Influenza A Virus Following 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 under-studied with no effective treatment approaches. While 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 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 were 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 towards more predominant pro-inflammatory, pro-fibrotic 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 while pro-fibrotic factors increased. These novel findings warrant further investigation of the risks of respiratory infection for those receiving thoracic radiation.