Influenza is a leading cause of respiratory disease worldwide. During pandemic and seasonal influenza, secondary Streptococcus pneumoniae infection is a severe complication that contributes to morbidity and mortality. With the clinical significance of this co-infection, it is imperative to understand the disease mechanisms and how our immune system would be modulated in dealing with the dual infection. First, in vivo co-infection model was established. Mice were sequentially infected with influenza virus and then Streptococcus pneumoniae. Co-infected mice lost their body weight significantly and had 100% mortality, whereas mice infected with either influenza virus or pneumococcus alone lost their body weight transiently and all recovered from the infection. Then, lung inflammatory response during the co-infection was examined. Although it is a common phenomenon that co-infection enhances inflammation, the kinetic of, and the relative contribution of influenza virus or pneumococcus to the lung inflammation is not well defined. Therefore, this study characterized the general lung inflammatory environment after co-infection. It was found that influenza virus and pneumococcus differentially modulated inflammatory response in terms of kinetics, leukocyte infiltration and cytokine production. At the early time point after co-infection, pneumococcal infection contributed more than the influenza virus infection to enhance inflammatory cytokine and neutrophil infiltrating the lung. At the later time point after co-infection, both influenza virus and pneumococcus contributed to synergistically increase inflammatory cytokine and macrophage infiltrating the lung. Influenza virus infection induced IFN-γ that contributed to the elevated IFN-γ level in co-infected mice. Influenza virus and pneumococcus synergistically increased Th2 associated cytokine including IL-4, IL-5, and IL-10. These up-regulated immune responses might contribute to the severe lung pathology. Next, adaptive immunity to co-infection was examined. Literature studying co-infection often reports how prior influenza virus infection impairs the immune response against subsequent bacterial infection. However, whether and how secondary pneumococcal infection would affect the immunity to the initial influenza virus is unknown. Therefore this study investigated the modulation of immunity to influenza virus by secondary pneumococcal infection. It was found that co-infection significantly enhanced virus titer in lung and depleted the number of cell in spleen. Secondary pneumococcal infection after influenza decreased influenza virus specific IgG in the lung and peripheral blood. The reduced level of virus specific IgG was associated with the decrease in the number and the percentage of follicular B cell and CD4 T follicular helper cell through both pneumococcal capsular polysaccharide dependent and independent manner. Treating co-infected mice with immune serum containing influenza virus specific IgG successfully improved survival, which suggested the important protective function of virus specific IgG to the co-infection. Taken together, these data suggested that secondary pneumococcal infection impairs the antibody response to influenza virus, which might enhance mortality after co-infection. In conclusion, this study provides new insight to understand the pathogenesis of co-infection, reveals the general lung inflammatory environment, highlights the negative role of pneumococcus to impair virus control and explores novel treatment for the co-infection. / published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Schizophrenia and autism are psychiatric disorders with a presumed neurodevelopmental origin, characterised by clinical features and aetiologies that overlap at multiple levels. In addition to genetic susceptibility, epidemiological studies revealed an association between environmental factors and these disorders. Immune activation in response to infection at early gestation has been identified as one of the key risk factors. Little is known about the underlying mechanism during maternal immune activation (MIA), but extrinsic apoptotic dysregulation has been postulated to play a role in MIA infection. In particular, emerging studies suggest apoptosis without triggering whole cell demise, namely synaptic apoptosis, is a potential event that leads to the abnormal behaviours in the affected offspring. In this study, C57BL/6N mice model was employed to investigate the impacts of viral mimetic polyriboinosinic-polyribocytidylic acid (Poly I:C) exposure at gestation day 9 in the resultant male offspring in adulthood in vivo by different parameters, including magnetic resonance imaging (MRI), behavioural tasks that assess sensorimotor gating, exploratory and anxiety behaviours, and protein quantification in the apoptotic pathway. In parallel, the direct effect of Poly (I:C) treatment for 24 hours on extrinsic apoptotic proteins were determined in primary cortical neurons in vitro. It was hypothesised that MIA would result in brain volumetric changes subsequent to behavioural anomalies in the adult offspring with maternal exposure to Poly (I:C), for which abnormalities are normally pronounced by that time. In addition, the hypothesis that foetuses exposed to Poly (I:C) in early gestation stage would have increased expression level of apoptotic proteins of extrinsic types, namely Fas receptor, caspase-8 and the death effector caspase-3. This study found that, although male adult offspring with early maternal exposure to Poly (I:C) had an increase in raw whole brain volume, this was not significant when body weight was included as a covariable. However, prenatal exposure caused behavioural features similar to those reported in schizophrenia and autism such as prepulse inhibition deficits, increased anxiety-level and higher locomotor activity in response to amphetamine challenge. On the other hand, a marked augmentation in caspase-8 level without any significant changes in Fas or caspase-3 was observed in the adult hippocampus. No alterations in the expression of selected apoptotic proteins were found in the embryonic cortical cells. Overall the present studies suggested that acute exposure to infection during early fetal development causes a range of aberrations in brain anatomy, behaviour and biochemistry that are of relevance to the pathophysiology of schizophrenia and autism. The results suggest a potential involvement of synaptic apoptosis in cellular events underlying neurodevelopmental disorders. / published_or_final_version / Psychiatry / Master / Master of Philosophy

