No abstract

The Leishmania tarentolae Parrot-TarII strain genome sequence was resolved to an average 16-fold mean coverage by next-generation DNA sequencing technologies. This is the first non-pathogenic to humans kinetoplastid protozoan genome to be described thus providing an opportunity for comparison with the completed genomes of pathogenic Leishmania species. A high synteny was observed between all sequenced Leishmania species. A limited number of chromosomal regions diverged between L. tarentolae and L. infantum, while remaining syntenic to L. major. Globally, >90% of the L. tarentolae gene content was shared with the other Leishmania species. We identified 95 predicted coding sequences unique to L. tarentolae and 250 genes that were absent from L. tarentolae. Interestingly, many of the latter genes were expressed in the intracellular amastigote stage of pathogenic species. In addition, genes coding for products involved in antioxidant defence or participating in vesicular-mediated protein transport were underrepresented in L. tarentolae. In contrast to other Leishmania genomes, two gene families were expanded in L. tarentolae, namely the zinc metallo-peptidase surface glycoprotein GP63 and the promastigote surface antigen PSA31C. Overall, L. tarentolae's gene content appears better adapted to the promastigote insect stage rather than the amastigote mammalian stage.

The intramacrophage protozoan parasites of Leishmania genus have developed sophisticated ways to subvert the innate immune response permitting their infection and propagation within the macrophages of the mammalian host. Several Leishmania virulence factors have been identified and found to be of importance for the development of leishmaniasis. However, recent findings are now further reinforcing the critical role played by the zinc-metalloprotease GP63 as a virulence factor that greatly influence host cell signaling mechanisms and related functions. GP63 has been found to be involved not only in the cleavage and degradation of various kinases and transcription factors, but also to be the major molecule modulating host negative regulatory mechanisms involving for instance protein tyrosine phosphatases (PTPs). Those latter being well recognized for their pivotal role in the regulation of a great number of signaling pathways. In this review article, we are providing a complete overview about the role of Leishmania GP63 in the mechanisms underlying the subversion of macrophage signaling and functions.

Leishmania parasites are able to secure their survival and propagation within their host by altering signalling pathways involved in the ability of macrophages to kill pathogens or to engage adaptive immune system. An important step in this immune evasion process is the activation of host protein tyrosine phosphatase SHP-1 by Leishmania. SHP-1 has been shown to directly inactivate JAK2 and Erk1/2 and to play a role in the negative regulation of several transcription factors involved in macrophage activation. These signalling alterations contribute to the inactivation of critical macrophage functions (e.g., Nitric oxide, IL-12, and TNF-α). Additionally, to interfere with IFN-γ receptor signalling, Leishmania also alters several LPS-mediated responses. Recent findings from our laboratory revealed a pivotal role for SHP-1 in the inhibition of TLR-induced macrophage activation through binding to and inactivating IL-1-receptor-associated kinase 1 (IRAK-1). Furthermore, we identified the binding site as an evolutionarily conserved ITIM-like motif, which we named kinase tyrosine-based inhibitory motif (KTIM). Collectively, a better understanding of the evasion mechanisms utilized by Leishmania parasite could help to develop more efficient antileishmanial therapies in the near future.

Th2-mediated immunity is critical for human defence against schistosome, and susceptibility to infection is controlled by a major genetic locus, mapped on the 5q31-q33 region comprising the genes IL4, IL5 and IL13. We have reported an association between the rs1800925 polymorphism in the IL13 promoter and infection levels in a Dogon population (693 subjects in Sé gué and 148 in Boul), where Schistosoma haematobium is endemic. In the same population, we investigated whether other polymorphisms in genes involved in type 2 cytokine immune response could affect susceptibility to schistosome infection. By logistic regression analysis, we found an association between a single-nucleotide polymorphism (SNP) in the STAT6 gene (rs324013) and infection levels (P ¼ 0.04). We confirmed this association in analyses restricted to subjects under 20 years age and living in Boul, the village with the highest levels of infection (P ¼ 0.005). We detected an additive effect of the rs324013 and rs1800925 polymorphisms (P ¼ 0.011). These SNPs were not strongly correlated with any other tested markers surrounding the two genes. Furthermore, electrophoretic mobility shift assay has shown that both polymorphisms affect transcription factor binding. These results are consistent with the Th2 cytokine pathway enhancing resistance to schistosome infection in humans.

