Polyomavirus-Associated Trichodysplasia Spinulosa Involves Hyperproliferation, pRB Phosphorylation and Upregulation of p16 and p21

Abstract

Trichodysplasia spinulosa (TS) is a proliferative skin disease observed in severely immunocompromized patients. It is characterized by papule and trichohyalin-rich spicule formation, epidermal acanthosis and distention of dysmorphic hair follicles overpopulated by inner root sheath cells (IRS). TS probably results from active infection with the TS-associated polyomavirus (TSPyV), as indicated by high viral-load, virus protein expression and particle formation. The underlying pathogenic mechanism imposed by TSPyV infection has not been solved yet. By analogy with other polyomaviruses, such as the Merkel cell polyomavirus associated with Merkel cell carcinoma, we hypothesized that TSPyV T-antigen promotes proliferation of infected IRS cells. Therefore, we analyzed TS biopsy sections for markers of cell proliferation (Ki-67) and cell cycle regulation (p16ink4a, p21waf, pRB, phosphorylated pRB), and the putatively transforming TSPyV early large tumor (LT) antigen. Intense Ki-67 staining was detected especially in the margins of TS hair follicles, which colocalized with TSPyV LT-antigen detection. In this area, staining was also noted for pRB and particularly phosphorylated pRB, as well as p16ink4a and p21waf. Healthy control hair follicles did not or hardly stained for these markers. Trichohyalin was particularly detected in the center of TS follicles that stained negative for Ki-67 and TSPyV LT-antigen. In summary, we provide evidence for clustering of TSPyV LT-antigen-expressing and proliferating cells in the follicle margins that overproduce negative cell cycle regulatory proteins. These data are compatible with a scenario of TSPyV T-antigen-mediated cell cycle progression, potentially creating a pool of proliferating cells that enable viral DNA replication and drive papule and spicule formation.

Emerging differential roles of the pRb tumor suppressor in trichodysplasia spinulosa-associated polyomavirus and Merkel cell polyomavirus pathogeneses

“…As TSPyV and MCPyV LT antigens both contain the characteristic LXCXE pRb binding domain, it is possible that LT antigen may also influence pRb phosphorylation [1,2]. Interestingly, TSPyV LT, which is highly expressed in TS lesions, has been found to colocalize with phosphorylated pRb upon immunohistochemical detection [3]. Nevertheless, if and how TSPyV or MCPyV LT antigens may affect pRb phosphorylation status require further investigation.…”

“…MCPyV is detected in approximately 80% of Merkel cell carcinomas (MCC), a rare, aggressive, and often fatal neuroendocrine skin cancer [1], while TSPyV mediates the development of trichodysplasia spinulosa (TS), a disfiguring folliculocentric disease characterized clinically by a moderate to severe papular eruption with keratin spine formation involving the central face [2]. The proliferative nature of TS is evidenced histologically by the abnormally high numbers of inner root sheath cells and the prominent positive staining for the cell proliferation marker Ki-67 [2,3]. The involvement of polyomaviruses in carcinogenic and proliferative pathways has been well documented in the literature.…”

“…Accordingly, deactivation of pRb occurs in a number of polyomavirus-associated diseases [3,8]. For example, Kazem et al utilized immunofluorescence of formalin-fixed paraffin-embedded (FFPE) TS lesions to demonstrate marked phosphorylation and resulting deactivation of pRb [3].…”

Characterization of T Antigens, Including Middle T and Alternative T, Expressed by the Human Polyomavirus Associated with Trichodysplasia Spinulosa

“…Of all T antigens identified, LT was the most abundant, as indicated by RT-PCR, Northern and Western blotting, immunoprecipitation, and immunohistochemistry. In a previous study we already provided evidence of LT involvement in inducing hyperproliferation of TSPyV-infected cells by hyperphosphorylation of the tumor suppressor protein pRB (26).…”

“…For MCPyV, the role of the T antigens in MCC pathogenesis has been largely resolved (20,(23)(24)(25). For TSPyV and TS, this piece of information is still lacking although we recently provided evidence of involvement of LT in the induction of pRB hyperphosphorylation and hyperproliferation of follicular skin cells (26), and Tyring and coworkers showed PP2A binding and hyperphosphorylation of cellular factors involved in the MAPK pathway by TSPyV ST (27,28). In order to study the role of TSPyV in pathogenesis and in cellular transformation in more detail and to position TSPyV among its virus family members, further knowledge is required regarding the presence and pattern of expression of the TSPyV-encoded T antigens.…”