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Aarhus University Hospital - Skejby Pathogenecity of Toxoplasma gondii Does genotype makes a difference ? Eskild Petersen, MD, DSc Department of Infectious Diseases Århus University Hospital, Skejby Denmark Department of Infectious Diseases, Aarhus University Hospital Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 1 Birth prevalence of congenital toxoplasmosis in Europe: Aarhus University Hospital - Skejby 2 - 3 per 1,000 liveborns France 1 - 2 per 10,000 liveborns in the Scandinavian countries. In Europe approximately 12% of newborn with CT has eye symptoms at birth (Gras et al., 2005). A population based study in Brazil found that 1.2% of adults had chorioretinal lesions probably due to Toxoplasma (Amorim Garcia et al. 2004). In the UK the life time risk of symptomatic T. gondii eye disease is about 2 per 10,000 population and a 100-fold higher risk in persons born in West Africa, living in the U.K. (Gilbert et al., 1999) Thus Toxoplasma gondii course more eye disease in Brazil compared to Europe. Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 2 Aarhus University Hospital - Skejby Known for many years that virulence in mice vary widely Early genotyping found 3 main groups. Sibley & Boothroyd Nature 1992,359:82-5 LD100 for the RH isolated (Sabin 1939) is 1 parasite genotype I LD100 for most other strains > 1000 parasites genotype II and III Boothroyd & Grigg Curr Opin Microbiol 2002;5:438-42 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 3 Aarhus University Hospital - Skejby Genotype difference and pathogenicity Saeij et al. Trends Parasitol 2005;10:476-81 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 4 Aarhus University Hospital - Skejby France Type II strains dominate in clinical T.gondii infections in HIV patients. 34/45 type II Congenital T.gondii infections 13/13 type II Other infections 8/10 type II Howe et al. JCM 1997;35:1411-4 Congenital T.gondii infections 30/44 type II or III 7/44 type I Ajzenberg et al. Int J Parasitol 2002;32:27-38 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 5 Aarhus University Hospital - Skejby Genotyping of T.gondii isolates from patients withs evere eye disease in the U.S. 12 patients Type I 3 Type II 3 Type III 1 Type I/III 5 Conclusion: Bias towards type I or type III bearing SAG1 allele type I Grigg et al. JID 2001;184:633-9 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 6 Aarhus University Hospital - Skejby T.gondii from cats in Sao Paulo state ¾ Isolates from tissue of 47 cats out of 84 seropositive cats (35%) ¾ Typing using the SAG2 locus ¾ 34 genotype I (72%) ¾ 12 genotype III (26%) ¾ 1 mixed genotype (2%) ¾ None type II Pena et al. Res Vet Sci 2005;8 Nov. 2005, epub ahead of print Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 7 Aarhus University Hospital - Skejby T. gondii genotypes from patient with eye disease in Brazil PCR RFLP analysis of SAG2 from enucleated eyes Out of 92 eyes, 11 was PCR positive for T.gondii SAG2, and all were genotype I Vallochi et al. Am J Ophthalmol 2005;139:350-1 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 8 Aarhus University Hospital - Skejby Genotyping type I strains from Brazil Ferreita AM et al. Infect, Genet Evol 2006;6:22-31 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 9 Aarhus University Hospital - Skejby Serotyping based on epitope-specific reactivity Make unbiased selection possible Allele specific peptides from: GRA1, GRA3, GRA4, GRA6, GRA7, NTPase I and III SAG1, SAG2, SAG3, SAG4, BSR4, SRS2 and ROP1 Standardized with sera from mice infected with known isolates Kong et al., JID 2003;187:1484-95 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 10 Aarhus University Hospital - Skejby Serotyping of Toxoplasma gondii in chronically infected pregnant women: Predominance of type II in the old world and type I and III in the new world Francois Peyron, Jean Lobry, Karine Musset, Josette Ferrandiz, Jorge Enrique Gomez-Marin, Eskild Petersen, Valeria Meroni, Béatrice Rausher, Corinne Mercier Stéphane Picot, Marie-France Cesbron-Delauw. Homogenous genotype II results in Europe Type I or III only in Colombia Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 11 Aarhus University Hospital - Skejby Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 12 Isoenzyme/PCR-RFLP Microsatellite Aarhus University Hospital - Skejby I II Ajzenberg et al. Int J Parasitol 2004,34:1185-96 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital III [email protected] 13 Aarhus University Hospital - Skejby Khan et al. Proc Natl Acad Sci U S A. 2007;10414872-7. Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 14 Aarhus University Hospital - Skejby Khan et al. Proc Natl Acad Sci U S A. 2007;10414872-7. Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 15 Aarhus University Hospital - Skejby Khan et al. Proc Natl Acad Sci U S A. 2007;10414872-7. Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 16 Aarhus University Hospital - Skejby Gilbert et al. PLoS Negl Trop Dis 2008;2:e277 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 17 Aarhus University Hospital - Skejby Gilbert et al. PLoS Negl Trop Dis 2008;2:e277 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 18 Aarhus University Hospital - Skejby Europe Brazil Any ritinitis (Neonatal) 23% 67% Lesions at 4 years 0.16 0.66 Hazard ratio, time to 1st lesion 1.02 5.36 Recurrence, 4 years i chld with ret. 0.19 0.43 Visual impairment 30% 87% (% of infected eyes) Gilbert et al. PLoS Negl Trop Dis 2008;2:e277 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 19 Aarhus University Hospital - Skejby No relationship between drug susceptibility and genotye Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 20 Aarhus University Hospital - Skejby Conclusions ¾ Genotype I, III and ”atypical” dominate in South America ¾ Genotype II dominate in Europe ¾ Genotype I and III seems more virulent compared to II ¾ Genotypes is more complex than just 3 main types ¾ Ocular toxoplasmosis more common in Brazil compared to Europe, probablydue to a more virulent genotype ¾ No difference in drug susceptibility between genotypes Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 21 Small peripheral lesion without Aarhus University Hospital - Skejby impaired sight Large lesion in central fovea region with severe impact on eye sight Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 22 Aarhus University Hospital - Skejby Genotyping performed on T. gondii isolated from clinical cases Selection bias, due to selection from symptomatic and severe cases only Recombinant strains, i.e. mixtures of genotype I, II and III are rare, and contain only two alleles from type I or III (Adam and Eve loci) But exotic or atypical strains which can not be classified into type I, II and III exist. Boothroyd & Grigg Curr Opin Microbiol 2002;5:438-42 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 23 Aarhus University Hospital - Skejby or atypical Su et al. Science 2003,299,414-6 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 24 Aarhus University Hospital - Skejby 86 women from France with T.gondii infection during pregnancy Ajzenberg et al., JID 2002;186:684-9 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 25 Aarhus University Hospital - Skejby T.gondii from ”green” chickens in Austria ¾ Seroprevalence 36% (302/830) from 10 farms ¾ Typing using the SAG2 locus from 33 isolates ¾ All 33 isolates were genotype II Dubey et al. Vet Parasitol 2005;133:299-306 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 26 Aarhus University Hospital - Skejby 21 T.gondii isolates from Animal study from Brazil Only genotype I or III Dubey et al., Int J Parasitol 2002;32:99-105 A study from 38 isolates from different animals and 2 children with CT from Denmark foundd genotype II only Jensen et al., Int J Parasitol 1998;28:1305-13 Genotype II and III dominate animal reservoir in the U.S. Howe & Sibley. JID 1995;172:1561-6 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 27 Aarhus University Hospital - Skejby Serology allow typing into genotype I/III or II Kong et al. JID 2003;187:1484-95 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 28 Recent work from Brazil suggest a more complex picture Aarhus University Hospital - Skejby 20 isolates, ¾ All contained recombinant genotype with type I, II and III alleles at different loci. ¾ Many isolates showed new haplotypes at specicifc loci ¾ 14 subtypes identified based on analysis of 8 loci Conclusion The role of sexual recombination in the population structure of T. gondii seem to be more important in Brazil compared to Europe and the United States Ferreita AM et al. Infect, Genet Evol 2006;6:22-31 Eskild Petersen Department of Infectious Diseases, Aarhus University Hospital [email protected] 29