The protease GP63 is an important virulence factor of Leishmania parasites. We previously showed that GP63 reaches the perinuclear area of host macrophages and that it directly modifies nuclear translocation of the transcription factors NF-κB and AP-1. Here we describe for the first time, using molecular biology and in-depth proteomic analyses, that GP63 alters the host macrophage nuclear envelope, and impacts on nuclear processes. Our results suggest that GP63 does not appear to use a classical nuclear localization signal common between Leishmania species for import, but degrades nucleoporins, and is responsible for nuclear transport alterations. In the nucleoplasm, GP63 activity accounts for the degradation and mislocalization of proteins involved amongst others in gene expression and in translation. Collectively, our data indicates that Leishmania infection strongly affects nuclear physiology, suggesting that targeting of nuclear physiology may be a strategy beneficial for virulent Leishmania parasites.

Urinary schistosomiasis is a parasitic disease caused by Schistosoma haematobium helminths. S. haematobium eggs may remain trapped within the bladder or the ureter walls, causing major pathological disorders in the urogenital system. The polymorphism rs1800925(C/T) of the IL13 gene promoter, which is functional, has previously been associated with susceptibility to S. haematobium infection. The aim of this study was to further our understanding and to determine whether, in the 5q31-q33 region, rs1800925 affects infection levels alone or in synergy with other polymorphisms. After sequencing the IL13 promoter and increasing the single-nucleotide polymorphism density, we performed a linkage disequilibrium analysis between rs1800925 and the other markers in a Malian population. Multivariate linear regression analysis and electrophoretic mobility shift assay (EMSA) were performed to characterized markers in linkage disequilibrium with rs1800925. An additional polymorphism, rs7719175, in the IL13 promoter was associated with controlling infection levels in multivariate analysis. The haplotype rs7719175T-rs1800925C was associated with high infection levels. EMSA indicated that rs7719175 affects the binding of transcriptional factors to the promoter region. Polymorphisms rs7719175 and rs1800925 have a synergistic role in the control of infection levels caused by S. haematobium and using them as a haplotype allows a better discrimination between infected subjects.

Human resistance to infection by schistosomes is associated to a strong Th2 immune. However a persistent Th2 response can cause severe kidney and liver disease in human. In this review, we mainly focused on the control of infection levels caused by schistosomes. Several experimental models allowed us to better understand the immunological mechanisms of the host against schistosome infection. High IgE and eosinophil levels are associated with resistance to infection by schistosomes and this effect is counterbalanced by IgG4. IgE and eosinophils are highly dependent on IL-4, IL-13, and Il-5, which are three main Th2 cytokines. We also examined the genetic factors involved in human susceptibility to infection by schistosomiasis. Infection levels are mainly regulated by a major locus SM1, in 5q31-q33 region, which contains the genes encoding for the IL-4, IL-13, and Il-5 cytokines. An association between an IL13 polymorphism, rs1800925, and infection levels has been shown. This polymorphism synergistically acts with another polymorphism (rs324013) in the STAT6 gene, encoding for the signal transducer of the IL13 pathway. This pathway has also been involved in atopic disorders. As helminthiasis, atopy is the result of aberrant Th2 cytokine response to allergens, with an increased production of IL-4, IL-13, Il-9 and Il-5, with high amounts of allergen-specific and total IgE and eosinophilia. However, the Th2 immune response is protective in helminthiasis but aggravating in atopic disorders. Several studies reported interplay between helminthic infections and allergic reactions. The different results are discussed here.