DiMeN Doctoral Training Partnership: BPIFA1: from anti-viral peptide to immunomodulator

Seasonal influenza is a major cause of respiratory infection resulting in substantial morbidity, mortality and economic burden worldwide. Pandemic influenza emerges sporadically and are a substantial global health concern. There are vaccines and antiviral drugs to combat influenza. However, due to rapid virus evolution, vaccines need to be re-formulated and re-administered annually with associated economic cost. For instance, the UK spent £1.24 billion preparing for and responding to the 2009 pandemic. It is therefore important to understand how host mechanisms modulate influenza virus infection and how these may be used to develop novel therapeutic interventions. This is particularly important in the elderly, where a decreased response means annual influenza vaccination is less effective in this age-group

The airway epithelium has a fundamental role in the defense against pathogens and secretes proteins/peptides that function in innate and adaptive immunity. BPIFA1 is a protein that is secreted into the airways. The supervisory team (virologist, respiratory biologist and immunologist) in collaboration has shown that BPIFA1 is an anti-viral peptide, restricting influenza A virus infection of cells (Mucosal Immunology, Published online in advance of print. DOI:10.1038/mi.2017.45). Also, BPIFA1 promotes the antibody response to influenza infection and therefore protection from re-infection. Vaccination against influenza relies upon the generation of high titre antibodies.

Combining in vitro and in vivo approaches we will determine whether BPIFA1 can enhance (act as an adjuvant to) the antibody response to influenza vaccination and so improve protection to transmission and severe clinical disease.
There are 3 specific aims:
1. Can BPIFA1 increase the antibody response to influenza A virus?
Recombinant BPIFA1 will be used with influenza vaccines in mice to measure increases in anti-influenza antibody and T cell responses and increased protection against infection/transmission. With our industrial partner, BPIFA1 and/or vaccine will be combined with ProSilic drug delivery technology to see if controlled release enhances the efficacy. Multiple strains of influenza virus will be used to assess protection against heterologous virus strains. We will also perform pathological analyses to see whether administration of BPIFA1 has any consequences in terms of adverse pathology on the mice before and after challenge.
2. Does the effect of BPIFA1 alter with ageing or predispose to disease.
To address this, we will use human nasopharyngeal aspirate samples, stratified by age to determine if the level of BPIFA1 decreases with age and whether it correlates with susceptibility to disease. This will be replicated in young and aged mice. We will also determine if BPIFA1 can positively enhance vaccine responses to influenza A in aged mice as in aim 1 above.
3. Does BPIFA1 alter the uptake by antigen-presenting cells

To understand mechanism, we will model the human airway using in vitro 3D air-liquid interface cultures. We will add dendritic cells to these, infect with influenza and look at the uptake of virus before and after the knockdown of BPIFA1 and with or without the use of ProSilic. We will also examine the phenotype of dendritic cells that take up virus, and whether BPIFA1 can enhance presentation of influenza proteins to CD4 and CD8 T cells

The results will significantly enhance our understanding of anti-viral defence, the inflammatory response during IAV infection and inform the generation of novel vaccines.