Title: Immune response to influenza
Funder: The Francis Crick Institute

Abstract: This programme focuses on host determinants of the early immune response to influenza. Widely documented determinants of the outcome of influenza infection include virulence of the infecting virus strain, and the host’s medical conditions or immune status. In contrast, no genetic determinants of resistance or susceptibility in naïve, healthy human hosts with intact immunity have as yet been identified. A major aim of this programme is therefore to determine mechanisms of how different host genetic backgrounds influence innate immunity to influenza infection, resulting in protection or pathogenesis. Since airway epithelia are the first and most important cell type infected by influenza virus, and their response likely determines the outcome of infection, we also characterise the signalling and transcription factor requirements for the epithelial anti-influenza response. These two distinct programmes converged to provide a more accurate and complete picture of the redundant functions of type I and type III interferon (IFN) systems in airway epithelia, which contrasts with the unique roles of type I IFN in immune cells, during influenza infection. This allowed us to resolve apparent contradictions regarding the role of type I and type III IFNs in protection and pathogenesis. One outcome with clinical relevance is that we predicted type III IFN to have fewer proinflammatory side effects than type I IFN and therefore to be superior as influenza therapy. We have shown this in in vivo infection models and have confirmed the response patterns in human primary airway epithelia and immune cells. We also aim to identify upstream regulators of type I IFN levels in influenza infection. We will test whether the determinants of severity we have found so far and novel ones we plan to identify, are relevant in human influenza. Since influenza – Streptococcus pneumoniae coinfection is an important factor of mortality in influenza epidemics and pandemics, we study this in an in vivo model and have identified protective and pathogenic factors in the immune response to coinfection. We will now explore in in vivo models the more general question of how previous infections induce long-term changes in the responsiveness to subsequent, unrelated infections. These models reflect the human situation of life-long sequential and overlapping microbial exposure and will help us to understand how the immune response evolves in the polymicrobial environment that characterizes the human condition. It is important that lung epithelia damaged during influenza are efficiently and timely repaired and re-differentiate, to guarantee the essential function of this organ throughout infection. We therefore explore factors promoting or suppressing epithelial maintenance and how they contribute to influenza protection or pathogenesis. The characterisation of these determinants of anti-influenza immunity may help devise better prevention and therapy of human influenza in the future.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM