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148 geographic distribution in sub-Saharan Africa and Asia (Pagnier et al., 1984), whereas HbC, which has no obvious CC segregational load, occurs only in a small area of central West-Africa. To address this apparent paradox, we adopted two partially independent haplotypic approaches in the Mossi population of Burkina Faso where both the local S (SBenin) and the C alleles are common (0.05 and 0.13). We showed that C has accumulated a 4-fold higher recombinational and DNA slippage haplotypic variability than the SBenin allele (P = 0.003) implying higher antiquity. These results, consistently with epidemiological evidences, imply that the C allele has been accumulated mainly through a recessive rather than a semidominant mechanism of selection. This evidence explains the apparent paradox of the uni-epicentric geographic distribution of HbC, representing a ‘slow but gratis’ genetic adaptation to malaria through a transient and long-lagged polymorphism, compared to the polycentric ‘quick but costly’ adaptation through balanced polymorphism of HbS. The demonstration that the selection of the C allele occurred mainly through homozygosis has obvious implications when studying the possible protective mechanisms (Fairhurst et al., 2005). Interethnic differences in the susceptibility to malaria: the role of T regulatory cells (Torcia et al., 2008) Previous inter-ethnic comparative studies on the susceptibility to malaria performed in West Africa showed that Fulani are more resistant to Plasmodium falciparum malaria than sympatric ethnic groups (Modiano et al., 1996; Dolo et al., 2006) with different genetic background Modiano et al., 2001b). This resistance was not associated to classic malaria resistance genes (Modiano et al., 2001c) and the analysis of the antibody response to P. falciparum antigens revealed higher immune reactivity in the Fulani (Modiano et al., 1996; 1998; 1999). The hypothesis of a stronger activation of the immune system in this ethnic group is also suggested by the higher frequency of the tropical splenomegaly syndrome reported in this population (Greenwood et al., 1987). In this context, the analysis of the expression, in selected cellular populations of the immune system, of a large panel of genes involved in the immune response by Microarray and Real-Time PCR techniques might be helpful in the identification of genes for genetic susceptibility studies. We analyzed, in peripheral blood mononuclear cells (PBMC) from Fulani and sympatric Mossi, the expression profile of a large panel of genes involved in the immune response and obtained evidences suggesting a functional deficit of the mechanisms of immune regulation in Fulani: they showed an increased expression of genes related to TH1 or TH2 function, together with a reduced expression of CTLA4 and FOXP3, two genes involved in the immune modulation operated by T cells. Microarray analysis on RNA purified from peripheral blood CD4+CD25+ T-regulatory cells (Treg), showed great differences between the two ethnic groups, with impor- F. Verra et al. - Genetic susceptibility to malaria tant genes such as TGFβ, TGFβRs, CTLA4, and FOXP3, being less expressed in Fulani compared to Mossi, as well as to European donors not living in malaria endemic areas. The reduced expression of genes related to suppressive activity seriously affected the ability of T reg cells to suppress P. falciparuminduced cell proliferation in Fulani. In fact depletion of these cells did not significantly increase the proliferation of PBMC to P. falciparum antigens in this group, while it restored an optimal response to the same antigens in the sympatric Mossi. Overall, these results suggested that a functional deficit of T-regulatory cells in Fulani could be involved in the lower susceptibility to malaria of this ethnic group. This study highligthed the existence of clear-cut differences in strategic pathways of the immunoregulatory network between sympatric populations differing in their genetic background and degree of susceptibility to malaria. The functional deficit of Treg here reported in Fulani is consistent with their higher susceptibility to diseases with autoimmune pathogenesis such as diabete mellitus (Fisch et al., 1987), pemphigus (Mahe et al., 1996) and onchocercal skin disease (Brieger et al., 1997). A higher resistance against infectious diseases like P. falciparum malaria could have been the driving selective force of this disorder. The definition of the genes involved could have important implications in the understanding of host-parasite relationships and in the development of anti-malaria vaccines. Interferon Regulator Factor-1 polymorphisms are associated with the control of Plasmodium falciparum infection (Mangano et al., 2008). Interferon Regulatory Factor 1 (IRF-1) is a transcription factor that regulates the expression of a number of genes whose products play crucial roles in innate as well as adaptive immunity (Kroger et al., 2002). IFNgamma is the strongest IRF-1 inducer known and IRF- 1 promotes transcription of a number of genes, acting as an important mediator