A community-based case-control study was carried out in South London, to investigate the determinants of herpes zoster in adults without underlying immunosuppression. Incident zoster cases were identified from general practices. Two controls were selected per case, matched by age, sex, and practice. Participants were interviewed to determine exogenous contacts with varicella and with children as proxies for varicella contacts; ethnicity, country of birth and age at varicella; micronutrient Intake and intake of fruit and vegetables; ultraviolet radiation (UVR) exposure in childhood and in the last year, and stressful events. Odds ratios were estimated using conditional logistic regression. Data from 244 cases and 485 controls were analysed. On multi variable analysis, contacts with children significantly protected against zoster - most heavily exposed individuals were at one fifth the risk ofunexposed individuals, and this appeared to be mediated by increased exposure to varicella cases. Childhood UVR exposure was associated with a strongly increased risk of zoster. Individuals eating fresh fruit less than once a week were at a six- fold risk of zoster compared to those with highest intakes, and individuals aged >60 years with a high combined micronutrient intake were protected against zoster. Individuals experiencing an incident stressful event in the last two months were at more than twice the risk of zoster, and stressful events in the last year were associated with increased risk amongst elderly individuals. The protective effect of Afro-Caribbean ethnicity was mostly explained by increased child contacts and high fresh fruit intake. This study identified new risk factors for zoster. Those factors that were restricted to older individuals may also be determinants of immunosenescence. The findings suggest that widespread varicella vaccination ,of children could lead to increased incidence of adult zoster by decreasing exogenous varicella exposures. Other implications for future research and for public health policy are discussed

This thesis focuses on the trajectory of the biomedical concept of virulence from 1880 until the present. Following the concept across disciplinary boundaries, from a longue durée history perspective, it explores how virulence was shaped through two distinct, although sometimes overlapping, “styles of reasoning”. Located at the intersection of several distinct research domains in biology and medicine, the concept of virulence provides, in addition, a window into the complex and changing relations between evolutionary biology and the health sciences (broadly construed) over the past two centuries. Moving back and forth between field experiments and the laboratory, this work examines, through the lens of historical epistemology, the emergence of what I call the molecular and the ecological styles, and their respective conceptual practices. It focuses on the ways in which these styles operationalize the distinction between virulent or avirulent organisms in sometimes opposite sense: Whereas in the molecular (or endogenous) style the expression of virulence is explained by properties of internal structures of the infectious agent (e.g. polysaccharide capsule, virulence gene, or pathogenicity island), the concept of virulence in the ecological (or exogenous) style reflects, in contrast, either a lack of adaptation between two species (avirulence hypothesis) or the existence of one or more ecological compromises between, say, the mode of transmission of a pathogen and its host’s recovery rate (trade-off model). Both styles can be said to originate in the medical bacteriology of the late-nineteenth century, but while the former grew mostly out of the work of Louis Pasteur and Robert Koch in Europe, the latter was primarily shaped by Theobald Smith in the United States. Nearly a century later, the introduction of the category of emerging infectious disease within public health discourses in the mid-1990s facilitated a rapprochement between the two styles that had, so far, remained apart. Employing the 1918–1919 influenza pandemic as an example in which to illustrate the trajectory of the molecular and the ecological approaches, the diversity of explanatory schemes developed to account for the pandemic’s exceptional virulence points toward an unresolved, and yet productive, epistemic tension between the two styles, on the one hand, and the intrinsic polarity of the concept of virulence itself, on the other.

Le virus Nipah (NiV) est un Paramyxovirus zoonotique hautement pathogène, porté par les chauves-souris frugivores, qui a émergé en 1998 en Malaisie. Les épidémies liées à ce virus encéphalitogène continuent de se succéder en Inde et au Bangladesh avec une mortalité pouvant dépasser les 90%. Devant l’absence de traitement et de vaccin, le NiV a été placé parmi les pathogènes de classe 4 requérant le plus haut niveau de biosécurité pour sa manipulation. L’étude des interactions entre le virus et les cellules du sang nous a permis de montrer que le NiV utilise les héparanes sulfates présents sur les leucocytes pour s’accrocher et se disséminer dans l’organisme et atteindre les cellules endothéliales. L’héparine inhibe ce processus ainsi que l’infection in vitro et in vivo mettant en avant une perspective de traitement applicable dans les pays émergents. Par ailleurs, l’analyse transcriptomique des cellules endothéliales infectées par le NiV a révélé l’implication de chimiokines dans la pathogenèse. CXCL10 apparaît en effet comme un marqueur voir une cible dans le cadre du développement de l’encéphalite virale, et l’interféron type 1 comme l’un des facteurs essentiels de la résistance des souris au NiV. Enfin, j’ai montré que la protéine non structurale C du NiV joue un rôle essentiel dans sa virulence, en atténuant la réponse interféron, en perturbant la réponse chimiokine lors de l’infection et en intervenant dans le maintien de la balance génome / antigénome lors du cycle réplicatif viral. Ces résultats permettent une meilleure compréhension de la pathogenèse du NiV et ouvrent de nouvelles perspectives de traitement contre ce virus zoonotique très dangereux pour l’homme / Nipah virus (NiV) is a highly pathogenic zoonotic Paramyxovirus that emerged in 1998 in Malaysia from frugivorous bats. The outbreaks of this encephalitic virus still occur annually in India and Bangladesh with the mortality rate reaching up to 90%. The lack of an effective vaccine or treatment limits experimentation with live virus to specially equipped BioSafety Level 4 laboratories. Studies of the interaction between the virus and blood cells revealed that NiV uses Heparan sulfates to stick on the surface of leukocytes for its dissemination within the host and reach endothelial cells. Heparin provided de possibility to inhibit this mechanism of transinfection, such as the infection in vitro and in vivo, opening new perspectives of low cost treatment for emerging countries. Then, transcriptomic analysis of NiV infected endothelial cells revealed the importance of cytokine in the pathogenesis. While CXCL10 appears as a good marker of encephalitis, interferon type 1 explains why mice are resistant to the infection with NiV. Finally, we show the essential role of the non structural C protein of NiV in its virulence, by limiting the interferon response, unbalancing the chemokine response during the infection and through the regulation of the genomic/antigenomic balance during the viral replication cycle. These results shed new light on NiV related pathogenesis and open new perspectives of treatment against this highly lethal zoonotic virus