HHV-6A and HCMV induce pro-fibrotic miRNA expression pattern in infected host cells

Pattern consistent with clinical studies suggesting these viruses may be one trigger of systemic sclerosis.

Investigators and clinicians have speculated that systemic sclerosis (SSc), a sometimes-devastating autoimmune fibrotic disease, can be triggered by HHV-6A or human cytomegalovirus (HCMV). The evidence for this is that: 1) HHV-6A has been found in the skin of SSc patients;  2) SSc subjects may have higher titers of antibodies directed against the HHV-6 U94 protein; 3) HCMV transcripts have been found in endothelial cells from the skin of people with SSc;  4) levels of antibodies to HCMV are reportedly higher in SSc; and  5) CD8+ T cells specifically targeting HCMV have been reported in SSc.

But how might HHV-6 and HCMV trigger the fibrotic process that is the hallmark of SSc?  Specific patterns of expression of miRNAs (the miRNome) have been correlated with various fibrotic diseases, and so investigators at the University of Ferrara in Italy examined the miRNA expression patterns induced in dermal fibroblasts by infection with HCMV and HHV-6A and in control uninfected fibroblasts. 

 miRNA expression was evaluated prior to infection and 4, 7 and 10 days post-infection. At various points in time, there were different profiles of miRNAs in the infected fibroblasts than in the uninfected control fibroblasts.  Some miRNAs were upregulated, and others were downregulated. Expression patterns of various miRNAs were different in the early phase compared to the intermediate and later phases of infection. 

Specifically, both viruses induced miRNA expression patterns that previously have been linked to fibrosis-associated signaling pathways including transforming growth factor (TGF)-ß, Wingless/Int (WNT), ß-catenin, vascular endothelial growth factor (VEGF) and its receptor (VEGF-R), epithelial growth factor (EGFR) and fibroblast growth factor (FGFR). Upregulated miRNAs associated with fibrosis included miR-7, miR-let-7g and miR-92a. The upregulated levels in infected cells were dramatically higher compared to uninfected control cells, and the downregulated levels were dramatically lower.

In summary, when dermal fibroblasts are infected with HHV-6A and HCMV, miRNA expression profiles associated with fibrosis are generated. This is consistent with the hypothesis that these viruses may be one trigger of systemic sclerosis (SSc). However, since these are ubiquitous viruses and SSc is an uncommon disease, other factors surely also are at play in the pathogenesis of this disease. 

Read the full article: Soffritti et al 2021