Download Pathogenecity of Toxoplasma gondii Does genotype makes a

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
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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
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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