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Genetic analysis of murine malaria
Umeå University, Faculty of Medicine, Medical Biosciences.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malaria, an infectious disease caused by Plasmodium parasites, is one of the major world-scale health problems. Despite the efforts aimed at finding an effective way to control the disease, the success has been thwarted by the emergence of parasite drug resistance and mosquito resistance to insecticides. This thesis focuses on the genetic analysis of resistance to murine malaria induced by the lethal Plasmodium berghei ANKA using a wild-derived-inbred strain (WDIS). The aim of this thesis was to exploit the genetic diversity represented among WDIS for identifying loci contributing to resistance/susceptibility to murine malaria.

The work included a genome-wide polymorphism survey using microsatellite markers performed on 10 WDIS. Comparisons of these strains to laboratory inbred strains confirmed a higher rate of polymorphism among the WDIS. We conclude that these WDIS represent repositories of unique naturally occurring genetic variability that may prove to be invaluable for the study of complex phenotypes. Next, we used the WDIS to search for novel phenotypes related to malaria pathogenesis. Whereas most laboratory strains were susceptible to experimental cerebral malaria (ECM) after infection with P. berghei ANKA, several WDIS were found to be resistant. To study the genetic inheritance of resistant/susceptibility to P. berghei ANKA infection we analysed backcross and F2 cohorts derived from crossing the WLA wild-derived strain with a laboratory mouse strain (C57BL/6). A novel phenotype represented by the cure of infection, clearance of parasitaemia and establishment of immunological memory was observed in the F2 progeny. The backcross progeny was used to genetically map one locus on chromosome 1 (Berr1) and one locus on chromosome 11 (Berr2) that mediate control of resistance to ECM induced by P. berghei ANKA. Genetic mapping using the F2 progeny showed that a locus on chromosome 1 (Berr1) and a locus on chromosome 9 (Berr3) were contributing to control survival time after infection with lethal Plasmodium. Finally, we identified, a locus on chromosome 4 (Berr4) that appears to control time of death due to hyperparasitaemia.

This thesis underlines the value of using WDIS to reveal genetic factors involved in the aetiology of disease phenotypes. The characterisation of the genetic factors represented by the malaria resistance loci identified here are expected to provide a better understanding of the malaria pathology.

Place, publisher, year, edition, pages
2003. , 60 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 861
Keyword [en]
Genetics, Malaria, genetic analysis, Plasmodium, wild derived inbred strains, loci, cerebral malaria, hyperparasitaemia.
Keyword [sv]
Genetik
National Category
Medical Genetics
Research subject
Genetics
Identifiers
URN: urn:nbn:se:umu:diva-124ISBN: 91-7305-528-X (print)OAI: oai:DiVA.org:umu-124DiVA: diva2:140541
Public defence
2003-11-06, Sal E04, byggnad 6E, Nus, byggnad 6E, Nus, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2003-10-15 Created: 2003-10-15 Last updated: 2010-01-18Bibliographically approved
List of papers
1. Unique genetic variation revealed by a microsatellite polymorphism survey in ten wild-derived inbred strains
Open this publication in new window or tab >>Unique genetic variation revealed by a microsatellite polymorphism survey in ten wild-derived inbred strains
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2002 In: Genomics, Vol. 79, no 5, 618-20. p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-2464 (URN)
Available from: 2003-10-15 Created: 2003-10-15Bibliographically approved
2. Susceptibility to experimental cerebral malaria induced by plasmodium berghei ANKA in inbred mouse strains recently derived from Wild Stock
Open this publication in new window or tab >>Susceptibility to experimental cerebral malaria induced by plasmodium berghei ANKA in inbred mouse strains recently derived from Wild Stock
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2002 In: Infection and immunity, Vol. 70, no 4, 2049-56 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-2465 (URN)
Available from: 2003-10-15 Created: 2003-10-15Bibliographically approved
3. Identification of two cerebral malaria resistance loci using an inbred wild-derived mouse strain.
Open this publication in new window or tab >>Identification of two cerebral malaria resistance loci using an inbred wild-derived mouse strain.
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2002 In: PNAS, Vol. 99, no 15, 9919-23 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-2466 (URN)
Available from: 2003-10-15 Created: 2003-10-15Bibliographically approved
4. Genetic analysis of murine malaria resistance that underlies parasite clearance and immunological memory
Open this publication in new window or tab >>Genetic analysis of murine malaria resistance that underlies parasite clearance and immunological memory
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2467 (URN)
Available from: 2003-10-15 Created: 2003-10-15 Last updated: 2010-01-13Bibliographically approved

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Citation style
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