The Perioperative Lung Transplant Virome

Primary graft dysfunction (PGD) is a principal cause of early morbidity and mortality after lung transplantation, but its pathogenic mechanisms are not fully clarified. Thus far, studies using standard clinical assays have not linked microbial factors to PGD. We previously used comprehensive metagenomic methods to characterize viruses in lung allografts >1 month post-transplant and found that levels of Anellovirus, mainly Torque teno viruses (TTV), were significantly higher than in non-transplant healthy controls. Here we used quantitative PCR to analyze TTV and shotgun metagenomics to characterize full viral communities in acellular bronchoalveolar lavage from donor organs and post-reperfusion allografts in PGD and non-PGD lung transplant recipient pairs. Unexpectedly, TTV DNA levels were 100-fold elevated in donor lungs compared with healthy adults (p=0.0026). Although absolute TTV levels did not differ by PGD status, PGD cases showed a smaller increase in TTV levels from pre- to post-transplant than did control recipients (p=0.041). Metagenomic sequencing revealed mainly TTV and bacteriophages of respiratory tract bacteria, but no viral taxa distinguished PGD cases from controls. These findings suggest that conditions associated with brain death promote TTV replication, and that greater immune activation or tissue injury associated with PGD may restrict TTV abundance in the lung.

原发性移植物功能障碍（Primary graft dysfunction, PGD）是肺移植术后早期发病与死亡的核心诱因，但其致病机制迄今尚未完全阐明。截至目前，采用标准临床检测方法开展的相关研究均未发现微生物因素与PGD存在关联。我们此前曾运用宏基因组学综合表征手段，对移植术后1个月以上的肺移植物中的病毒组进行分析，结果显示环转病毒属（Anellovirus，主要为Torque teno viruses, TTV）的载量显著高于非移植健康对照人群。本研究通过定量聚合酶链反应（quantitative PCR）检测TTV载量，并结合鸟枪宏基因组测序（shotgun metagenomics）技术，对供体器官以及PGD与非PGD肺移植受体配对病例的供体器官、再灌注后移植物的无细胞支气管肺泡灌洗液中的完整病毒群落展开表征。出乎意料的是，与健康成年人相比，供体肺组织中的TTV DNA载量升高了100倍（p=0.0026）。尽管TTV的绝对载量在PGD组与对照组间无显著差异，但PGD患者术后TTV载量从术前到术后的增幅显著低于对照受体（p=0.041）。宏基因组测序结果显示，病毒群落主要由环转病毒属与呼吸道细菌噬菌体构成，但未发现可有效区分PGD病例与对照的病毒类群。上述研究结果提示，与脑死亡相关的病理状态可促进TTV复制，而与PGD相关的更强免疫激活或组织损伤，或可限制肺内TTV的丰度。