The structure and function of the human respiratory syncytial virus M2-1 protein and its critical interaction with viral cofactors

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Human respiratory syncytial virus (HRSV) is responsible for an extremely common respiratory disease, with most humans on earth being infected at least once before they reach the age of 2. In most adults, the disease is not life threatening. However, in the very young, the elderly and the immunocompromised, HRSV infections often require hospitalization and can be fatal. Recent studies suggest that each year HRSV is responsible for over 34 million lower respiratory tract infections and between 66,000 and 199,000 deaths. In addition, HRSV infection early in life may contribute towards increased incidence of asthma later in adulthood, which affects over 5 million people in the UK alone. There is no HRSV vaccine, and the only current option for preventing HRSV disease is to give vulnerable people repeated injections of a drug called palivizumab. However, this treatment is only moderately effective and is prohibitively expensive, therefore new treatments to combat HRSV disease are required. The experiments described in this proposal will identify several critical weaknesses in HRSV that will allow new drugs to be developed to prevent HRSV disease.HRSV is made of several different building blocks called proteins that must fit together very precisely in order to do their specific job. One of these building blocks is known as the M2-1 protein, and previous work has shown that it must interact with other pieces of the virus in order for HRSV to multiply. These interactions include: (1) interactions with the viral genetic material, (2) interactions with other copies of the M2-1 protein, and (3) interactions with another virus protein called P. The interactions occur because the shape of these individual components allows them to fit together very precisely, just like pieces of a very complicated jigsaw puzzle. The aim of this grant is to determine the shapes of the individual components in very high detail. By doing so, we will be able to design drugs that will interfere with the interaction and therefore prevent the virus from growing and causing disease.To do this work accurately, we will use a technique called X-ray crystallography, which will allow us to determine the precise shape of the N protein in three dimensions. This technique will reveal all the tiny clefts and crevices that allow these interactions, and critically, it will how us how this interaction could be blocked.