Bourema Kouriba

Reemergence of Chloroquine-Sensitive Plasmodium falciparum Malaria after Cessation of Chloroquine Use in Malawi

In 1993, Malawi became the first African country to replace chloroquine with sulfadoxine-pyrimethamine nationwide in response to high rates of chloroquine-resistant falciparum malaria. To determine whether withdrawal of chloroquine can lead to the reemergence of chloroquine sensitivity, the prevalence of the pfcrt 76T molecular marker for chloroquine-resistant Plasmodium falciparum malaria was retrospectively measured in Blantyre, Malawi. The prevalence of the chloroquine-resistant pfcrt genotype decreased from 85% in 1992 to 13% in 2000. In 2001, chloroquine cleared 100% of 63 asymptomatic P. falciparum infections, no isolates were resistant to chloroquine in vitro, and no infections with the chloroquine-resistant pfcrt genotype were detected. A concerted national effort to withdraw chloroquine from use has been followed by a return of chloroquine-sensitive falciparum malaria in Malawi. The reintroduction of chloroquine, ideally in combination with another antimalarial drug, should be considered in areas where chloroquine resistance has declined and safe and affordable alternatives remain unavailable.

A Field Trial to Assess a Blood-Stage Malaria Vaccine

BACKGROUND Blood-stage malaria vaccines are intended to prevent clinical disease. The malaria vaccine FMP2.1/AS02(A), a recombinant protein based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, has previously been shown to have immunogenicity and acceptable safety in Malian adults and children. METHODS In a double-blind, randomized trial, we immunized 400 Malian children with either the malaria vaccine or a control (rabies) vaccine and followed them for 6 months. The primary end point was clinical malaria, defined as fever and at least 2500 parasites per cubic millimeter of blood. A secondary end point was clinical malaria caused by parasites with the AMA1 DNA sequence found in the vaccine strain. RESULTS The cumulative incidence of the primary end point was 48.4% in the malaria-vaccine group and 54.4% in the control group; efficacy against the primary end point was 17.4% (hazard ratio for the primary end point, 0.83; 95% confidence interval [CI], 0.63 to 1.09; P=0.18). Efficacy against the first and subsequent episodes of clinical malaria, as defined on the basis of various parasite-density thresholds, was approximately 20%. Efficacy against clinical malaria caused by parasites with AMA1 corresponding to that of the vaccine strain was 64.3% (hazard ratio, 0.36; 95% CI, 0.08 to 0.86; P=0.03). Local reactions and fever after vaccination were more frequent with the malaria vaccine. CONCLUSIONS On the basis of the primary end point, the malaria vaccine did not provide significant protection against clinical malaria, but on the basis of secondary results, it may have strain-specific efficacy. If this finding is confirmed, AMA1 might be useful in a multicomponent malaria vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00460525.).

IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani

IL-17 and IL-22 have been shown to increase protection against certain bacteria and fungal pathogens in experimental models. However, no human studies have demonstrated a crucial role of IL-17 and IL-22 in protection against infections. We show here that Leishmania donovani, which can cause the lethal visceral disease Kala Azar (KA), stimulates the differentiation of Th17 cells, which produce IL-17, IL-22, and IFN-gamma. Analysis of Th1, Th2, and Th17 cytokine responses by cultured PBMCs from individuals in a cohort of subjects who developed KA or were protected against KA during a severe outbreak showed that IL-17 and IL-22 were strongly and independently associated with protection against KA. Our results suggest that, along with Th1 cytokines, IL-17 and IL-22 play complementary roles in human protection against KA, and that a defect in Th17 induction may increase the risk of KA.

Analysis of the 5q31-q33 Locus Shows an Association between IL13-1055C/T IL-13-591A/G Polymorphisms and Schistosoma haematobium Infections

