Impact of Monocyte Age on Influenza A Virus‐induced Lung Injury

Abstract

RationaleInfluenza A virus (IAV) causes more life‐threatening infections in healthy children than in healthy adults. In our mouse model of juvenile IAV infection, juvenile mice clear the virus at the same rate as adult mice, but develop more severe lung injury and have increased mortality compared to adult mice. We previously found that the monocytes recruited to the lungs during IAV infection exhibited a more inflammatory phenotype in juvenile mice than in adult mice. These juvenile monocytes exacerbated IAV‐induced lung injury in juvenile mice, and inhibition of their recruitment protected juvenile mice from IAV‐induced lung injury without impacting viral clearance. Based on these findings, we hypothesized that juvenile monocytes contribute to excessive inflammation and lung injury during IAV infection, and that adult monocytes could protect juvenile mice from IAV‐induced lung injury and death.MethodsPregnant mice were treated with busulfan (15 mg/kg i.p. day E18 and E19) to cause myelosuppression in fetal pups. Following birth, additional busulfan was given to juvenile pups (10 mg/kg i.p. day of life 1). Bone marrow derived stem cells were harvested from adult (10 week old) donor mice bearing the CD45.1 marker and injected into the myelosuppressed recipient pups (CD45.2) on day 2 of life (7.5 × 106 cells intravenously). Four weeks following transplantation, juvenile recipient mice were then infected with IAV (strain WSN, 25 PFU, intratracheally) and monitored for the development of lung injury and survival.ResultsJuvenile mice expressing juvenile CD45.2 cells had a median survival of 9 dpi. In contrast, 90% of the juvenile mice expressing adult CD45.1 were alive at 9 dpi and the median survival was >62%. Histological examination of the lungs showed decreased lung injury in IAV‐infected juvenile mice expressing adult CD45.1, as compared to control mice. Juvenile mice that recruited adult monocytes to the lungs during IAV infection had decreased lung injury compared to juvenile mice that recruited juvenile monocytes to the lungs during IAV infection.ConclusionsJuvenile mice are more susceptible to IAV‐induced lung injury and death than adult mice. Recruitment of juvenile monocytes to the lungs during IAV infection exacerbates inflammation and worsens outcomes. Transplantation of adult monocytes into juvenile mice lessens lung injury and improves survival. This suggests that juvenile monocytes are particularly injurious in juvenile IAV infection and may have age‐related cell‐intrinsic properties that exacerbate lung injury.Support or Funding InformationPediatric Critical Care and Trauma Scientist Development Program (NICHD K12)American Thoracic Society/American Lung AssociationNHLBIThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.