Long term changes in lung immunity induced by influenza infection

Abstract

Influenza A virus (IAV) is an extremely relevant human pathogen, infecting ~10% of the global population annually. Although most of the infected individuals merely experience transient disease, the effect on the lung environment may be more prolonged. The aim of this thesis was to study persistent consequences of this common viral infection, which may include an altered responsiveness to unrelated pathogens. This was achieved by the characterisation of the lung, and challenge of mice with an antigenically distinct pathogen at one-month post-influenza infection. Initially, we demonstrated that mice displayed an increased protection to the bacteria Streptococcus pneumoniae after recovery from influenza infection. This was accompanied by a significant increase in the number of alveolar macrophages (AMs) in post-influenza lungs. Influenza-experienced macrophages were demonstrated to be central to protection, as their adoptive transfer could confer protection to naïve mice. Despite minimal differences between these cells at the steady state, AMs isolated from post-influenza lungs produced >10fold higher amounts of cytokines from secondary genes (IL-6, CSF3), but equivalent amounts of cytokines from primary genes (TNFα, CXCL1). Next, we developed a chimeric mouse model in which the origin of AMs could be characterised. Using this approach, we determined that alveolar macrophages were partially comprised of monocyte-derived cells, following their depletion and replenishment during acute influenza. Monocyte-derived macrophages were exclusively responsible for the increased production of IL-6 post-influenza, and were required for the subsequent protection against S. pneumoniae infection. This work demonstrates prolonged consequences of a single exposure to a transient viral infection, and provides in vivo evidence for a sustained altered responsiveness in innate immune cells, as a consequence of their origin. This phenomenon has major implications for humans, who are exposed to multiple respiratory infections, both simultaneously and sequentially