of IFN-gamma activity. IRF-1 activity is essential for recognition of micro-organisms and antigen presentation, as it regulates the expression of genes such as Toll-like Receptor 9, MHC class I and class II genes. IRF-1 locus lies in the 5q31 human genome region previously shown to be linked to Plasmodium falciparum infection (Rihet et al., 1998). To determine whether genetic variation at the IRF-1 locus affects resistance to malaria infection in humans, and might therefore underlie the P. falciparum infection-level locus, we studied IRF-1 genetic diversity in two West African ethnic groups that show striking differences in their susceptibility and immune response to malaria, and conducted a candidate gene association study with carriage of P. falciparum infection. In order to evaluate the effect of IRF-1 polymorphisms on disease severity, we also conducted a classical intra-ethnic case-control study where we compared the allele frequency of three haplotype-tagging SNPs (htSNPs) between healthy population controls, mild malaria
cases and severe malaria cases of Mossi ethnicity. We showed that IRF-1 polymorphisms entail different abilities to control P. falciparum infection, both in healthy adult subjects and in children with uncomplicated and severe malaria. This study provided the first evidence on the role of a specific locus within the 5q31 region, in the control of P. falciparum infection. Acknowledgements These projects were performed in collaboration with the following Institutions: Centre National de Recherche et de Formation sur le Paludisme, Ministère de la Santé, Burkina Faso; Centre National de Transfusion Sanguine, Burkina Faso; Centre de Recherche Biomoleculaire Pietro Annigoni (CERBA), Burkina Faso; Wellcome Trust Centre for Human Genetics, Oxford, UK; Wellcome Trust Sanger Institute, Hinxton, UK; Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom; Kenya Medical Research Institute, Wellcome Trust Programme, Kilifi, Kenya; Medical Research Council Laboratories, Fajara, Banjul, The Gambia; Department of Biology, University of Rome, Tor Vergata, Italy; Department of Clinical Physiopathology, Center of Excellence “DENOTHE”, University of Firenze, Italy; Istituto Superiore di Sanità, Italy. Financial support was from: EU, Sixth Framework Programme, BioMalPar Network of Excellence; Italian Ministry of Education; Compagnia di San Paolo, Turin; Istituto Pasteur-Fondazione Cenci Bolognetti of the University of Rome ‘La Sapienza’. References Agarwal, A., Guindo, A., Cissoko, Y., Taylor, J.G., Coulibaly, D., Kone, A., Kayentao, K., Djimde, A., Plowe, C.V., Doumbo, O., Wellems TE, Diallo D. (2000). Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S. Blood 96: 2358-2363. Allison, A.C. (1954). The distribution of the sickle-cell trait in East Africa and elsewhere, and its apparent relationship to the incidence of subtertian malaria. Trans. R. Soc. Trop. Med. Hyg. 48: 312-318. Brieger, W. R., Ososanya, O. O., Kale, O. O., Oshiname, F. O., Oke, G. A. (1997). Gender and ethnic differences in onchocercal skin disease in Oyo State, Nigeria. Trop. Med. Int. Health 2: 529-534. Cholera R, Brittain NJ, Gillrie MR, Lopera-Mesa TM, Diakite’ SA, Arie T, Krause MA, Guindo A, Tubman A, Fujioka H, Diallo DA, Doumbo OK, Ho M, Wellems TE, Fairhurst RM (2008). Impaired cytoadherence of Plasmodium falciparum-infected erythrocytes containing sickle haemoglobin. Proc Natl Acad Sci U S A 105: 991-996. Dolo, A., Modiano, D., Maiga, B., Daou, M., Dolo, G., Guindo, H., Ba, M., Maiga, H., Coulibaly, D., Perlman, H., Blomberg MT, Touré YT, Coluzzi M, Doumbo O. (2005). Am. J. Trop. Med. Hyg. 72: 243-248. Fairhurst RM, Baruch DI, Brittain NJ, Ostera GR, Wallach JS, Hoang HL, Hayton K, Guindo A, Makobongo MO, Schwartz OM, Tounkara A, Doumbo OK, Diallo DA, Fujioka H, Ho M, Wellems TE. (2005). Abnormal display of PfEMP-1 on erythro- F. Verra et al. - Genetic susceptibility to malaria 149 cytes carrying haemoglobin C may protect against malaria. Nature 435:1117-1121. Fisch, A., Pichard, E., Prazuck, T., Leblanc, H., Sidibe, Y. & Brucker, G. Prevalence and risk factors of diabetes mellitus in the rural region of Mali (West Africa): a practical approach. (1987). Diabetologia 30, 859-862. Greenwood, B. M., Groenendaal, F., Bradley, A. K., Greenwood, A. M., Shenton, F., Tulloch, S. & Hayes, R. Ethnic differences in the prevalence of splenomegaly and malaria in The Gambia (1987). Ann. Trop. Med. Parasitol. 81, 345-354. Kroger A, Koster M, Schroeder K, Hauser H and Mueller PP Activities of IRF-1. Activities of IRF-1. (2002). J Interferon Cytokine Res. 22: 5-14. Kwiatkowski DP. (2005). How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet 77: 171-192. Mahe, A., Flageul, B., Cisse, I., Keita, S. & Bobin, P. Pemphigus in Mali: a study of 30 cases. (1996). Br. J. Dermatol. 