BPIFA1: from anti-viral peptide to immunomodulator

The respiratory tract is under constant attack from microbial invasion. The cells lining the respiratory tract have therefore evolved to secrete molecules that defend against infection. The BPIFA1 molecule is produced continuously in the respiratory tract of mammals. Using genetically modified mice that are unable to produce BPIAF1, we have shown that it helps defend against influenza A virus by inhibiting infection of cells lining the respiratory tract and also by helping the generation of immunity against influenza. BPIAF1 is therefore a critical factor in the response to influenza. The aims of this project are to:
1. Discover the precise way that BPIFA1 interacts with virus and inhibits infection of cells. This will involve making recombinant forms of BPIFA1 and measuring their effectiveness at blocking virus infection.
2. Discover exactly how BPIFA1 affects the immune response to influenza. This will involve comparing the progress of viral infection in genetically modified mice deficient in BPIFA1 with normal mice. The response of individual cells and components of the immune response will then be measured to determine the mechanism of action
3. Determine if BPIFA1 can improve influenza vaccination.

The results will significantly enhance our understanding of fundamental aspects of defence to virus infection as well as aspects of respiratory biology.
The research will be carried out at the Universities of Liverpool and Sheffield by a multi-disciplinary team comprising members of the Medical and Veterinary Faculties using well-equipped facilities currently situated at these sites.
In view of the recognised limitations of influenza virus vaccines understanding detailed mechanisms of action offers a very real alternative to address the need for "universal" influenza virus therapeutics, Importantly, understanding how BPIFA1 modulates the immune response to IAV may lead to the production of improved vaccination strategies

Defence proteins produced by epithelial cells are a critical component of the host response to respiratory infection. BPIFA1/SPLUNC1 is secreted into the mammalian respiratory tract. We have generated mice that are deficient in BPIFA1 that are apparently normal. We have used these mice to show that BPIFA1 plays a fundamental protective role during influenza A virus (IAV) infection. Thus, BPIFA1 are more susceptible to transmission and cannot generate efficient immune response to IAV leading to poor immunity from re-challenge.
We therefore hypothesise that BPIFA1 restricts IAV by binding to virus particles and enhances protection from re-infection by modulating the generation of the immune response in the respiratory tract. We will test these hypotheses using a complementary series of in vivo and in vitro assays. The application therefore has 3 specific aims:
1. Characterise how BPIFA1 restricts IAV infection to multiple IAV strains
2. Define how BPIFA1 modulates the immune response to IAV
3. Can BPIFA1 act as an adjuvant to the antibody response to IAV?

To fulfil these aims we will use mice deficient in BPIFA1, an in vitro air-liquid interface culture system based on these mice and recombinant BPFA1. The transgenic models will be infected with IAV and the mechanisms of BPIFA1 action will be elucidated using a range of virological and immunological assays

The results will significantly enhance our understanding of fundamental aspects of host responses to virus infection in the lung as well as respiratory biology. Importantly, understanding how BPIFA1 modulates the immune response to IAV may lead to the production of improved vaccination strategies

Respiratory virus infections are of global significance to both the human and animal populations. The zoonotic potential of influenza and the implications of emerging new strains are well recognised by both the scientific community and the general public. Improved understanding of the pathogenesis of infection and the host response to these pathogens is critical in improving treatment and management of respiratory disease and the associated morbidity and mortality. This work aims to further this understanding by looking at the role of BPIFA1 in the innate and adaptive responses of the host respiratory tract following infection with influenza virus.

The academic impact of this work therefore will be to further the knowledge of the host response to viral infection, providing the foundations of academic knowledge and understanding on which future advancements in treatment and disease control can be built. The use of the multi-disciplinary approach as proposed here brings together expertise in cell biology, molecular virology, immunology and veterinary pathology, thereby maximising the potential outputs of the research. This is also advantageous to the PDRA in providing the experience and training involving multiple fields fostering a multi-disciplinary approach and its advantages for enhanced, productive science as well as allowing them to develop a range of transferable skills that will enhance their career development. This is achieved by collaboration between the Liverpool and Sheffield sites.

Elements of the research will be applicable to novel vaccine design and immunotherapy and as such will be of interest to the pharmaceutical industry in terms of how to improve vaccine responses in the respiratory tract to influenza and other respiratory pathogens.

The societal impact of furthering the understanding of the host response to infection with Influenza virus on the health of the individual and the wider population is significant. Contribution to the improved treatment of individual high-risk patients where infection with Influenza virus has a higher morbidity and mortality than the general population, or increased understanding of the risk factors associated with epidemic strains, both are important in the future of prevention and control of Influenza infection, in both veterinary species and the human population.