La cryptococcose neuro-méningée au Mali

Cryptococcal meningitis is the most common fatal central nervous system infection in AIDS patients in Sub-Saharan Africa. The purpose of this prospective study conducted from March 2003 to February 2004 in the internal medicine and infectious diseases departments of the Point G University Hospital Center was to investigate the clinical, prognostic and epidemiological profile of Cryptococcus neoformans infection in patients hospitalized for brain and meningeale infection (BMI). Diagnosis of neuromeningeal cryptococcosis (NMC) was based on positive identification of Cryptococcus by direct exam of the cebrospinal fluid (CSF) after India ink staining and/or culture on Sabouraud medium without actidione. During the study period, a total of 569 patients were hospitalized including 235 (41.3%) with HIV infection. Overall C. neoformans was identified in 14 patients. Median patient age was 39 ± 8 years. There was a male preponderance with a sex ratio of 1.8 (9 men/5 women). Patients with BMI were HIV positive in 85.7% of cases (n=12) and HIV-negative in 14.3% (n=2). The overall and HIV-specific prevalence of BMI was 2.5% and 5.1% respectively. The CD4 lymphocyte count was between 1 and 49 cells/mm3 in 64.3% of cases. The main clinical symptoms were cephalea in 85.7% of cases, altered consciousness in 50% and nausea/vomiting in 35.7%. Neurological manifestations (hemiparesis and cranial nerve deficit) were noted in 14.3%. HIV infection is the main purveyor of NMC in Mali. The actual incidence of cryptococcosis is unclear due to the poor sensitivity of diagnostic techniques. This study highlights diagnostic difficulties related to clinical polymorphism and poor technical facilities. Agglutination testing of blood and CSF is recommended, but mortality remains

Insights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania

The human genetic factors that affect resistance to infectious disease are poorly understood. Here we report a genome-wide association study in 17,000 severe malaria cases and population controls from 11 countries, informed by sequencing of family trios and by direct typing of candidate loci in an additional 15,000 samples. We identify five replicable associations with genome-wide levels of evidence including a newly implicated variant on chromosome 6. Jointly, these variants account for around one-tenth of the heritability of severe malaria, which we estimate as -23% using genome-wide genotypes. We interrogate available functional data and discover an erythroid-specific transcription start site underlying the known association in ATP2B4, but are unable to identify a likely causal mechanism at the chromosome 6 locus. Previously reported HLA associations do not replicate in these samples. This large dataset will provide a foundation for further research on thegenetic determinants of malaria resistance in diverse populations.Peer reviewe

‘Lactomassilus timonensis,’ a new anaerobic bacterial species isolated from the milk of a healthy African mother

We here report the main characteristics of a new anaerobic bacterial genus and species ‘Lactomassilus timonensis,’ strain Marseille-P4641T (CSUR = P4641), isolated by microbial culturomics from the milk of a 35-year-old healthy lactating mother from Mali. Keywords: Culturomics, Human breast milk microbiota, Lactomassilus timonensis, Taxonom

Protection of Malian children from clinical malaria is associated with recognition of multiple antigens

Contains fulltext : 153754.pdf (publisher's version ) (Open Access)BACKGROUND: Naturally acquired immunity to clinical malaria is thought to be mainly antibody-mediated, but reports on antigen targets are contradictory. Recognition of multiple antigens may be crucial for protection. In this study, the magnitude of antibody responses and their temporal stability was assessed for a panel of malaria antigens in relation to protection against clinical Plasmodium falciparum malaria. METHODS: Malian children aged two to 14 years were enrolled in a longitudinal study and followed up by passive and active case detection for seven months. Plasma was collected at enrolment and at the beginning, in the middle and after the end of the transmission season. Antibody titres to the P. falciparum-antigens apical membrane protein (AMA)-1, merozoite surface protein (MSP)-1(1)(9), MSP-3, glutamine-rich protein (GLURP-R0) and circumsporozoite antigen (CSP) were assessed by enzyme-linked immunosorbent assay (ELISA) for 99 children with plasma available at all time points. Parasite carriage was determined by microscopy and nested PCR. RESULTS: Antibody titres to all antigens, except MSP-1(1)(9), and the number of antigens recognized increased with age. After malaria exposure, antibody titres increased in children that had low titres at baseline, but decreased in those with high baseline responses. No significant differences were found between antibody titers for individual antigens between children remaining symptomatic or asymptomatic after exposure, after adjustment for age. Instead, children remaining asymptomatic following parasite exposure had a broader repertoire of antigen recognition. CONCLUSIONS: The present study provides immune-epidemiological evidence from a limited cohort of Malian children that strong recognition of multiple antigens, rather than antibody titres for individual antigens, is associated with protection from clinical malaria

Sulfadoxine-pyrimethamine impairs Plasmodium falciparum gametocyte infectivity and Anopheles mosquito survival.

