Development and characterization of an immunodeficient mouse model for {\it Plasmodium falciparum\/} malaria

Human malaria remains a serious health threat in many tropical regions of the world, despite decades of research aimed at controlling this disease. While animal models of malaria have been indispensable in expanding our knowledge of the genus Plasmodium, there are limits to which observations in these systems can be extrapolated to human malaria. The development of a murine model for falciparum malaria will greatly enhance our ability to study the pathophysiology of this infection and will facilitate the pretesting of candidate drugs and vaccines.^ The focus of this dissertation was to develop such a model. A primary requirement for maintaining Plasmodium falciparum, as well as other human-infecting malarial parasites, is human red blood cells (hRBCs). Unlike other strains of immunodeficient mice, non-obese diabetic scid/scid (NOD/LtSz-scid) mice were found to be well-suited to long term maintenance of hRBCs in the vascular circulation.^ To test whether these mice could support the growth of Plasmodium falciparum, parasites which were adapted to the mouse physiology by in vitro growth in the presence of ascitic fluid from SCID mice were injected intraperitoneally (IP). With daily, supplemental, IP boosts of uninfected hRBCs, parasites could be detected in the peripheral circulation of NOD/LtSz-scid mice up to forty days post-injection. Splenectomy of NOD/LtSz-scid mice increased both the level and duration of parasitemia in the periphery and, in some cases, promoted the circulation of sexual stage parasites. These gametocytes were found to be transmittable and infectious to blood feeding mosquitoes.^ Lack of long term persistence of parasites in the peripheral circulation implicated IP maintenance as an important factor in this model and may limit its utility. It was also found that there is considerable mouse to mouse variability in the ability to support parasites; phagocytic cells, as well as other physiologic parameters, are likely to be responsible.^ Despite these drawbacks, the model holds great promise, and with further development, could have great utility in vaccine and anti-malarial drug development.