The role of gamma/delta T- and NK cells in immunity and/or pathogenesis to malaria

Gamma/delta T cells have been implicated to participate in the human immune responses to malaria.Activation and increase in the percentage and total numbers of gamma/delta T cells have been observed in the peripheral blood during acute infection. A preferential expansion and activation of gamma/deltaT cells has also been shown after in vitro stimulation of peripheral blood mononuclear cells from malaria-nonexposed donors with crude extract of P. falciparum cultures. These finding have led to the suggestion that Gamma/delta T cells play a role in controlling blood stage infection. In support of this we have recently shown that gamma/delta T cells from derived from P. falciparum activated peripheral blood mononuclear cells of healthy donors, inhibit the in vitro growth of the intraerythrocytic stages of the P. falciparum parasite, while similarly activated alpha/beta T cells do not. The inhibition was mediatedby a granule exocytosis-dependent cytotoxic pathway that required granulysin. However, neither the parasite constituents nor how the inhibitory action of gamma/delta T cells are mediated are known. In this project we will elucidate the role of gamma/delta T cells in immunity/pathogenesis of malaria by 1) comparing the capacity of antigen-activated gamma/delta -, alpha/beta and NK cells to inhibit the in vitro growth of P. falciparum; 2) in inhibitory cells investigating the cytolytic machinery and 3) receptors involved in the inhibition.

People involved in the project: PhD students: Giulia Costa, Maiga Boubacar

Role of allele polymorphism in the IL-4 gene or promoter gene in the regulation of anti-malarial IgE antibodies

In the human Plasmodium falciparum system we have recently reported that people living in malaria endemic areas have elevated level of both total and anti-malaria specific IgE antibodies. Evidence points to a role of the IgE antibodies in both the pathogenesis of the disease and/or in the regulation of malaria-specific immune responses. Importantly, the IgE levels were much more concordant within monozygotic twins compared to dizygotictwins and MHC class II identical donors, suggesting that the IgE levels are controlled by non-MHC genes, possibly by allelic variants in the IL-4 or promoter gene. The specific aims of this project are to more in detail elucidate the genetic regulation of the anti-malarial IgE antibodies, with special emphasis to: 1) determine the IL 4- and promoter-genepolymorphisms in children living in malaria-endemic areas of Tanzania; 2) relate gene polymorphisms to actual IL-4 production and serum levels of total as well as anti-malarial IgE antibodies; 3) correlate gene-polymorphism with outcome of disease; 4) investigate if ratios between Th1 (IgG1, IgG3) and Th2 (IgG4, IgE) subclass antibodies could be used as a surrogate assay for measuring functionally distinct T-cell responses. Identification and correlation of promoter- or gene polymorphisms with pattern of expression and linkage of this over-expression to severity of malaria disease may provide insight into why some individuals succumb to the disease and while others do not. Elucidation of these mechanisms could lead to safer and more effective tools for treatment or prevention of disease.

People involved in the project: PhD students Manijeh Vafa

Is an efficient early immune response the reason why the Fulani are more protected against malaria than their sympattic ethnic group, the Dogon?

The aim of this project is to increase our knowledge on how the innate immune system responds to the malaria parasite and how the parasite influence the innate and downstream adaptive responses in sympatric ethnic groups differing in susceptibility to malaria, the Fulani and Dogon. Emphasis will be on different subpopulations of dendritic cells i.e myeloid (MDC) and plasmacytoid (PDC), known to be the most important cell types in the activation of the early immune response. Our hypothesis is that the Fulani has a more effective innate immune response than the Dogon that will protect them against malaria before the development of the acquired immune system. The specific objectives are to 1) compare the proportions and activation levels of MDC and PDC in asymptomatic and symptomatic Fulani and Dogon; 2) estimate the risk of clinical malaria in relation to the proportions and activation levels of MDC and PDC; 3) estimate the activation levels and cytokines (TNF-?, IL-12, IL-6 and IL-10) in in vitro P.falciparum antigen activated peripheral blood mononuclear cells obtained from Fulani and Dogon, 4) characterize the migratory properties and receptor expression in dendritic cells after in vitro stimulation with P.falciparum antigens and 5) determine the downstream effects of differently activated dendritic cells on cells of the acquired immunity and other lymphoid cells in the immune system.

People involved; Stefania Varani,(Post Doc), Pablo Giusti (PhD student), Charles Arama (PhD student), Olivia Simone (PhD student)

Preclinical studies towards an affordable, safe and efficacious two-component paediatric malaria vaccine

Malaria is one of the major public health challenges in the world, causing more than one million deaths each year. The disease affects primarily children in the developing world, and it is understood to be both a disease of poverty and a cause of poverty. A safe, affordable and efficacious paediatric malaria vaccine, which fits in the existing WHO Expanded Program on Immunizations, would solve tremendous suffering to human kind. Taking up this challenge, the PRIBOMAL consortium proposes to generate and test in pre-clinical models the safety and efficacy of an innovative novel recombinant BCG vector carrying three antigens derived from the Plasmodium falciparum parasite, the cause of malaria. The priming vaccine is followed at day 14 after birth by a booster vaccination using proprietary, industrially developed, recombinant adenoviral vector carrying the indentical P.falciparum antigens as the r-BCG-based malaria vaccine. The antigens inserted into the vaccine carriers are circumsporozoite protein, liver stage antigen-1 and sporozoite threonine and asparagines rich protein, which all three are proven highly immunogenic in humans.
Generation of these novel vaccine candidate as well as testing in established and novel pre-clinical models to determine potency and safety is the major aim of this project.

People involved; Nnaemeka.Iriemenam (PhD student)