INFLUENZA TROPISM

Evolutionary Determinants of Influenza Virus Pathogenesis and Tissue Tropism

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 Obiettivo del progetto (Objective)

'Influenza A virus bears high morbidity and mortality burdens in humans following yearly seasonal epidemics and occasional yet potentially devastating pandemics. These burdens are a result of disease severity following infection in individual hosts, and the size of influenza epidemics/pandemics at the population level. The relationships and feedbacks between influenza virus pathogenesis at the individual host level and influenza virus epidemiology at the population level are ill understood. Influenza virus tissue tropism contributes to determining which regions of the respiratory tract (from nasal cavity to deep lungs) are infected. The spatial location of influenza virus infection along the human respiratory tract is a determinant of the virus’ pathogenicity and transmissibility. While disease severity increases deeper down the respiratory tract, transmissibility appears favoured higher up. Both pathogenicity and transmissibility, associated with tissue tropism, contribute to the virus reproductive fitness, defining the size of the epidemic or pandemic. Therefore, strong selective pressures acting within hosts and at the population level likely shape tissue tropism to maximize influenza virus reproductive fitness. The aim of the project is to characterize these selective pressures and their interplay at the interface of within- and between-host dynamics, by combining experimental work and mathematical modelling. Key objectives are to determine the selective pressures associated with transmission and pre-existing immunity on influenza virus tissue tropism in an experimental setting; and determine the mutual interactions of these selective pressures by use of combined within- and between-host mathematical models. Modelling skills and knowledge will be transferred by the candidate to the European host. This project intends to clarify the cross-scale dynamics of influenza virus to better characterize and predict influenza morbidity and mortality burdens.'

Introduzione (Teaser)

Understanding how influenza virus evolves within its host is central to predicting the emergence and spread of new strains.

Descrizione progetto (Article)

Influenza A virus is responsible for annual seasonal epidemics but occasionally causes pandemics with devastating outcome. The virus is also capable of zoonotic infections, in other words, it gets transmitted from animals to humans.

Disease severity ranges from mild trachea-bronchitis to life-threatening pneumonia and depends on the regions of the respiratory tract that are infected. Virus localisation in the upper respiratory tract system is associated with high transmissibility while infection of the lower tract is usually more severe.

Overall, the reproductive fitness of the virus seems to define disease severity and hence influence the size of the epidemic or pandemic. Strong selective pressures acting within hosts and at the population level are responsible for this and eventually shape tissue tropism. The aim of the EU-funded INFLUENZA TROPISM (Evolutionary determinants of influenza virus pathogenesis and tissue tropism) project was to characterise these selective pressures.

The consortium worked under the hypothesis that transmission constraints and pre-existing immunity determine the tissue tropism patterns of this virus. This in turn drives the evolution of novel influenza virus variants. To validate this, scientists analysed the experimental evolution of influenza virus H1N1 taken from nose or lung in ferrets under different selective pressures.

Researchers found rapidly occurring changes in the tissue tropism of viruses passaged in the upper respiratory tract of ferrets. This was also associated with a more severe phenotype than viruses passaged in the lower respiratory tract of ferrets.

Pandemic viruses are faced with little pre-existing immunity compared to seasonal influenza viruses, which encounter significant immunity. Researchers investigated the tropism patterns of pandemic influenza viruses and their seasonal descendants in experimental ferrets. They found that pandemic influenza viruses caused a more severe phenotype than their seasonal descendants clearly indicating that herd immunity acts as a strong selective pressure. These observations were validated through mathematical modelling approaches capable of predicting the evolution of influenza virus tissue tropism.

The INFLUENZA TROPISM study findings could be exploited to support measures and policy decisions for alleviating the public health threat continuously posed by influenza A viruses.