In this thesis, mechanisms of immunoregulation by CD4$ sp+$ T cells during blood-stage P. chabaudi AS infection in C57BL/6 mice were studied. The kinetics of in vitro production of the Th1-derived cytokine, IFN-$ gamma$, versus the Th2-derived cyokines, IL-4, IL-5 and IL-10, by spleen cells as well as of polyclonal and malaria-specific antibodies in the sera were examined during infection using enzyme-linked immunosorbent assays. Upon antigenic stimulation, spleen cells were found to produce high levels of IFN-$ gamma$ several days prior to peak parasitemia, while high levels of IL-10 production occurred at the time of peak parasitemia followed by IL-4 and IL-5 later in infection. The levels of polyclonal IgG2a isotype were found to be increased during both the acute and chronic phases of infection, whereas the levels of polyclonal IgM, IgG1 and IgG2b isotypes were found to be increased only during the chronic phase of infection. High titers of malaria-specific IgG2a and IgG1 were detected during the primary as well as secondary infections. Investigation of in vitro proliferation of spleen cells to mitogens and malaria specific antigen revealed that the responses of splenic lymphocytes from infected mice to Con A, PHA and LPS were suppressed, with the most severe suppression occurring during the first 14 days post infection. Evidence is provided demonstrating that nitric oxide (NO) and prostaglandins (PG), products of activated macrophages, mediated suppression of lymphocyte proliferation in response to Con A and PHA, whereas only PG were found to suppress LPS-stimulated proliferation. In addition, NO was found to mediate suppression of proliferation of spleen cells from infected mice in response to parasite antigen. Taken together, results from these studies suggest that immune activation and immunosuppression occur simultaneously during blood-stage malaria with P. chabaudi AS infection in C57BL/6 mice. (Abstract shortened by UMI.)

<p>Malaria remains the most important parasitic disease worldwide. It is estimated that over 500 million infections and more that 2.7 million deaths arising from malaria occur each year. Most (90%) of the infections occur in Africa with the most affected groups being children of less than five years of age and women. this dire situation is exacerbated by the emrggence of drug resistant strains of Plasmodium falciparum. The work reported in this thesis focuses on improving the purification of PfHPRT by investigating the characteristics of anion exchange DE-52 chromatography (the first stage of purification), developing an HPLC gel filtration method for examining the quaternary structure of the protein and possible end stage purification, and initialcrystalization trials. a homology model of the open, unligaded PfHPRT is constructed using the atoomic structures of human, T.ccruz and STryphimurium HPRT as templates.</p>

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Malaria remains the most important parasitic disease worldwide. It is estimated that over 500 million infections and more that 2.7 million deaths arising from malaria occur each year. Most (90%) of the infections occur in Africa with the most affected groups being children of less than five years of age and women. this dire situation is exacerbated by the emrggence of drug resistant strains of Plasmodium falciparum. The work reported in this thesis focuses on improving the purification of PfHPRT by investigating the characteristics of anion exchange DE-52 chromatography (the first stage of purification), developing an HPLC gel filtration method for examining the quaternary structure of the protein and possible end stage purification, and initialcrystalization trials. a homology model of the open, unligaded PfHPRT is constructed using the atoomic structures of human, T.ccruz and STryphimurium HPRT as templates. / Magister Scientiae - MSc

Malaria and tuberculosis together account for more than 2 million deaths worldwide each year. The present body of work examines interactions between these leading pathogens and cross-cutting themes in innate immunity to both diseases. Not only are malaria and tuberculosis important threats to public health in their own right, but malaria-tuberculosis co-infection appears to generate more severe pathology than either disease on its own, and malaria may exacerbate primary or re-activation tuberculosis (Chapter 2). Moreover, both diseases appear to share common host defense pathways, including CD36, a macrophage cell surface receptor important for innate immunity (Chapter 3). Biomarkers of host defense pathways common to both malaria and tuberculosis distinguish between clinical disease phenotypes and predict mortality in severe malaria (Chapters 4-7). Biomarker discovery led to the identification of angiopoitetin-2 (Ang-2) as a surrogate marker of disease severity in malaria and a potential therapeutic target. Nitric oxide, in addition to its antimycobacterial properties, is known to inhibit Ang-2 release from the endothelium, and is therefore hypothesized to improve outcomes in African children with severe malaria (Chapters 8 and 9). A broad range of methods are applied to address these diseases and their interactions, ranging from mammalian cell culture experiments in vitro, animal models of disease, analysis of human samples, and clinical epidemiology (randomized controlled trial). Translational aspects of this research are emphasized, outlining how advances in understanding of infectious disease pathogenesis can be applied to improved diagnosis, prognosis, and novel adjunctive therapies for two of the leading global infectious threats.

Malaria and tuberculosis together account for more than 2 million deaths worldwide each year. The present body of work examines interactions between these leading pathogens and cross-cutting themes in innate immunity to both diseases. Not only are malaria and tuberculosis important threats to public health in their own right, but malaria-tuberculosis co-infection appears to generate more severe pathology than either disease on its own, and malaria may exacerbate primary or re-activation tuberculosis (Chapter 2). Moreover, both diseases appear to share common host defense pathways, including CD36, a macrophage cell surface receptor important for innate immunity (Chapter 3). Biomarkers of host defense pathways common to both malaria and tuberculosis distinguish between clinical disease phenotypes and predict mortality in severe malaria (Chapters 4-7). Biomarker discovery led to the identification of angiopoitetin-2 (Ang-2) as a surrogate marker of disease severity in malaria and a potential therapeutic target. Nitric oxide, in addition to its antimycobacterial properties, is known to inhibit Ang-2 release from the endothelium, and is therefore hypothesized to improve outcomes in African children with severe malaria (Chapters 8 and 9). A broad range of methods are applied to address these diseases and their interactions, ranging from mammalian cell culture experiments in vitro, animal models of disease, analysis of human samples, and clinical epidemiology (randomized controlled trial). Translational aspects of this research are emphasized, outlining how advances in understanding of infectious disease pathogenesis can be applied to improved diagnosis, prognosis, and novel adjunctive therapies for two of the leading global infectious threats.