Coinfection of Dermal Fibroblasts by Human Cytomegalovirus and Human Herpesvirus 6 Can Boost the Expression of Fibrosis-Associated MicroRNAs

Abstract

Tissue fibrosis can affect every type of tissue or organ, often leading to organ malfunction; however, the mechanisms involved in this process are not yet clarified. A role has been hypothesized for Human Cytomegalovirus (HCMV) and Human Herpesvirus 6 (HHV-6) infections as triggers of systemic sclerosis (SSc), a severe autoimmune disease causing progressive tissue fibrosis, since both viruses and antiviral immune responses toward them have been detected in patients. Moreover, HCMV or HHV-6A infection was reported to increase the expression of fibrosis-associated transcriptional factors and miRNAs in human dermal fibroblasts. However, it is unlikely that they have separate effects in the infected host, as both viruses are highly prevalent in the human population. Thus, our study aimed to investigate, by quantitative real-time PCR microarray, the impact of HCMV/HHV-6A coinfection on the expression of pro-fibrotic miRNAs in coinfected cells, compared to the effect of single viruses. The results showed a possible synergistic effect of the two viruses on pro-fibrotic miRNA expression, thus suggesting that HCMV and HHV-6 may enhance each other and cooperate at inducing enhanced miRNA-driven fibrosis. These data may also suggest a possible use of virus-induced miRNAs as novel diagnostic or prognostic biomarkers for SSc and its clinical treatment.

Virus-Induced MicroRNA Modulation and Systemic Sclerosis Disease

“…Recent observations have confirmed the high prevalence of beta-herpesvirus infection in sclerodermic patients, highlighting HHV-6/HCMV presence both in the tissue and/or blood level (in particular of HHV-6A, which show a prominent tissue tropism), together with significantly enhanced immune response toward viral antigens, such as UL94 (HCMV) and U94 (HHV-6), compared to the healthy population [ 41 , 121 , 122 , 123 , 124 , 125 , 126 ]. In order to understand their potential role and their joint involvement in inducing fibrosis, the effects of in vitro infection of primary human dermal fibroblasts (one of the main cell targets affected in SSc pathology, together with endothelial cells) were evaluated [ 42 , 43 , 44 , 82 ]. HHV-6A and HCMV in vitro infections induced a rapid and sustained up-modulation of several profibrotic and pro-apoptotic factors, that resulted even more marked by HHV-6A/HCMV coinfection [ 43 , 44 ].…”

“…HCMV and HHV-6A viruses, highly prevalent in the human population, are likely to infect or reactivate simultaneously in the host. According to this, their synergistic effect on the modulation of miRNAs in coinfected cells has been investigated [ 82 ]. Interestingly, the copresence of HCMV and HHV-6A induced a remarkable dysregulation of fibrosis-associated miRNAs expression compared to what was observed in single-infected primary dermal fibroblasts.…”

“… Profile of miRNAs deregulated in SSc disease, both at the tissue and extracellular level, and effects of oxidative stress and beta-herpesviruses infection on SSc-associated miRNAs [ 42 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 ] (SSc, Systemic Sclerosis; upward red arrows, up-regulated miRNAs; downward blue arrows, down-regulated miRNAs). …”

“…The miRNAs mainly altered in SSc disease, also highlighting the involvement of HCMV and HHV6-A single or double infections, are summarized in Table 1. * Asterisks indicate miRNAs affected by HHV-6A and/or HCMV infection [42,82] (see Figure 1).…”