Coinfection of CMV and HHV-6A boosts fibrosis-associated microRNAs in fibroblasts

Investigators see possible links to systemic sclerosis, liver fibrosis and cardiovascular remodeling.

Systemic sclerosis is a chronic autoimmune disease in which the skin and various internal organs develop progressive fibrosis.  Human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6) have both been found to be reactivated in the skin of some people with systemic sclerosis, and patients often have unusually high levels of antibodies against HCMV and HHV-6. Higher levels of CD8+ T cells directed at HCMV antigens also have been reported.

Both viruses can productively infect fibroblasts and endothelial cells, and experimental infection of these cells by HCMV or HHV-6 leads to the production of pro-fibrotic factors (Soffritti 2022, Arcangeletti 2020, Soffritti 2021). Experimental infection of these cells by both HCMV and HHV-6 leads to a more exuberant production of pro-fibrotic factors.

Exploring mechanisms for this phenomenon, Italian investigators from the University of Ferrara and University of Parma studied the expression of micro-RNAs (miRNAs) in skin fibroblasts, after infection with either or both HCMV or HHV-6A. Levels of miRNAs were assessed using PCR microarrays and confirmed for 10 of the differentially expressed miRNAs by individual miRCURY LNA miRNA PCR assays.  The interesting findings included:

  • Infection by either HCMV or HHV-6A produced an up-regulation of miRNAs (up to 60-fold with some miRNAs) previously found to have pro-fibrotic effects, and to the down-regulation of miRNAs (down as much as 25-fold with some miRNAs) known to have anti-fibrotic effects.
  • This pattern was greatly accentuated following coinfection with both viruses.
  • The pattern persisted for up to 7 days following infection.
  • Infection with just CMV, but not infection with just HHV-6A, produced a cytopathic effect (CPE). However, dually infected cells produced an earlier CPE (at 2 days instead of 4) and increased the total copy number of both viruses.

This study adds to the evidence that both HHV-6A and HCMV may contribute to the underlying fibrotic pathology of systemic sclerosis.  Moreover, systemic sclerosis is just one of several devastating fibrotic diseases that can involve the liver, heart, lung and kidney. It is plausible that these viruses might play a role in the pathology of these other fibrotic diseases, as well.

Read the full text: Soffritti 2023