Sulfadoxine-pyrimethamine (SP) is currently the drug of choice for intermittent preventive treatment of Plasmodium falciparum both in pregnancy and infancy. A prolonged parasite clearance time conferred by dhfr and dhps mutations is believed to be responsible for increased gametocyte prevalence in SP treated individuals. However, using a direct feeding assay in Mali, we showed that gametocytes present in peripheral venous blood post-SP treatment had reduced infectivity for Anopheles gambiae sensu stricto (ss) mosquitoes. We investigated the potential mechanisms involved in the dhfr and dhps quintuple mutant NF-135 and the single dhps 437 mutant NF-54. Concentrations of sulfadoxine (S) and pyrimethamine (P) equivalent to the serum levels of the respective drugs on day 3 (S=61 microg/ml, P=154.7 ng/ml) day 7 (S=33.8 microg/ml, P=66.6 ng/ml) and day 14 (S=14.2 microg/ml, P=15.7 ng/ml) post-SP treatment were used to study the effect on gametocytogenesis, gametocyte maturation and infectivity to Anopheles stephensi mosquitoes fed through an artificial membrane. The drugs readily induced gametocytogenesis in the mutant NF-135 strain but effectively killed the wild-type NF-54. However, both drugs impaired gametocyte maturation yielding odd-shaped non-exflagellating mature gametocytes. The concomitant ingestion of both S and P together with gametocytemic blood-meal significantly reduced the prevalence of oocyst positivity as well as oocyst density when compared to controls (P<0.001). In addition, day 3 concentrations of SP decreased mosquito survival by up to 65% (P<0.001). This study demonstrates that SP is deleterious in vitro for gametocyte infectivity as well as mosquito survival

A barcode of organellar genome polymorphisms identifies the geographic origin of Plasmodium falciparum strains

Contains fulltext : 137597.pdf (publisher's version ) (Open Access)Malaria is a major public health problem that is actively being addressed in a global eradication campaign. Increased population mobility through international air travel has elevated the risk of re-introducing parasites to elimination areas and dispersing drug-resistant parasites to new regions. A simple genetic marker that quickly and accurately identifies the geographic origin of infections would be a valuable public health tool for locating the source of imported outbreaks. Here we analyse the mitochondrion and apicoplast genomes of 711 Plasmodium falciparum isolates from 14 countries, and find evidence that they are non-recombining and co-inherited. The high degree of linkage produces a panel of relatively few single-nucleotide polymorphisms (SNPs) that is geographically informative. We design a 23-SNP barcode that is highly predictive (~92%) and easily adapted to aid case management in the field and survey parasite migration worldwide

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/AS02A, 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 malariavaccine 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

Memory-like IFN-gamma response by NK cells following malaria infection reveals the crucial role of T cells in NK cell activation by P. falciparum.

NK cells are rapid IFN-gamma responders to Plasmodium falciparum-infected erythrocytes (PfRBC) in vitro and are involved in controlling early parasitaemia in murine models, yet little is known about their contribution to immune responses following malaria infection in humans. Here, we studied the dynamics of and requirements for in vitro NK responses to PfRBC in malaria-naive volunteers undergoing a single experimental malaria infection under highly controlled circumstances, and in naturally exposed individuals. NK-specific IFN-gamma responses to PfRBC following exposure resembled an immunological recall pattern and were tightly correlated with T-cell responses. However, although PBMC depleted of CD56(+) cells retained 20-55% of their total IFN-gamma response to PfRBC, depletion of CD3(+) cells completely abrogated the ability of remaining PBMC, including NK cells, to produce IFN-gamma. Although NK responses to PfRBC were partially dependent on endogenous IL-2 signaling and could be augmented by exogenous IL-2 in whole PBMC populations, this factor alone was insufficient to rescue NK responses in the absence of T cells. Thus, NK cells make a significant contribution to total IFN-gamma production in response to PfRBC as a consequence of their dependency on (memory) T-cell help, with likely positive implications for malaria vaccine development

Distinct interethnic differences in immunoglobulin G class/subclass and immunoglobulin M antibody responses to malaria antigens but not in immunoglobulin G responses to nonmalarial antigens in sympatric tribes living in West Africa

The well-established relative resistance to malaria observed in the Fulani as compared with other sympatric tribes in West Africa has been attributed to their higher levels of serum immunoglobulin (Ig) G antibodies to malarial antigens. In this study, we confirm and extend the previous findings by analyses of the levels of IgM, IgG and IgG subclasses of anti-malarial antibodies in asymptomatic individuals of different sympatric tribes in Burkina Faso (Fulani/Mossi) and Mali (Fulani/Dogon). The Fulani showed significantly higher median concentrations of anti-malarial IgG and IgM antibodies than the sympatric tribes at both locations. Although the overall subclass pattern of antibodies did not differ between the tribes, with IgG1 and IgG3 as dominant, the Fulani showed consistently significantly higher levels of these subclasses as compared with those of the non-Fulani individuals. No significant differences were seen in the levels of total IgG between the tribes, but the Fulani showed significantly higher levels of total IgM than their neighbours in both countries. While the antibody levels to some nonmalarial antigens showed the same pattern of differences seen for antibody levels to malaria antigens, no significant such differences were seen with antibodies to other nonmalarial antigens. In conclusion, our results show that the Fulani in two different countries show higher levels of anti-malarial antibodies than sympatric tribes, and this appears not to be a reflection of a general hyper-reactivity in the Fulani