Relationship between antipyretic effects and cytokine levels in uncomplicated falciparum malaria during different treatment regimes

We have previously shown that both chloroquine and paracetamol (acetaminophen) have antipyretic activity during treatment of acute uncomplicated Plasmodium falciparum malaria in children 1-4 years old. Here, we studied if this effect was accompanied by changes in plasma cytokine levels. The 104 children were treated with either chloroquine or sulfadoxine/pyrimethamine (SP) alone, SP + chloroquine or SP + paracetamol for 4 days. Cytokine levels were determined days 0, 2 and 3, body temperature every sixth hour until 72 h and parasitemia once daily for 4 days. At admission, body temperature correlated with levels of IL-10, IFN-γ and IL-6, and parasitemia correlated with IL-10 and IL-6. Except for TNF-α and IL-1β, where no significant effect was found, all cytokine levels (IL-10, IFN-γ, IL-6, IL-12, IL-13, IL-18 and IL-4) decreased up to day 2 (p \u3c 0.05). IL-6 levels continued to fall from days 2 to 3 (p \u3c 0.05), whereas increased levels were found for several cytokines (IL-12, IL-13, IL-18 and IL-1β) (p \u3c 0.05). The antipyretic effects of chloroquine and paracetamol could not be related to any specific changes in the evaluated cytokine production or in Th1/Th2 or inflammatory/anti-inflammatory cytokine ratios. Alternative mechanisms for antipyretic effects and associations between fever and cytokine levels during uncomplicated P. falciparum malaria are therefore discussed. © 2006 Elsevier B.V. All rights reserved

IL4 gene polymorphism and previous malaria experiences manipulate anti-Plasmodium falciparum antibody isotype profiles in complicated and uncomplicated malaria

<p>Abstract</p> <p>Background</p> <p>The <it>IL4</it>-590 gene polymorphism has been shown to be associated with elevated levels of anti-<it>Plasmodium falciparum </it>IgG antibodies and parasite intensity in the malaria protected Fulani of West Africa. This study aimed to investigate the possible impact of <it>IL4</it>-590C/T polymorphism on anti-<it>P. falciparum </it>IgG subclasses and IgE antibodies levels and the alteration of malaria severity in complicated and uncomplicated malaria patients with or without previous malaria experiences.</p> <p>Methods</p> <p>Anti-<it>P.falciparum </it>IgG subclasses and IgE antibodies in plasma of complicated and uncomplicated malaria patients with or without previous malaria experiences were analysed using ELISA. <it>IL4</it>-590 polymorphisms were genotyped using RFLP-PCR. Statistical analyses of the IgG subclass levels were done by Oneway ANOVA. Genotype differences were tested by Chi-squared test.</p> <p>Results</p> <p>The <it>IL4</it>-590T allele was significantly associated with anti-<it>P. falciparum </it>IgG3 antibody levels in patients with complicated (<it>P </it>= 0.031), but not with uncomplicated malaria (<it>P </it>= 0.622). Complicated malaria patients with previous malaria experiences carrying <it>IL4</it>-590TT genotype had significantly lower levels of anti-<it>P. falciparum </it>IgG3 (<it>P </it>= 0.0156), while uncomplicated malaria patients with previous malaria experiences carrying the same genotype had significantly higher levels <it>(P </it>= 0.0206) compared to their <it>IL4</it>-590 counterparts. The different anti-<it>P. falciparum </it>IgG1 and IgG3 levels among IL4 genotypes were observed. Complicated malaria patients with previous malaria experiences tended to have lower IgG3 levels in individuals carrying TT when compared to CT genotypes (<it>P </it>= 0.075). In contrast, complicated malaria patients without previous malaria experiences carrying CC genotype had significantly higher anti-<it>P. falciparum </it>IgG1 than those carrying either CT or TT genotypes (<it>P </it>= 0.004, <it>P </it>= 0.002, respectively).</p> <p>Conclusion</p> <p>The results suggest that <it>IL4</it>-590C or T alleles participated differently in the regulation of anti-malarial antibody isotype profiles in primary and secondary malaria infection and, therefore, could play an important role in alteration of malaria severity.</p

Antibody acquisition models: a new tool for serological surveillance of malaria transmission intensity

Serology has become an increasingly important tool for the surveillance of a wide range of infectious diseases. It has been particularly useful to monitor malaria transmission in elimination settings where existing metrics such as parasite prevalence and incidence of clinical cases are less sensitive. Seroconversion rates, based on antibody prevalence to Plasmodium falciparum asexual blood-stage antigens, provide estimates of transmission intensity that correlate with entomological inoculation rates but lack precision in settings where seroprevalence is still high. Here we present a new and widely applicable method, based on cross-sectional data on individual antibody levels. We evaluate its use as a sero-surveillance tool in a Tanzanian setting with declining malaria prevalence. We find that the newly developed mathematical models produce more precise estimates of transmission patterns, are robust in high transmission settings and when sample sizes are small, and provide a powerful tool for serological evaluation of malaria transmission intensity