Millions of humans are exposed to schistosome infections, which cause severe kidney and liver disease and 280,000 deaths annually. Th2-mediated immunity is critical to human defenses against this pathogen and susceptibility to infection is controlled by a major genetic locus that includes IL4, IL5, and IL13 genes. These observations led us to evaluate whether certain polymorphisms in IL4, IL5, or IL13 determine schistosome infection. The study was performed in two Dogon villages where Schistosoma haematobium is endemic. Schistosome infections were evaluated by counting eggs and measuring worm Ags in urine. Genetic polymorphisms were determined by restriction enzyme analysis or by primer extension and denaturing high-performance liquid chromatography analysis. Associations were tested using family-based association tests and logistical regression analysis. The alleles IL13-1055C (p = 0.05) and IL13-591A (p = 0.01) are shown, by family-based association test, to be preferentially transmitted to children with the 10% highest infections. A logistic regression analysis that included IL13-1055 G/G, G/T and T/T genotypes, age, gender, and village of residency, applied to the whole study population, showed that subjects bearing the IL13-1055T/T genotype were on average much less infected than individuals with other genotypes. Previous studies on asthma indicated that the IL13-1055T allele increased gene transcription, which is in agreement with the fact that this cytokine enhances resistance to infection by schistosome in humans.

IFN-gamma polymorphisms (IFN-gamma +2109 and IFN-gamma +3810) are associated with severe hepatic fibrosis in human hepatic schistosomiasis (Schistosoma mansoni).

Schistosome infection is a major public health concern affecting millions of people living in tropical regions of Africa, Asia, and South America. Schistosomes cause mild clinical symptoms in most subjects, whereas a small proportion of individuals presents severe clinical disease (as periportal fibrosis (PPF)) that may lead to death. Severe PPF results from an abnormal deposition of extracellular matrix proteins in the periportal spaces due to a chronic inflammation triggered by eggs and schistosome Ags. Extracellular matrix protein production is regulated by a number of cytokines, including IFN-γ. We have now screened putative polymorphic sites within this gene in a population living in an endemic area for Schistosoma mansoni. Two polymorphisms located in the third intron of the IFN-γ gene are associated with PPF. The IFN-γ +2109 A/G polymorphism is associated with a higher risk for developing PPF, whereas the IFN-γ +3810 G/A polymorphism is associated with less PPF. The polymorphisms result in changes in nuclear protein interactions with the intronic regions of the gene, suggesting that they may modify IFN-γ mRNA expression. These results are consistent with the results of previous studies. Indeed, PPF is controlled by a major locus located on chromosome 6q22-q23, closely linked to the gene encoding the α-chain of the IFN-γ receptor, and low IFN-γ producers have been shown to have an increased risk of severe PPF. Together, these observations support the view that IFN-γ expression and subsequent signal transduction play a critical role in the control of PPF in human hepatic schistosome infection (S. mansoni).

HIV, HCV, HBV and syphilis rate of positive donations among blood donations in Mali: Lower rates among volunteer blood donors

Good data on background seroprevalence of major transfusion transmitted infections is lacking in Mali. We gathered data on the rate of positive donations of human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV) and syphilis among blood donations in Mali for calendar year 2007. Donations with repeatedly reactive results on screening enzyme immunoassay (EIA) were considered to be seropositive. Rate of positive donations per blood unit collected was 2.6% for HIV, 3.3% for HCV, 13.9% for hepatitis B surface antigen (HBsAg) and 0.3% for syphilis. For HIV, HBsAg and syphilis, rate of positive donations was significantly (p<0.001) higher among donations from replacement donors than those from volunteer donors, while HCV rate of positive donations was similar in the two groups. Rate of positive donations was also significantly (p<0.0001) lower in blood units from regular than from first-time donors. These data reinforce WHO recommendations for increasing the number of regular, volunteer blood donors in Africa.

Interleukin-13 in the skin and interferon-gamma in the liver are key players in immune protection in human schistosomiasis.

Summary:  Immunity against schistosomes includes anti‐infection immunity, which is mainly active against invading larvae in the skin, and anti‐disease immunity, which controls abnormal fibrosis in tissues invaded by schistosome eggs. Anti‐infection immunity is T‐helper 2 (Th2) cell‐dependent and is controlled by a major genetic locus that is located near the Th2 cytokine locus on chromosome 5q31‐q33. Mutations in the gene encoding interleukin (IL)‐13 that decrease or increase IL‐13 production account, at least in part, for that genetic control. In contrast, protection against hepatic fibrosis is dependent on interferon (IFN)‐γ and is controlled by a major genetic locus that is located on 6q23, near the gene encoding the IFN‐γ receptor β chain. Mutations that modulate IFN‐γ gene transcription are associated with different susceptibility to disease. These data indicate that IL‐13 in the skin and IFN‐γ in the liver are key players in protective immunity against schistosomes. These roles relate to the high anti‐fibrogenic activities of IFN‐γ and to the unique ability of IL‐13 in Th2 priming in the skin and in the mobilization of eosinophils in tissues. The coexistence of strong IFN‐γ and IL‐13‐mediated immune responses in the same subject may involve the compartmentalization of the anti‐schistosome immune response between the skin and the liver.

