Distinct Pulmonary Virome Signature Accentuates Influenza Related Lung Injury And Is Associated With Chronic Rejection in Lung Transplant Recipients

Rationale: The lung bacteriome in lung transplant recipients (LTRs) have been described, but the lung virome (LV) has not been well characterized. Here for the first time, we report distinct LV signatures in chronic lung allograft dysfunction (CLAD) and illuminate a novel mechanistic pathway that modulates the host interferon responses and predisposes LTRs to lung injury.

Objectives: We hypothesize that specific Torque Teno Virus (TTV) signatures dysregulate host interferon responses and promote allograft injury associated with respiratory viral infections.

Material and Methods: Shotgun metagenomic sequencing was performed in bronchoalveolar lavage fluid from CLAD and non-CLAD recipients. TTV viral constructs from group 8 TTV with ORF1 protein (kV1) were transfected in primary bronchial epithelial cells (PBECs) or airways of C56/BL7 mice. Viral proliferation and PBEC apoptosis were evaluated using co-cultures with RSV and Influenza A (IA).

Results: LV in LTRs was dominated by viruses from the family Anelloviridae. The CLAD LV was characterized by increased enrichment of TTV-like viruses from a novel TTV clade (group 8). Independent validation confirmed group 8 TTV abundance in CLAD. Group 8 TTV ORF1 protein (kV1) suppressed PBEC IFN-γ responses. Co-culture of RSV and IA in kV1 transfected PBECs significantly augmented proliferation of RSV and IA and increased cellular injury and apoptosis. Likewise, in vivo transfection of kV1 in mice increased IA proliferation and lung injury associated with IA.

Conclusion: Distinct LV signatures are present and associated with CLAD. These changes appear to place the lung allograft at risk for injury from respiratory viral infections.