Malaria-derived hemozoin exerts early modulatory effects on the phenotype and maturation of human dendritic cells

Plasmodium falciparum (P. falciparum)-induced effects on the phenotype of human dendritic cells (DC) could contribute to poor induction of long-lasting protective immunity against malaria. DC ability to present antigens to naïve T cells, thus initiating adaptive immune responses depends on complex switches in chemokine receptors, production of soluble mediators and expression of molecules enabling antigen-presentation and maturation. To examine the cellular basis of these processes in the context of malaria, we performed detailed analysis of early events following exposure of human monocyte-derived DC to natural hemozoin (nHZ) and the synthetic analog of its heme core, β-hematin. DC exposed to either molecule produced high levels of the inflammatory chemokine MCP-1, showed continuous high expression of the inflammatory chemokine receptor CCR5, no upregulation of the lymphoid homing receptor CCR7 and no cytoskeletal actin redistribution with loss of podosomes. DC partially matured as indicated by increased expression of major histocompatibility complex (MHC) class II and CD86 following nHZ and β-hematin exposure, however there was a lack in expression of the maturation marker CD83 following nHZ but not β-hematin exposure. Overall our data demonstrate that exposure to nHZ partially impairs the capacity of DC to mature, an effect in part differential to β-hematin

IDOMAL: an ontology for malaria

<p>Abstract</p> <p>Background</p> <p>Ontologies are rapidly becoming a necessity for the design of efficient information technology tools, especially databases, because they permit the organization of stored data using logical rules and defined terms that are understood by both humans and machines. This has as consequence both an enhanced usage and interoperability of databases and related resources. It is hoped that IDOMAL, the ontology of malaria will prove a valuable instrument when implemented in both malaria research and control measures.</p> <p>Methods</p> <p>The OBOEdit2 software was used for the construction of the ontology. IDOMAL is based on the Basic Formal Ontology (BFO) and follows the rules set by the OBO Foundry consortium.</p> <p>Results</p> <p>The first version of the malaria ontology covers both clinical and epidemiological aspects of the disease, as well as disease and vector biology. IDOMAL is meant to later become the nucleation site for a much larger ontology of vector borne diseases, which will itself be an extension of a large ontology of infectious diseases (IDO). The latter is currently being developed in the frame of a large international collaborative effort.</p> <p>Conclusions</p> <p>IDOMAL, already freely available in its first version, will form part of a suite of ontologies that will be used to drive IT tools and databases specifically constructed to help control malaria and, later, other vector-borne diseases. This suite already consists of the ontology described here as well as the one on insecticide resistance that has been available for some time. Additional components are being developed and introduced into IDOMAL.</p

Interethnic Differences in Antigen-Presenting Cell Activation and TLR Responses in Malian Children during Plasmodium falciparum Malaria

The Fulani ethnic group from West Africa is relatively better protected against Plasmodium falciparum malaria as compared to other sympatric ethnic groups, such as the Dogon. However, the mechanisms behind this lower susceptibility to malaria are largely unknown, particularly those concerning innate immunity. Antigen-presenting cells (APCs), and in particular dendritic cells (DCs) are important components of the innate and adaptive immune systems. Therefore, in this study we investigated whether APCs obtained from Fulani and Dogon children exhibited differences in terms of activation status and toll-like receptor (TLR) responses during malaria infection. Lower frequency and increased activation was observed in circulating plasmacytoid DCs and BDCA-3+ myeloid DCs of infected Fulani as compared to their uninfected counterparts. Conversely, a higher frequency and reduced activation was observed in the same DC subsets obtained from peripheral blood of P. falciparum-infected Dogon children as compared to their uninfected peers. Moreover, infected individuals of both ethnic groups exhibited higher percentages of both classical and inflammatory monocytes that were less activated as compared to their non-infected counterparts. In line with APC impairment during malaria infection, TLR4, TLR7 and TLR9 responses were strongly inhibited by P. falciparum infection in Dogon children, while no such TLR inhibition was observed in the Fulani children. Strikingly, the TLR-induced IFN-γ release was completely abolished in the Dogon undergoing infection while no difference was seen within infected and non-infected Fulani. Thus, P. falciparum infection is associated with altered activation status of important APC subsets and strongly inhibited TLR responses in peripheral blood of Dogon children. In contrast, P. falciparum induces DC activation and does not affect the innate response to specific TLR ligands in Fulani children. These findings suggest that DCs and TLR signalling may be of importance for the protective immunity against malaria observed in the Fulani