RHD allele distribution in Africans of Mali

BackgroundAberrant and non-functional RHD alleles are much more frequent in Africans than in Europeans. The DAU cluster of RHD alleles exemplifies that the alleles frequent in Africans have evaded recognition until recently. A comprehensive survey of RHD alleles in any African population was lacking.ResultsWe surveyed the molecular structure and frequency of RHD alleles in Mali (West Africa) by evaluating 116 haplotypes. Only 69% could be attributed to standard RHD (55%) or the RHD deletion (14%). The aberrant RHD allele DAU-0 was predicted for 19%, RHDΨ for 7% and Ccdesfor 4% of all haplotypes. DAU-3 and the new RHD allele RHD(L207F), dubbed DMA, were found in one haplotype each. A PCR-RFLP for the detection of the hybrid Rhesus box diagnostic for the RHD deletion in Europeans was false positive in 9 individuals, including all carriers of RHDΨ . Including two silent mutations and the RHD deletion, a total of 9 alleles could be differentiated.ConclusionBesides standard RHD and the RHD deletion, DAU-0, RHDΨ and Ccdesare major alleles in Mali. Our survey proved that the most frequent alleles of West Africans have been recognized allowing to devise reliable genotyping and phenotyping strategies.

Induction of a protection against S. mansoni with a MAP containing epitopes of Sm37-GAPDH and Sm10-DLC. Effect of coadsorbtion with GM-CSF on alum

Studies of anti-S. mansoni immunological responses in individuals living in endemic areas identified immunogens (Sm37-GAPDH and Sm10-DLC) with vaccine candidate properties. Analysis of the epitopes of these immunogens indicated that: (i) Sm37-5 is a major B-cell epitope of Sm37-GAPDH and the IgG antibody reactivity toward this determinant is associated with resistance to reinfection; (ii) Sm10-T is a T-cell epitope of the major T-cell immunogen Sm10-DLC. This led us to test a multiple antigen peptide (MAP) containing Sm37-5 and Sm10-T as an anti-schistosome vaccine. This MAP induced a significant protective immune response in mice when injected in Freunds adjuvant or coadsorbed with GM-CSF on aluminium hydroxide. In the latter case the physical link between the cytokine and the antigen via the coadsorption on alum was necessary to obtain a protective response. Results of the antibody response indicated that when the MAP and GM-CSF were coadsorbed on alum, the antibody response against the Sm10-T epitope located in the NH(2)-terminal position was significantly amplified up to 30% of the anti-Sm37-5 response.

Immunity against HIV/AIDS, malaria, and tuberculosis during co-infections with neglected infectious diseases: recommendations for the European Union research priorities.

Author Summary Infectious diseases remain a major health and socioeconomic problem in many low-income countries, particularly in sub-Saharan Africa. For many years, the three most devastating diseases, HIV/AIDS, malaria, and tuberculosis (TB) have received most of the worlds attention. However, in rural and impoverished urban areas, a number of infectious diseases remain neglected and cause massive suffering. It has been calculated that a group of 13 neglected infectious diseases affects over one billion people, corresponding to a sixth of the worlds population. These diseases include infections with different types of worms and parasites, cholera, and sleeping sickness, and can cause significant mortality and severe disabilities in low-income countries. For most of these diseases, vaccines are either not available, poorly effective, or too expensive. Moreover, these neglected diseases often occur in individuals who are also affected by HIV/AIDS, malaria, or TB, making the problem even more serious and indicating that co-infections are the rule rather than the exception in many geographical areas. To address the importance of combating co-infections, scientists from 14 different countries in Africa and Europe met in Addis Ababa, Ethiopia, on September 9–11, 2007. The message coming from these scientists is that the only possibility for winning the fight against infections in low-income countries is by studying, in the most global way possible, the complex interaction between different infections and conditions of malnourishment. The new scientific and technical tools of the post-genomic era can allow us to reach this goal. However, a concomitant effort in improving education and social conditions will be needed to make the scientific findings effective.