Nov 222013
Is Idiopathic Pulmonary Fibrosis Caused by a Virus?

The cause(s) of idiopathic pulmonary fibrosis have vexed researchers for decades. Although risk factors (smoking, familial gene mutations) provide clues, the actual trigger for the proliferative, fibrotic cellular process resulting in usual interstitial pneumonitis (on biopsy specimens) and IPF (clinically) have remained frustratingly elusive.

But an exciting new case-control study suggests that in at least some people, idiopathic pulmonary fibrosis may be caused by a virus called herpesvirus saimiri. Virginia Folcik, Gerard Nuovo et al report their findings online in Modern Pathology.

Nuovo and colleagues suspected herpesvirus saimiri might have a causative role in IPF because the virus expresses a gene very similar to one found in regenerating epithelial cells in people with idiopathic pulmonary fibrosis. In people, epithelial cells expressing the gene secrete IL-17, a cytokine.

Viral infections, including Epstein-Barr virus (which causes mononucleosis), influenza A virus, hepatitis C virus, HIV, and herpes virus 6 have also long been known to be risk factors for development of idiopathic pulmonary fibrosis. (Viruses' role in IPF exacerbations has been cast in doubt.)

Looking further, authors took lung tissue biopsy samples from 21 patients (cases) confirmed to have idiopathic pulmonary fibrosis (by consensus of their treating physician, radiologist, and pathologist) at Weill Cornell Medical Center and the Medical College of Wisconsin.

They also examined open lung biopsy samples from 21 controls, who had pulmonary fibrosis of a known etiology (associated with adenocarcinoma, emphysema, NSIP or virus-associated).

Using molecular diagnostic techniques (in-situ hybridization, immunohistochemistry, PCR) and spectroscopy, authors confirmed the presence of herpesvirus saimiri in all 21 samples from IPF patients. None of the control patients had herpesvirus saimiri DNA in their biopsy samples.

In total, 4 “pirated proteins” (cyclin D, thymidylate synthase, dihydrofolate reductase, in addition to IL-17) were strongly expressed in the epithelial cells of people with IPF. These proteins were not expressed highly in controls.

Investigators then cloned and sequenced part of the genome of an IPF tissue sample, and found it exactly matched the relevant herpesvirus saimiri gene sequence.

Herpesvirus saimiri is part of the gamma-herpesvirus (rhadinovirus) family, which also includes HHV-8 (the cause of Kaposi’s sarcoma). Other viruses in this family have been shown to cause pulmonary fibrosis in animals. Herpesvirus saimiri’s natural host is the the Central American squirrel monkey, in which it does not cause disease. Little is known about how herpesvirus saimiri might be transmitted to (or between) humans.

At the very least, this exciting new finding opens the door to new lines of research into the cause and potential treatments for idiopathic pulmonary fibrosis, which affects about 200,000 people in the U.S. alone. Today, there is no effective treatment for IPF.

"While the sample size is small," Nuovo told an interviewer, "there are multiple data points that support our findings that herpesvirus saimiri infection may be the cause of IPF."

Folcik VA et al. Idiopathic pulmonary fibrosis is strongly associated with productive infection by herpesvirus saimiri.  Modern Pathology online 15 November 2013; doi: 10.1038/modpathol.2013.198

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Idiopathic pulmonary fibrosis linked to herpesvirus infection