Anellovirus-Mediated Interferon Dysregulation Enhances Virus-Induced Lung Injury

Abstract Background The lung virome (LV) and its interactions with the host-immune system leading to allograft injury after lung transplantation are not well characterized. Methods Shotgun metagenomics and qPCR was performed on a multicenter BAL/serum cohort from lung transplant recipients (LTRs). Viral constructs from betatorquevirus clade and group 2 TTVs were transfected in primary bronchial epithelial cells (PBECs) or airways of C57BL/6 mice with and without exposure to Influenza A (IAV) or RSV. Results LV in LTRs was dominated by viruses from the family Anelloviridae. CLAD LV was characterized by the enrichment of betatorquevirus clade (BTV). Validation in an independent cohort confirmed BTV abundance in CLAD BAL, serum and lung tissues. BTV ORF1 protein (kV1) suppressed PBEC IFNα and IFNγ responses by preventing intranuclear STAT translocation. Co-culture of IAV or RSV in kV1 transfected PBECs significantly augmented replication of RSV and IAV and increased cellular injury. Likewise, in-vivo transfection of kV1 increased replication and lung injury associated with IAV. Conclusion Our work illuminates a novel virus-associated dysregulation of host interferon responses that promote lung injury associated with respiratory viral infections and, in part, explain differential host responses to viral infections after lung transplantation.