populations with transgenic strains refractory to parasite development could interrupt the cycle of disease transmission and support eradication efforts.

Production of P. falciparum-resistant mosquitoes is a necessary first step towards investigating the population replacement strategy. Alison T. Isaacs and colleagues engineered Anopheles stephensi to produce P.falciparum-targeting effector molecules; these mosquitoes exhibit resistance to this important human malaria parasite. Two of the three effector molecules represent a novel combination of components derived from the immune systems of mosquitoes and mice. Transgenes with this design coupled with a gene-drive system could be used alongside vaccines and drugs to provide sustainable local elimination of malaria as part of a long-term strategy for eradication.

Author Franck Prugnolle writes about his team’s review article, A Fresh Look at the Origin of Plasmodium falciparum, the Most Malignant Malaria

Figure 2. Distribution of the different subspecies of chimpanzees, bonobos, and gorillas in Africa and representation of the spread of the different Plasmodium species in these subspecies.

Agent.

Until very recently, Plasmodium falciparum, the main malignant agent of human malaria, appeared phylogenetically isolated from the other Plasmodium species infectinghuman and non-human primates. Only one sister species, P. reichenowi from chimpanzees was recognised and molecularly characterised. In 2009 and 2010, thanks in particular to the use of new non-invasive methods to diagnose the presence of Plasmodium species in wild great apes, several studies have revealed the existence of a number of distinct new phylogenetic species infecting chimpanzees, bonobos, and gorillas. P. falciparum parasites were also found to naturally infect wild gorillas. In our paper, we discuss how these discoveries irrevocably changed our perception of the evolution and origin of P. falciparum but also how this opens vast new areas of research to explore the origin of these different species, their ecology and their evolution.

Dr. Christian Engwerda, an Associate Editor for PLoS Pathogens, edited the paper Dendritic Cells and Hepatocytes Use Distinct Pathways to Process Protective Antigen from Plasmodium in vivo by Cockburn et al., and offers his comments:

CD8+ T cells recognize intracellular peptide antigens presented on the cell surface by major histocompatibility complex (MHC) I molecules. In this way, CD8+ T cells can recognize and kill tumours and cells infected with intracellular pathogens. Malaria is

Figure 6. Pexel/VTS motifs are not required for the presentation of CD8+ epitopes in the CS protein.

caused when a female mosquito injects Plasmodium Spp. parasites while taking a blood meal. The parasites first infect hepatocytes in the liver, prior to establishing the blood stage of infection responsible for all clinical symptoms of malaria. Evidence to date indicates that the malaria liver stage is a good target for vaccine-induced CD8+ T cell-mediated protective immunity. However, CD8+ T cells first need to be activated by specialized antigen presenting cells called dendritic cells (DCs) in lymph nodes before they can migrate to the liver and kill infected hepatocytes, and hence much work has been devoted to studying parasite antigens presented via MHC I on DCs. However, malaria-specific CD8+ T cells must recognize parasite peptide antigens presented by MHC I on both DCs and hepatocytes.

Recently, Cockburn, Zavala and colleagues reported in PLoS Pathogens that DCs and hepatocytes use different mechanisms to process Plasmodium Spp. antigens prior to presentation by MHC I on the cell surface. Furthermore, they discovered that in hepatocytes, well-recognised parasite protein export motifs were not required for parasite antigens to leave the parasitophorous vacuole, where parasites reside in the cell, to enter the cell cytoplasm prior to antigen processing. These data are important because they show that the potential number of parasite proteins presented on MHC I molecules by hepatocytes may be much greater than previously thought, and importantly, suggest that identifying protective CD8+ T cell parasite antigen epitopes might best be achieved by looking for them in infected hepatocytes, the targets for CD8+ T cell-mediated killing, rather than restricting our search to those that can be presented by DCs. This information will help in developing a safe and effective malaria vaccine.

All together, PLoS ONE, PLoS Pathogens and PLoS Medicine have over 400 research articles focused on Malaria.  To browse more of the research, click here.  In addition, PLoS Medicine launched the malERA – a research agenda for malaria eradication collection earlier this year.  The collection contains 12 Reviews,  three reflective pieces, and nine research and development agendas. They have also posted on their Speaking of Medicine blog an interesting post by Nathan Ford, a medical coordinator for Médecins Sans Frontières (MSF), on improving treatment for severe malaria.

Many thanks to Mary Kohut, the PLoS Pathogens Publications Manager, for her assistance in this post.

First image shown in this post is courtesy of SomosMedicina.

This entry was posted in Featured Image, Images, Interviews, Media, Open Access, Topic Focus and tagged , , , , , , , , . Bookmark the permalink.
Add Comment Register



Leave a Reply

Your email address will not be published. Required fields are marked *

You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>