Influenza A virus in natural and artificial environments

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Microbiology, Tumor and Cell Biology

Sammanfattning: Influenza is caused by influenza A virus, a single stranded RNA virus of the orthomyxoviridae family. In humans, it causes yearly outbreaks with high morbidity and excess fatality rates as a direct effect. Placed in its ecological niche however, in dabbling ducks, avian influenza virus (AIV) induce quite mild disease. It is when the virus crosses the species barrier that pathogenic traits are attributed to infection. Also infection of close relatives to dabbling ducks, the domestic chicken, cause morbidity and may in some cases change the virus into a highly pathogenic variant with nearly 100% fatality rate. Being a very adaptable virus, these spill-over events are frequent, and numerous species are susceptible to influenza virus. When a subtype of influenza which has not previously infected humans crosses the species barrier, adapts to humans and spread easily, a pandemic event is imminent. There is no cure for influenza infection, and vaccination is a cumbersome endeavor, so currently the strategy when a pandemic strikes is damage control. In this thesis, I have been involved in a surveillance project, to increase our knowledge of how influenza travels across the globe with its natural host. We have also used animal models to investigate the pathological effects in mallard ducks and their susceptibility to re-infection. Furthermore, we have evaluated the effect and the potential risk of frivolous use of the anti-viral agent oseltamivir, and also investigated a novel approach to the classic virus isolation method of growing virus in embryonated chicken eggs (ECE s). Indication was found in northern Alaska that prevalence of influenza is probably not lower here than in other breeding areas for dabbling ducks, as has been previously suggested. As these birds travel over the Bering Strait, the reason for the genetic isolation of Eurasian and North American influenza A strains remains unclear. Inoculation of mallards equipped with subcutaneous data transmitters indicated very little effect on the host and no stress above background level, and all birds gained weight throughout the trial. Only in four of six birds (65%) could a small temperature increase related to infection be recorded. However, more studies in a natural environment need to be conducted, to discern whether this variable is associated with an ecological cost as the captive trial ducks had access to food ad libitum. The most commonly used anti-viral drug, oseltamivir, is poorly degraded in sewage plants and surface water, where dabbling ducks forage. Extensive use of the drug thus increases environmental levels of the active metabolite, oseltamivir carboxylate (OC). We show that mallards inoculated with A/H1N1 in an OC enriched environment generates resistant virus sporadically at OC level found today. Higher level of OC caused the resistant subspecies to dominate the virus population, which is not desirable in the influenza reservoir. An introduction of a OC-resistant pandemic virus to the human population would render the only antiviral defense toothless. Isolation of influenza virus is traditionally performed by inoculation of infectious material into embryonated chicken eggs. As the chicken host is known to induce changes in AIV, we compared isolating and passaging two viruses both in ECE s and embryonated mallard eggs. Both egg species induced mutations in the primary passage, with no furthers changes in subsequent passages. Only in ECE s did one virus maintain wild-type configuration before one mutation was observed. Mallard eggs can based on these results not be advocated as preferable to ECE s when isolating and passaging AIV.

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