RNA-seq analysis does not substantiate a causative link between herpes virus infection and IPF

There are a number of publications showing an association between herpes virus infection and idiopathic pulmonary fibrosis (IPF). These reports use immunohistochemistry and/or PCR, which are susceptible to specificity artifacts. Thus, we investigated the possible association between IPF and viral RNA expression using next-generation sequencing, which has the potential to provide both a high degree of sensitivity as well as specificity. We quantified viral RNA expression for 740 viruses in 21 IPF patient lung biopsy samples and 17 age-matched controls. Our RNA-seq results were confirmed using Real-time RT-PCR for select viruses (EBV, herpes Saimiri and HERV-k). HERV-k expression was examined because of reports indicating that it is elevated in other fibrotic diseases, and because conceptually HERV-k could promote fibrogenesis by inducing cellular stress. Moreover, HERV-k expression is reported to be enhanced in response to herpes virus infection. Although we identified sporadic low-level evidence of viral infections in our lung tissue samples, we did not find statistical difference for expression of any virus, including HERV-k, between IPF and control lungs. To our knowledge, this is the first report that employs RNA-seq to assess whether or not viral infections are linked to IPF. Our results do not address the role of viral infection in the so-called acute exacerbation of IPF, however, they clearly do not support a causative connection between herpes virus infection and IPF.