Les proprotéines convertases (PC) sont d’importantes enzymes impliquées dans l’activation par clivage de précurseurs protéiques dans la voie de sécrétion cellulaire et qui permettent la régulation de la physiologie animale. Toutefois, les PC ont un rôle particulier lors d’infections, puisqu’elles participent à la fois à l’activation de pathogènes et au contrôle de la réponse immunitaire qu’ils induisent. Cette thèse présente le développement d’un inhibiteur peptidique de PC à des fins thérapeutiques contre les pathogènes et se penche sur le rôle de PC1/3, une PC dite neuroendocrinienne, dans le contrôle de la réponse immunitaire au sein des macrophages. Dans un premier temps, l’inhibiteur de PC a été optimisé par peptidomimétique afin de bloquer l’activation de deux pathogènes activés par les PC, l’un viral et l’autre bactérien. Dans un second temps, l’utilisation de shRNA sur un modèle de macrophages en culture NR8383 et du modèle de souris où PC1/3 est inactivée ont permis de déterminer les conséquences physiologiques et moléculaires de l’inactivation de PC1/3 au sein des macrophages grâce au développement d’une approche par spectrométrie de masse. L’approche par spectrométrie de masse s’est avérée être un catalyseur dans cette recherche et a pu être appliquée à l’étude de tissus de patientes atteintes du cancer de l’ovaire, démontrant ainsi tous les avantages de cet outil. En somme, les résultats de cette thèse montrent la faisabilité d’inhiber les PC pour contrôler les infections et ouvrir de nouvelles perspectives sur le contrôle de l’immunité en établissant les bases moléculaires du rôle de PC1/3 dans le maintien de l’homéostasie immunitaire. / The proprotein convertases (PCs) are important enzymes mainly involved in the activation of protein precursors into the cell secretory pathway. This critical activation step that generates various biologically active polypeptides makes the PCs a cornerstone in a variety of biological process, including the neuroendocrine system. However, the PCs are described as very special players during infection, since they both activate various pathogens and control the immune response they induce. This thesis presents the development of a PCs peptide inhibitor for therapeutic purposes against pathogens and examines the role of PC1/3, which is mainly associated with the neuroendocrine system, in the control of the immune response in macrophages. As a first step, the PC inhibitor has been optimized by a peptidomimetic approach to block pathogens activation by PC for both a viral pathogen and a bacterial pathogen. In a second step, gene expression control tools have been used (shRNA) on a macrophage NR8383 cell line combined with the use of PC1/3 inactivated mouse (KO) to determine the physiological and molecular consequences of PC1/3 inactivation in macrophages by the mean of mass spectrometry approaches. The mass spectrometry approaches were proven to be a catalyst in this research and were further applied on ovarian cancer tissues studies, demonstrating the benefits of these tools. Overall, the results of this thesis demonstrate the feasibility of inhibiting PC to control infections and establish new avenues to modulate immunity by laying the foundations of PC1/3 molecular functions in the maintenance of immune homeostasis.

Those who are interested in the public mood, including politicians and economists, comment that the public are becoming ever more sceptical about many things, but health risk information should not be one of them. If health risk information is perceived by the public as ‘just another scary story’, or ‘more of the same we heard last month’, then the ability of risk messages to convey urgency and recommend action could be greatly diminished; the ‘cry wolf’ scenario becomes more real every time a threat appears in the media but fails to materialise. This thesis explores how avian influenza, (H₅N₁), as a health risk category, has been reported and represented in the New Zealand media. By analysing avian influenza-related items in four New Zealand newspapers over a six-year period, 2002-2008, and by comparing results with those found in a U.S. study by Dudo, Dahlstrom & Brossard (2007), this thesis explores the dominant themes and discourses the media drew upon when reporting the health threat of avian influenza. In addition, data from four focus groups sessions was analysed for the purpose of exploring public perceptions of health risk messages and the influence of the media on those perceptions. This thesis was situated within a constructionist epistemology, and employed a mixed-methods methodology with content, thematic and textual analyses. Risk communication theories and models, media conventions of agenda-setting and framing, and sociological concepts informed how the topic of health risk communication was operationalised. The analysis of the focus group data explored how the participants discussed the threat of H₅N₁; how they constructed concepts of personal and community risk, what role, if any, they attributed to the media in their construction and how they positioned themselves in regards to illness and contagion. The focus group analysis revealed that three dominant themes - risk, media and ‘othering’ – represented how the focus group participants talked about the risk of avian influenza. These and several sub-dominant themes shared similarities to those found in the newspaper analysis. Whilst initial discussions seemed to indicate a nonchalant attitude towards the risk of avian influenza, the many topics and themes that characterised the way the participants discussed the risk between them, showed that they had thought about the personal consequences of a possible health risk, and had formed strong opinions about many facets of that risk. Results from the newspaper analysis largely mirrored those of the above U.S. study, and showed that the New Zealand media favoured episodic over thematic framing; sensationalising the reporting of avian influenza, whilst providing little in the way of scientific and contextual information. Moreover, the analysis showed that, when reporting health risks, media templates are well established. The analysis of the focus group data revealed that the participants wanted media health risk messages to be clear, concrete and factual. However, this desire for messages that communicate certainty about risk, which is, by definition inherently uncertain, raises questions about the very nature of risk communication. Findings of this thesis suggest that future risk communication research should focus, not on how the media are reporting health risks, but how the public conceptualise risk, construct it in times of crisis and evaluate their ability to control it.