title: 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.
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, Leiden, South-Holland, The Netherlands.
authors.forename: Siamaque
authors.initials: S
authors.lastname: Kazem
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, Leiden, South-Holland, The Netherlands.
authors.forename: Els
authors.initials: E
authors.lastname: van der Meijden
authors.affiliation: Department of Dermatology, UT Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Wang
authors.affiliation: Department of Dermatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Arlene S
authors.initials: AS
authors.lastname: Rosenberg
authors.affiliation: Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Elena
authors.initials: E
authors.lastname: Pope
authors.affiliation: Department of Dermatology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Taylor
authors.initials: T
authors.lastname: Benoit
authors.affiliation: Division of Dermatology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Philip
authors.initials: P
authors.lastname: Fleckman
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, Leiden, South-Holland, The Netherlands.
authors.forename: Mariet C W
authors.initials: MC
authors.lastname: Feltkamp
mesh_terms: D000293:Adolescent; D000328:Adult; D000957:Antigens, Viral, Tumor / Q000235:genetics; D001706:Biopsy; D002453:Cell Cycle / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D006965:Hyperplasia; D007381:Intermediate Filament Proteins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011120:Polyomavirus / Q000235:genetics; D027601:Polyomavirus Infections / Q000150:complications*; D011485:Protein Binding; D021381:Protein Transport; D016160:Retinoblastoma Protein / Q000378:metabolism*; D012871:Skin Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D014412:Tumor Virus Infections / Q000150:complications*; D055815:Young Adult
chemical_list: D000957:Antigens, Viral, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007381:Intermediate Filament Proteins; D019394:Ki-67 Antigen; D016160:Retinoblastoma Protein; C016159:trichohyalin