Replication of influenza virus at the molecular level

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The fundamental aim of this proposed research programme is to develop a much deeper understanding of the molecular and cell biology of influenza viruses, allowing the development of novel strategies to combat influenza. Influenza viruses are a major contributor to disease and death in humans, and with their ability to cause yearly epidemics and occasional pandemics they represent a considerable burden to healthcare systems globally. The most devastating influenza pandemic, the 1918 "Spanish" flu, caused over 50 million deaths worldwide. Wild birds represent an important reservoir for influenza A viruses from which novel pandemic strains can emerge. Currently the H5N1, H7N7 and H9N2 subtypes are considered the biggest threats as these are prevalent in birds and can infect humans directly. Although these viruses lack the ability to transmit between humans, they can cause severe disease and death. The concern is that these viruses, through adaptation or by mixing with other virus subtypes, could gain the ability to easily transmit between humans and lead to a new pandemic. Although vaccines against seasonal influenza and a very limited number of antiviral drugs are available, we are surprisingly defenceless against emerging pandemic influenza viruses. To prepare a vaccine matching a pandemic strain could take several months and resistance to drugs is an increasing problem. Therefore novel strategies for the control of influenza need to be developed. The focus of the proposed research programme is the transcriptional machinery of influenza virus, a complex of several proteins which is responsible for copying the genetic information of the virus in a host cell. The genetic information of influenza virus is stored in segments of RNA. These need to be copied into messenger RNA (transcription) to be translated into viral proteins, as well as replicated to produce new copies of the genome. These new copies are then assembled with viral proteins to be incorporated into new virus particles that are released from the host cell to initiate new cycles of viral reproduction. Interestingly, transcriptional machineries of influenza viruses that infect birds tend to work poorly in human cells. When "bird flu" transmits to humans the machinery usually undergoes changes to become adapted to its new host. In other words, the transcriptional machinery of an influenza virus can determine which host the virus could infect, and can also determine the severity and the outcome of the disease caused.Although the viral transcriptional machinery performs essential functions in a host cell-specific manner without which the virus cannot survive, we do not understand how this machine works at the molecular level or how the host cell's species (whether bird or human) affects its function. We therefore wish to determine the molecular mechanisms used by the viral transcriptional machinery to transcribe and replicate the viral genome, and the molecular interactions between the viral transcriptional machinery and the host cell. This research programme will help to understand the molecular basis of virulence, host range restriction and adaptation of influenza viruses to new hosts. It will therefore allow a better understanding of the emergence of strains with pandemic potential. Importantly, it will underpin the development of novel antiviral strategies by indentifying targets for antiviral drugs in the viral transcriptional machinery as well as in cellular proteins. It could also facilitate the development of novel influenza vaccines, offering protection against a wide variety of influenza virus strains. Any emerging information during the course of the programme will be exploited, potentially with the involvement of industrial partners.