Using strain distribution pattern in a series of recombinant inbred strains derived from malaria susceptible A/J and resistant C57BL/6J (B6) inbred strains of mice, it was established that the genetic control of infection with Plasmodium chabaudi AS is multigenic. Quantitative trait linkage analysis in backcross and F2 crosses derived from A/J and B6 mice identified a major locus on mouse chromosome 8 (Pchr/Char2) controlling the extend of blood-stage parasite replication. The Chr.8 interval contains several candidate genes, one of them being the macrophage scavenger (Scvr) locus encoding for the scavenger receptor type A (SR-AI/AII) expressed at the surface of monocytes and macrophages. The possible role of the SR-A in host defense, and particularly as a candidate for being Char2, was investigated. Sequencing of the coding region and immunoprecipitation of the receptors from A/J and B6 mice, as well as functional studies in transfected CHO cells showed that the B6 strain has a particular haplotype at the Scvr locus. Despite the fact that a link between differential function of SR-A and resistance/susceptibility to P. chabaudi AS was not established, results have shown that the conformation of B6 SR-A at the cell surface differ from one of the known haplotype. Novel loci regulating response to P. chabaudi AS infection were investigated using an alternative strategy based on a newly derived set of AcB/BcA recombinant congenic strains (RCS) bred from A/J and B6 strains. One of the AcB strains, AcB55, was shown to be highly resistant to infection despite having 83% susceptible A/J genomic composition, which includes susceptibility alleles at Char2. Linkage analysis in an informative (AcB55 X A) F2 population located a new resistance locus on chromosome 3 (Char4). Early onset of parasite clearance in AcB55 is associated with lower peak parasitemia and absence of mortality. Investigation of possible mechanisms mediating P. chabaudi AS resistanc
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.82874 |
| Date | January 2002 |
| Creators | Fortin, Anny |
| Contributors | Gros, Philippe (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Biochemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001973809, proquestno: AAINQ88469, Theses scanned by UMI/ProQuest. |
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