BackgroundPlasmodium falciparum malaria remains a major health problem in Africa. The mechanisms of pathogenesis are not fully understood. Transcriptomic studies may provide new insights into molecular pathways involved in the severe form of the disease.MethodsBlood transcriptional levels were assessed in patients with cerebral malaria, non-cerebral malaria, or mild malaria by using microarray technology to look for gene expression profiles associated with clinical status. Multi-way ANOVA was used to extract differentially expressed genes. Network and pathways analyses were used to detect enrichment for biological pathways.ResultsWe identified a set of 443 genes that were differentially expressed in the three patient groups after applying a false discovery rate of 10%. Since the cerebral patients displayed a particular transcriptional pattern, we focused our analysis on the differences between cerebral malaria patients and mild malaria patients. We further found 842 differentially expressed genes after applying a false discovery rate of 10%. Unsupervised hierarchical clustering of cerebral malaria-informative genes led to clustering of the cerebral malaria patients. The support vector machine method allowed us to correctly classify five out of six cerebral malaria patients and six of six mild malaria patients. Furthermore, the products of the differentially expressed genes were mapped onto a human protein-protein network. This led to the identification of the proteins with the highest number of interactions, including GSK3B, RELA, and APP. The enrichment analysis of the gene functional annotation indicates that genes involved in immune signalling pathways play a role in the occurrence of cerebral malaria. These include BCR-, TCR-, TLR-, cytokine-, FcεRI-, and FCGR- signalling pathways and natural killer cell cytotoxicity pathways, which are involved in the activation of immune cells. In addition, our results revealed an enrichment of genes involved in Alzheimer’s disease.ConclusionsIn the present study, we examine a set of genes whose expression differed in cerebral malaria patients and mild malaria patients. Moreover, our results provide new insights into the potential effect of the dysregulation of gene expression in immune pathways. Host genetic variation may partly explain such alteration of gene expression. Further studies are required to investigate this in African populations.

BackgroundSevere forms of malaria (SM) are an outcome of Plasmodium falciparum infection and can cause death especially in children under 4 years of age. RNASE3 (ECP) has been identified as an inhibitor of Plasmodium parasites growth in vitro, and genetic analysis in hospitalized Ghanaian subjects has revealed the RNASE3 +371G/C (rs2073342) polymorphism as a susceptibility factor for cerebral malaria. The +371 C allele results in an Arg/Thr mutation that abolishes the cytotoxic activity of the ECP protein. The present study aims to investigate RNASE3 gene polymorphisms and their putative link to severe malaria in a malaria cohort from Senegal.Methods/resultsPatients enrolled from hospitals were classified as having either uncomplicated (UM) or severe malaria (SM). The analysis of the RNASE3 gene polymorphisms was performed in 241 subjects: 178 falciparum infected (96 SM, 82 UM) and 63 non-infected subjects as population control group (CTR). Six frequent SNPs (MAF > 3%) were identified, and one SNP was associated with malaria severity by performing a logistic regression analysis SM vs.UM: RNASE3 +499G/C (rs2233860) under age, sex as covariates and HbS/HbC polymorphisms adjustment (p = 0.003, OR 0.43, CI 95% 0.20–0.92). The polymorphisms: +371G/C (rs2073342), +499G/C (rs2233860) and +577A/T (rs8019343) defined a haplotype risk (G-G-T) for malaria severity (Fisher exact test, p = 0.03) (OR 4.1, IC 95% (1.1–14.9).ConclusionIn addition to the previously described association of +371G/C polymorphism in Ghanaians cohort, the RNASE3 +499G/C polymorphism was associated with susceptibility to SM in a Senegalese population. The haplotype +371G/+499G/+577T defined by RNASE3 polymorphisms was associated with severity. The genetic association identified independently in the Senegalese population provide additional evidence of a role of RNASE3 (ECP) in malaria severity.

BackgroundHost factors, including host genetic variation, have been shown to influence the outcome of Plasmodium falciparum infection. Genome-wide linkage studies have mapped mild malaria resistance genes on chromosome 6p21, whereas NCR3-412 polymorphism (rs2736191) lying within this region was found to be associated with mild malaria.MethodsBlood samples were taken from 188 Plasmodium falciparum malaria patients (76 mild malaria patients, 85 cerebral malaria patients, and 27 severe non-cerebral malaria patients). NCR3-412 (rs2736191) was analysed by sequencing, and haematological parameters were measured. Finally, their association with clinical phenotypes was assessed.ResultsWe evidenced an association of thrombocytopenia with both cerebral malaria and severe non-cerebral malaria, and of an association of high leukocyte count with cerebral malaria. Additionally, we found no association of NCR3-412 with either cerebral malaria, severe non-cerebral malaria, or severe malaria after grouping cerebral malaria and severe non-cerebral malaria patients.ConclusionsOur results suggest that NCR3 genetic variation has no effect, or only a small effect on the occurrence of severe malaria, although it has been strongly associated with mild malaria. We discuss the biological meaning of these results. Besides, we confirmed the association of thrombocytopenia and high leukocyte count with severe malaria phenotypes.

Cholera toxin (CT) and the heat-labile enterotoxin of E. coli (LT), as well as their non toxic mutants, are potent mucosal adjuvants of immunization eliciting mucosal and systemic responses against unrelated co-administered antigens in experimental models and in humans (non toxic mutants). These enterotoxins are composed of two subunits, the A subunit, responsible for an ADP-ribosyl transferase activity and the B subunit, responsible for cell binding. Paradoxically, whereas the whole toxins have adjuvant properties, the B subunits of CT (CTB) and of LT (LTB) have been shown to induce antigen specific tolerance when administered mucosally with antigens in experimental models as well as, recently, in humans, making them an attractive strategy to prevent or treat autoimmune or allergic disorders. Immunomodulation is a complex process involving many cell types notably antigen presenting cells and regulatory T cells (Tregs). In this review, we focus on Treg cells and cholera-like enterotoxins and their non toxic derivates, with regard to subtype, in vivo/in vitro effects and possible role in the modulation of immune responses to coadministered antigens.