Abstract
Despite the prevalence and clinical importance of influenza, its long-term effect on lung immunity is unclear. Here we describe that following viral clearance and clinical recovery, at one month post-influenza, mice are better protected from Streptococcus pneumoniae infection due to a population of monocyte-derived alveolar macrophages (AMs) which produce increased IL-6. Influenza-induced monocyte-derived AMs have a surface phenotype similar to resident AMs but display a unique functional, transcriptional and epigenetic profile which is distinct from resident AMs. In contrast, influenza-experienced resident AMs remain largely similar to naive AMs. Thus, influenza changes the composition of the AM population to provide prolonged antibacterial protection. Monocyte-derived AMs persist over time but lose their protective profile. Our results help to understand how transient respiratory infections, a common occurrence in human life, can constantly alter lung immunity by contributing monocyte-derived, recruited cells to the AM population.
Highlights
Influenza A virus is a common respiratory pathogen that infects 10% of the global population annually
This study shows a profound impact of monocyte legacy in the transcriptional profile and chromatin accessibility of recruited alveolar macrophages for an extended period after resolved influenza infection, which offers a molecular explanation for the functional responses of these cells
Recruited alveolar macrophages (AMs) have a similar surface phenotype to resident AMs, but differ in their functional, transcriptional and epigenetic profile which is beneficial during S.p. infection
Summary
Influenza A virus is a common respiratory pathogen that infects 10% of the global population annually. Most humans will experience influenza once or several times over their lifetime, as one of many diverse respiratory infections. While prior infections play a crucial role in maturation and memory of adaptive immunity, examples of sustained changes in innate immune cells have been demonstrated[1,2,3]. It is largely unclear by which mechanisms prior infections confer such a long-term imprint in the lung. We established a model to study the long-term consequences of influenza on lung immunity, including the response to an unrelated pathogen, to investigate infectious disease in a setting that more closely resembles the human situation of sequential polymicrobial exposure
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