Expression profiling of Epstein-Barr virus-derived microRNA in systemic chronic active EBV disease

Systemic chronic active Epstein-Barr virus disease (sCAEBV) is an intractable disorder characterized by clonal proliferation of EBV-infected T- and NK-cells, leading to persistent systemic inflammation and progression to hemophagocytic lymphohistiocytosis (HLH). The EBV genome encodes 40 mature microRNAs known as miR-BARTs. The expression of miR-BARTs has been reported in other EBV-positive diseases and is associated with tumorigenesis. In this study, we investigated the expression of miR-BARTs in sCAEBV. Expression of miR-BARTs was highly abundant in 4 sCAEBV-derived EBV-positive T- or NK-cell lines and in EBV-infected T- or NK-cells from 23 sCAEBV patients. The highest expression levels were observed for miR-BART7-3p. Sequence analysis revealed no deletions in the EBV genome encoding miR-BARTs. Inhibition of miR-BART7-3p altered the expression of immune-related genes in sCAEBV-derived cell lines. Abundant miR-BART expression was also observed in patients' plasma, with miR-BART7-3p showing the highest levels. Notably, miR-BART7-3p expression was detected in macrophages within the spleen of an sCAEBV patient with HLH. These findings suggest that miR-BARTs are highly expressed and secreted by EBV-infected cells in sCAEBV. We hypothesize that secreted miR-BARTs may be taken up by monocytes, potentially regulating their functions and contributing to inflammation in sCAEBV. Further studies are needed to elucidate these mechanisms.