published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

A dissertation submitted to the Faculty of Science University of the Witwatersrand Johannesburg, in fulfilment of the requirements of the degree of Master of Science 14 February 2017. / Spirooxindoles are an important class of spirocycles in organic and medicinal chemistry. They are characterised by a spiro-ring fused with the oxindole scaffold and have a wide range of biological activity. We are particularly interested in spirooxindoles because of their antimalarial activity. Malaria is a major health problem in many parts of the world and the burden caused by the disease is still of great concern. In 2015 alone, an estimated 438 000 deaths due to malaria were reported across the world, with 90% of the deaths occurring in Africa. The increase in drug resistance to currently used antimalarial agents has rendered most of them ineffective, thereby contributing to the high mortality rates. As a result, there is a need for the development of new effective antimalarial agents. In the search for a new class of antimalarial chemotypes, cipargamin, introduced as NITD609 by norvatis in 2010 was synthesised. This compound is a novel synthetic antimalarial candidate, with an IC50 of ~1 nM against P. falciparum strains, including multi drug-resistant strains. Previously in our laboratory, several spirooxindole derivatives were synthesised using an imino Diels-Alder reaction, also known as the Povarov reaction. Of all the compounds synthesised, only those derived from a para-substituted aniline displayed activity in the low micromolar range (~5μM) against P. falciparum in vitro. In this project, we aimed to further explore the antimalarial activity of these compounds by designing and synthesising ring-opened analogues. The analogues were successfully synthesised by a Grignard addition reaction using N-Boc protected arylimines as electrophiles. Despite several attempts, we were unable to remove the Boc-protecting group in the final step. The second series of compounds we aimed to synthesise were ring closed analogues lacking one aromatic ring. The compounds were synthesised starting from an imine condensation reaction between benzyl protected isatin with para-substituted 2-allyanilines. The 2-allylanilines were prepared by subjecting N-allylanilines to an aza-Cope rearrangement. The arylimines prepared were then subjected to a nucleophilic Grignard addition reaction with commercially available vinylmagnesium bromide to yield the intermediate necessary for the ring closure step. Unfortunately, the nucleophilic addition reaction was unsuccessful. The ring-closure step is very crucial during the synthetic route as it gives rise to the desired ring closed analogues via ring-closing metathesis. Although we were unable to reach the final step in the synthesis of ring-closed analogues, some progress was made in developing methodology for the synthesis of these analogues. The synthesised ring-opened analogues were screened for antimalarial activity against P. falciparum in vitro. Six hit compounds were identified from the series of compounds tested with tert-butyl 3-(2,4-dichlorophenethyl)-2-oxo-3-(p-tolylamino)indoline-1-carboxylate 60 being the most active compound in the series with an IC50 value of 0.60 nM against the FCR 3 Strain. In general, compounds derived from p-toluidine displayed the most potent activity. / MT2017

Typescript (photocopy) / xiii, 192 leaves, [44] leaves of plates : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--Dept. of Medicine, University of Adelaide, 1980

viii, 122 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1974

211 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1975

135 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, Dept. of Microbiology, 1978

2v. : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D. 1979) from the Dept. of Obstetrics and Gynaecology, University of Adelaide

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