Parvovirus B19 activates in vitro normal human dermal fibroblasts: a possible implication in skin fibrosis and systemic sclerosis

Abstract

Objective Fibrosis is the most characteristic pathological hallmark of SSc, a connective tissue disease characterized by vascular and immunological abnormalities, inflammation and enhanced extracellular matrix production, leading to progressive fibrosis of skin and internal organs. We previously demonstrated that parvovirus B19 (B19V) can infect normal human dermal fibroblasts (NHDFs) and that B19V persists in SSc fibroblasts. In this study, we investigated whether parvovirus B19V is able to activate in vitro NHDFs and to induce in these cells some phenotypic features similar to that observed in the SSc fibroblasts. Methods We preliminarily analysed the time course of B19V infection in cultured NHDFs, then we investigated the ability of B19V to induce cell migration, invasive phenotype and mRNA expression of some profibrotic and/or proinflammatory genes. Results We confirmed our previous findings that B19V infects NHDFs, but the infection is not productive. After incubation with B19V, NHDFs showed a significant increase of both migration and invasiveness, along with mRNA expression of different profibrotic genes (α-SMA, EDN-1, IL-6, TGF-β1 receptors 1 and 2, Col1α2), some genes associated with inflammasome platform (AIM2, IFI16, IL-1β, CASP-1) and genes for metalloprotease (MMP 2, 9 and 12). Conclusion These data suggest that B19V can activate dermal fibroblasts and may have a role in the pathogenesis of fibrosis. B19V-induced fibroblast migration and invasiveness could be due to the B19V-associated MMP9 overexpression and activation. Moreover, the up-regulation of MMP12, typical of SSc, could link the B19V infection of fibroblasts to the anti-angiogenic process.

Intussusceptive angiogenesis in Covid-19: hypothesis on the significance and focus on the possible role of FGF2

“…The Orf virus, a zoonotic parapoxvirus that may be transmitted to humans, rarely provokes an extensive vasculo-endothelial proliferation through the early expression of a VEGF-like viral gene product [ 9 ]. Moreover, despite the infection of fibroblasts by parvovirus B19 has been suggested to have anti-angiogenic effects in vitro [ 10 ], it has been recently reported [ 11 ] that parvovirus B19-related induction of myocarditis caused a distinct formation of new blood vessels around inflammatory sites both by SA and IA. An anti-angiogenic effect has been instead observed in other viral models: Zika virus (ZIKV), besides neurogenesis, also seems impair angiogenesis during murine embryonic development [ 12 ], and Dengue virus infection proved to inhibit SA in vitro [ 13 ].…”

Insights into the knowledge of complex diseases: Environmental infectious/toxic agents as potential etiopathogenetic factors of systemic sclerosis

“…HCMV, HHV-6A, B19V); iiii) virus triggered expression of pro-fibrotic microRNA (e.g. HCMV, HHV-6A) [16,36,44,[49][50][51][52]65,73,106,109,124,146,148,152].…”

“…In vitro studies provided evidence that B19V can infect the target cells of SSc such as dermal fibroblasts [145,146], endothelial cells from various tissues [145,147] but also different cell types belonging to the heterogenous group of marrow-derived circulating angiogenic cells (CACs) [124], which play a key role in vascular regeneration. B19V infection was associated with impaired endothelial regeneration through induction of apoptosis and dysregulated trafficking of infected CACs.…”

“…Moreover, our recent investigations showed that B19V is able to activate in vitro normal dermal fibroblasts by increasing their ability of both migration and invasiveness, along with mRNA expression of different profibrotic genes (α-SMA, EDN-1, IL-6, TGF-β1 receptors 1 and 2, Col1α2), some genes associated with inflammasome platform (AIM2, IFI16, IL-1β, CASP-1) and genes for some metalloproteases (MMP 2, 9 and 12) [146]. These data suggest that B19V can activate dermal fibroblasts and may have a role in the pathogenesis of fibrotic lesions.…”

“…Since it has been previously demonstrated that MMP12 overexpressed by SSc fibroblasts is able to induce impaired HMVECs proliferation, invasion, and capillary morphogenesis [153,154], B19V infection of NHDFs could contribute to the anti-angiogenic process, a pathological trait of SSc, responsible for the capillary loose and the subsequent ischemic organ injury [146].…”