Anellovirus-mediated interferon dysregulation enhances virus-induced lung injury.

OBJECTIVES

To characterize the lung virome after lung transplantation and test whether anelloviruses modulate innate immune responses that influence susceptibility to respiratory viral-associated allograft injury.

RATIONALE: 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 a Betatorquevirus clade (BTV) and group 2 torque teno viruses were transfected in primary bronchial epithelial cells (PBECs) or airways of C57BL/6 mice with and without exposure to influenza A virus (IAV) or respiratory syncytial virus (RSV).

MEASUREMENTS AND MAIN

RESULTS

LV in LTRs was dominated by viruses from the family Anelloviridae. Chronic lung allograft dysfunction (CLAD) LV was characterized by the enrichment of BTV. Validation in an independent cohort confirmed BTV abundance in CLAD BAL fluid, serum, and lung tissues. BTV ORF1 protein (kV1) suppressed PBEC IFN-α and IFN-γ 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.

CONCLUSIONS

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.