A Genetic Analysis of Two Strains of Plasmodium chabaudi adami that Differ in Growth and Pathogenicity
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Date
2008Author
Gadsby, Naomi Jane
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Abstract
Malaria is still a significant public health problem in the Tropics, with an estimated
200 million cases a year and more than 1 million deaths, mostly in young children in
sub-Saharan Africa. Plasmodium falciparum is the parasite responsible for the
majority of the morbidity and mortality due to malaria. We know from the historical
use of malaria to treat neurosyphilis that there were several different strains of P.
falciparum, some of which were more pathogenic and had higher multiplication rates
than others. High multiplication rates of P. falciparum isolates have been associated
with severe disease in Thailand, but not in Kenya or Mali. In determining what
differences exist between fast- and slow-growing malaria parasites, and
understanding their relationship with clinical outcome, we may discover a way of
targeting those parasites that cause most disease.
This thesis describes a genetic analysis of the determinants of growth and
pathogenicity in the rodent malaria parasite, Plasmodium chabaudi. The use of
rodent malaria parasite strains for genetic analysis has several experimental, ethical
and financial advantages over the use of human malaria parasites. In addition, rodent
malaria parasite strains also vary significantly in their growth and pathogenicity,
making them excellent candidates for a genetic analysis of these characteristics. The
first section of this thesis is concerned with the characterisation of the growth,
pathogenicity and transmissibility of two strains, DS and DK, of the rodent malaria
parasite P. c. adami. The DS strain is fast-growing, pathogenic, non-selective in its
invasion of red blood cells and a poor transmitter to mosquitoes. The DK strain is
slow-growing, non-pathogenic, selective in its invasion of red blood cells and a good
transmitter to mosquitoes. In the second section of this thesis is a detailed study of
the growth characteristics of DS and DK in mixed infections, relative to their growth
in single infections. Both sections provide information relevant for the main
objective of this thesis, but also contribute to the body of work on pathogenicity and
transmissibility, and pathogenicity and strain behaviour in mixed infections, which
has been carried out in rodent malaria parasites to-date.
The third section of the thesis contains the results of a genetic analysis of the
difference in growth between P. c. adami strains DS and DK, using the Linkage
Group Selection (LGS) technique. On several occasions, DS and DK were crossed in
the mosquito vector and, following selection for fast growth in mice, the cross
progeny were initially screened with genome-wide, quantitative AFLP markers.
Markers specific to the slow-growing parent DK which were greatly reduced in
intensity after selection were found on P. chabaudi chromosomes 6, 7 and 9. This
result suggests that the difference in growth between the two strains is determined by
multiple genetic loci. The selection on chromosomes 7 and 9 was then looked at in
greater detail, using SNP-based markers quantified by Pyrosequencing™. It was
found, consistently, that a region at one end of DS chromosome 9 was inherited as a
single, non-recombining unit in cross progeny selected for fast growth. As this was
the region most strongly selected against, it suggests that a gene (or genes) in this
region has a major role in the determination of growth characteristics, and therefore
pathogenicity, in P. c. adami. Narrowing down this region further, in order to
identify the candidate gene(s), remains a key future objective.