Differences in Fcgamma receptor IIa genotypes and IgG subclass pattern of anti-malarial antibodies between sympatric ethnic groups in Mali

<p>Abstract</p> <p>Background</p> <p>The Ig Fc receptor family is an important link between the humoral and cellular immune systems. The association of a dimorphism in amino acid 131 (R/H) of the FcγRIIa with malaria severity, the R-allele being associated with a milder disease outcome, led to the investigation of the possible impact of this polymorphism in the interethnic difference in malaria susceptibility seen between the Fulani and Dogon in Mali.</p> <p>Methods</p> <p>Plasma from individuals from Mali (164 Fulani and 164 Dogon) were analysed for malaria-reactive and total IgG subclass antibodies using ELISA, and the same individuals were also genotyped for the FcγRIIa R131H polymorphism using RFLP-PCR. Statistical analyses of the IgG subclass levels were done by unpaired t-test and ANOVA, and genotype differences were tested by χ²-test.</p> <p>Results</p> <p>While the two ethnic groups showed a similar frequency of the FcγRIIa 131 R/H heterozygote genotype, 131R/R dominated over the 131 H/H genotype in the Dogon whereas the Fulani presented a similar frequency of the two homozygote genotypes. The two alleles were evenly distributed in the Fulani, while the Dogon were clearly biased towards the R-allele. The Fulani showed higher levels of anti-malarial IgG1, -2 and -3 antibodies, with a higher proportion of IgG2, than the Dogon. In the Fulani, H-allele carriers had higher anti-malarial IgG2 levels than R/R homozygotes, while in the Dogon, the R-allele carriers showed the higher IgG2 levels. For anti-malarial IgG3, the R-allele carriers in the Fulani had higher levels than the H/H homozygotes.</p> <p>Conclusion</p> <p>Taken together, the results showed marked interethnic differences in FcγRIIa R131H genotypes. Furthermore, the results indicate that the FcγRIIa R131H genotype may influence the IgG subclass responses related to protection against malaria, and that IgG2 may be of importance in this context.</p

Open Access

Haptoglobin phenotype prevalence and cytokine profiles during Plasmodium falciparum infection in Dogon and Fulani ethnic groups living in Mal

EU-funded malaria research under the 6th and 7th Framework Programmes for research and technological development

While malaria research has traditionally been strong in Europe, targeted and sustained support for cooperative malaria research at EU level, namely through the EU's 6th and 7th Framework Programmes for research and technological development, FP6 (2002-2006) and FP7 (2007-2013), has boosted both impact and visibility of European malaria research. Most of the European malaria research community is now organized under a number of comprehensive and complementary research networks and projects, assembled around four key areas: (1) fundamental research on the malaria parasite and the disease, (2) development of new malaria drugs, (3) research and development of a malaria vaccine, and (4) research to control the malaria-transmitting mosquito vector. Considerable efforts were undertaken to ensure adequate participation of research groups from disease-endemic countries, in particular from Africa, with the long-term aim to strengthen cooperative links and research capacities in these countries. The concept of organizing European research through major strategic projects to form a "European Research Area" (ERA) was originally developed in the preparation of FP6, and ERA formation has now turned into a major EU policy objective explicitly inscribed into the Lisbon Treaty. EU-funded malaria research may serve as a showcase to demonstrate how ERA formation can successfully be implemented in a given area of science when several surrounding parameters converge to support implementation of this strategic concept: timely coincidence of political stimuli, responsive programming, a clearly defined - and well confined - area of research, and the readiness of the targeted research community who is well familiar with transnational cooperation at EU level. Major EU-funded malaria projects have evolved into thematic and organizational platforms that can collaborate with other global players. Europe may thus contribute more, and better, to addressing the global research agenda for malaria

Epigenetics and Malaria Susceptibility/Protection: A Missing Piece of the Puzzle

A better understanding of stable changes in regulation of gene expression that result from epigenetic events is of great relevance in the development of strategies to prevent and treat infectious diseases. Histone modification and DNA methylation are key epigenetic mechanisms that can be regarded as marks, which ensure an accurate transmission of the chromatin states and gene expression profiles over generations of cells. There is an increasing list of these modifications, and the complexity of their action is just beginning to be understood. It is clear that the epigenetic landscape plays a fundamental role in most biological processes that involve the manipulation and expression of DNA. Although the molecular mechanism of gene regulation is relatively well understood, the hierarchical order of events and dependencies that lead to protection against infection remain largely unknown. In this review, we propose that host epigenetics is an essential, though relatively under studied, factor in the protection or susceptibility to malaria