134: 114- 119. Mangano VD, Luoni G, Rockett KA, Sirima BS, Konaté A, Forton J, Clark TG, Bancone G, Akha ES, Kwiatkowski DP, Modiano D. (2008). Interferon regulatory factor-1 polymorphisms are associated with the control of Plasmodium falciparum infection. Genes Immun 9:122-129. Modiano, D., Petrarca, V., Sirima, B. S., Nebie, I., Diallo, D., Esposito, F. & Coluzzi, M. Different response to Plasmodium falciparum malaria in West African sympatric ethnic groups. (1996). Proc Natl Acad Sci U S A 93, 13206-13211. Modiano, D., Chiucchiuini, A., Petrarca, V., Sirima, B. S., Luoni, G., Perlmann, H., Esposito, F. & Coluzzi, M. (1998). Humoral response to Plasmodium falciparum Pf155/ring-infected erythrocyte surface antigen and Pf332 in three sympatric ethnic groups of Burkina Faso. Am J Trop Med Hyg 58: 220-224. Modiano, D., Chiucchiuini, A., Petrarca, V., Sirima, B. S., Luoni, G., Roggero, M. A., Corradin, G., Coluzzi, M. & Esposito, F. (1999). Interethnic differences in the humoral response to non-repetitive regions of the Plasmodium falciparum circumsporozoite protein. Am J Trop Med Hyg 61: 663-667. Modiano, D., Luoni, G., Sirima, B.S., Simpore, J., Verra, F., Konate, A., Rastrelli, E., Olivieri, A., Calissano, C., Paganotti GM, D’Urbano L, Sanou I, Sawadogo A, Modiano G, Coluzzi M.. (2001a); Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 414: 305-308. Modiano, D., Luoni, G., Petrarca, V., Sodiomon, S. B., De Luca, M., Simpore, J., Coluzzi, M., Bodmer, J. G. & Modiano, G. HLA class I in three West African ethnic groups: genetic distances from sub-Saharan and Caucasoid populations. (2001b) Tissue Antigens 57: 128-137. Modiano, D., Luoni, G., Sirima, B. S., Lanfrancotti, A., Petrarca, V., Cruciani, F., Simpore, J., Ciminelli, B. M., Foglietta, E., Grisanti, P. Bianco I, Modiano G, Coluzzi M. (2001c) The lower susceptibility to Plasmodium falciparum malaria of Fulani of Burkina Faso (west Africa) is associated with low frequencies of classic malaria-resistance genes. Trans R Soc Trop Med Hyg 95: 149- 152. Modiano D, Bancone G, Ciminelli BM, Pompei F, Blot I, Simporé J, Modiano G. (2008).Haemoglobin S and haemoglobin C: ‘quick but costly’ versus ‘slow but gratis’ genetic adaptations to Plasmodium falciparum malaria. Hum Mol Genet 17: 789-99. Pagnier, J., Mears, J.G., Dunda-Belkhodja, O., Schaefer-Rego,
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PARASSITOLOGIA A publication of the
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P A R A SSIT O L O GIA Founded in 1
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The individual authors take respons
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Parassitologia 50, 2008 RICORDO DEL
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eceptor subunits move closer togeth
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tion of the brain. Nature 421:744-8
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adic or imported cases have been ob
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other EU countries, yet the impact
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Fasciola hepatica. II: La fasciolos
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Parassitologia 50: 25-29, 2008 Arte
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Ferry along the Potomac River. The
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for each of these chemical entities
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SIMPOSIO 1 ZOONOSI PROTOZOARIE: TOX
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36 Many children with congenital to
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38 Health promotion (Primary Preven
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40 infants with CT newly synthesise
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42 References Ades AE, Gilbert R, T
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C. Contini - management of toxoplas
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C. Contini - management of toxoplas
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V. Meroni, F. Genco - Toxoplasmosis
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56 A.W. Pfaff, E. Candolfi - Immuno
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58 A.W. Pfaff, E. Candolfi - Immuno
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60 (Kijlstra et al., 2006). Regardi
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SIMPOSIO 2 IL PIANETA MALASSEZIA
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66 C. Cafarchia, D. Otranto - Malas
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Parassitologia 50: 69-71, 2008 Skin
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E. M. Difonzo, E. Faggi - Skin dise
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74 R. Galuppi, M.P. Tampieri - Mala
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76 R. Galuppi, M.P. Tampieri - Mala
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78 Table 1. Current composition of
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86 A. Peano, M.G. Gallo - Treatment
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88 A. Peano, M.G. Gallo - Treatment
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90 (vii) Antimycotic properties, pr
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Parassitologia 50: 93-95, 2008 Unco
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SIMPOSIO 3 AEDES ALBOPICTUS IN ITAL
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