Influenza A Virus after Radiotherapy Amplifies Lung Injury and Monocyte-derived Macrophage Responses

Improvements in radiation therapy (RT) for thoracic cancers have increased survival; thus, preventing radiotoxicity in normal lung tissue becomes even more important. Respiratory infection is a lung stressor that increases the risk of RT toxicity. However, this risk factor remains understudied with no effective treatment approaches. Although RT is toxic to tissue-resident alveolar macrophages, recruited monocyte-derived macrophages (MDMs) drive fibrogenesis. We therefore investigated how these macrophage populations are impacted by a respiratory infection subsequent to lung RT. Mice received whole-thorax RT (5-12.5 Gy), then were infected with influenza A virus (IAV) 1 or 20 weeks later. Chronic lung injury and acute and chronic macrophage responses were evaluated. RT plus IAV was lethal at doses that were well tolerated when either was administered singly. IAV potentiated chronic pathology from even a benign RT dose of 5 Gy, even when IAV was delayed for 20 weeks. Macrophage dynamics shifted toward more predominant proinflammatory, profibrotic MDM responses. Acutely, RT plus IAV amplified loss of tissue-resident alveolar macrophages but increased inflammatory MDMs. Expression of maturation receptors and antigen presentation factors by inflammatory MDMs decreased, whereas profibrotic factors increased. These novel findings warrant further investigation of the risks of respiratory infection for those receiving thoracic radiation.