The small tumor antigen of Merkel cell polyomavirus accomplishes cellular transformation by uniquely localizing to the nucleus despite the absence of a known nuclear localization signal.

BACKGROUND: Merkel Cell Carcinoma (MCC) is an aggressive skin cancer that is three times deadlier than melanoma. In 2008, it was found that 80% of MCC cases are caused by the genomic integration of a novel polyomavirus, Merkel Cell Polyomavirus (MCPyV), and the expression of its small and truncated large tumor antigens (ST and LT-t, respectively). MCPyV belongs to a family of human polyomaviruses; however, it is the only one with a clear association to cancer. METHODS: To investigate the role and mechanisms of various polyomavirus tumor antigens in cellular transformation, Rat-2 and 293A cells were transduced with pLENTI MCPyV LT-t, MCPyV ST, TSPyV ST, HPyV7 ST, or empty pLENTI and assessed through multiple transformation assays, and subcellular fractionations. One-way ANOVA tests were used to assess statistical significance. RESULTS: Soft agar, proliferation, doubling time, glucose uptake, and serum dependence assays confirmed ST to be the dominant transforming protein of MCPyV. Furthermore, it was found that MCPyV ST is uniquely transforming, as the ST antigens of other non-oncogenic human polyomaviruses such as Trichodysplasia Spinulosa-Associated Polyomavirus (TSPyV) and Human Polyomavirus 7 (HPyV7) were not transforming when similarly assessed. Identification of structural dissimilarities between transforming and non-transforming tumor antigens revealed that the uniquely transforming domain(s) of MCPyV ST are likely located within the structurally dissimilar loops of the MCPyV ST unique region. Of all known MCPyV ST cellular interactors, 62% are exclusively or transiently nuclear, suggesting that MCPyV ST localizes to the nucleus despite the absence of a canonical nuclear localization signal. Indeed, subcellular fractionations confirmed that MCPyV ST could achieve nuclear localization through a currently unknown, regulated mechanism independent of its small size, as HPyV7 and TSPyV ST proteins were incapable of nuclear translocation. Although nuclear localization was found to be important for several transforming properties of MCPyV ST, some properties were also performed by a cytoplasmic sequestered MCPyV ST, suggesting that MCPyV ST may perform different transforming functions in individual subcellular compartments. CONCLUSIONS: Together, these data further elucidate the unique differences between MCPyV ST and other polyomavirus ST proteins necessary to understand MCPyV as the only known human oncogenic polyomavirus.

Trichodysplasia Spinulosa Polyomavirus Endothelial Infection, California, USA.

We describe 3 patients in California, USA, with trichodysplasia spinulosa polyomavirus (TSPyV) infection of endothelium after steroid administration. We detected TSPyV RNA in tissue specimens by in situ hybridization, which revealed localization to endothelial cells. These cases suggest that diseases associated with endothelial inflammation could be associated with TSPyV infection.

Sustained Trichodysplasia Spinulosa Polyomavirus Viremia Illustrating a Primary Disseminated Infection in a Kidney Transplant Recipient.

Novel human polyomaviruses (HPyV) have been recently identified in solid organ transplant recipients. Trichodysplasia spinulosa (TS) is a rare disease associated with immunosuppression and induced by a polyomavirus (TSPyV). We report here a case of primary and disseminated TSPyV infection after kidney transplantation with extensive skin lesions, sustained viremia, and high viral loads in urine specimens, anal, nasal and throat swabs, assessed via specific real-time PCR for TSPyV during a follow-up period of 32 months after transplantation. The detection of TSPyV with a high viral load in respiratory and anal swab samples is compatible with viral replication and thus may suggest potential respiratory and oro-fecal routes of transmission.

Recent developments in trichodysplasia spinulosa disease.

Trichodysplasia Spinulosa (TS) is a rare proliferative skin disease that occurs primarily in immunocompromised patients, specifically organ transplant recipients. TS is characterized by uncontrolled inner root sheath cell proliferation and folliculocentric papular eruption that can progress to disfiguring leonine facies when left untreated. TS presents with distinct histological features including the presence of large eosinophilic, trichohyaline granules within hyperproliferating inner root sheath cells of the hair bulb. The discovery of the Trichodysplasia Spinulosa Polyomavirus (TSPyV) and recent studies highlighting the role of TSPyV tumor antigens in cell proliferation pathways have provided new insight into the mechanisms of TS development. In this review, we discuss the expansion of our understanding of TS, specifically over the past 5 years. We summarize novel cases of TS and recent developments in the mechanisms underlying TSPyV-mediated disease progression. We also evaluate advancements in diagnostic methods and treatment options. As the incidence of TS continues to rise, it is becoming critical for clinicians to understand the clinical features of TS and emerging research regarding pathogenesis and therapeutics for early treatment of this potentially disfiguring disease.

Impact of HPyV9 and TSPyV coinfection on the development of BK polyomavirus viremia and associated nephropathy after kidney transplantation.

BACKGROUND: BK polyomavirus (BKPyV) persistently infects the urinary tract and causes viremia and nephropathy in kidney transplantation (KTx), recipients. In a previous study, we observed an increased incidence and load of BKPyV viremia in KTx patients coinfected with human polyomavirus 9 (HPyV9). Here we sought confirmation of this observation and explored whether novel HPyVs that have been detected in urine (HPyV9 and trichodysplasia spinulosa polyomavirus [TSPyV]) potentially aggravate BKPyV infection. METHODS: A well-characterized cohort of 209 KTx donor-recipient pairs was serologically and molecularly analyzed for HPyV9 and TSPyV coinfection. These data were correlated with the occurrence of BKPyV viremia and BKPyVAN in the recipients within a year after KTx. RESULTS: Seropositivity for HPyV9 (19%) and TSPyV (89%) was comparable between donors and recipients and did not correlate with BKPyV viremia and BKPyVAN that developed in 25% and 3% of the recipients, respectively. Two recipients developed TSPyV viremia and none HPyV9 viremia. Modification of the predictive effect of donor BKPyV seroreactivity on recipient BKPyV viremia by HPyV9 and TSPyV was not observed. CONCLUSIONS: Our data provide no evidence for a promoting effect of HPyV9 and TSPyV on BKPyV infection and BKPyVAN in renal allograft patients. Therefore, we do not recommend including HPyV9 and TSPyV screening in KTx patients.

Trichodysplasia Spinulosa Polyomavirus in Respiratory Tract of Immunocompromised Child.

Trichodysplasia spinulosa polyomavirus causes trichodysplasia spinulosa, a skin infection, in immunocompromised persons, but the virus is rarely detected in respiratory samples. Using PCR, we detected persistent virus in respiratory and skin samples from an immunocompromised boy with respiratory signs but no characteristic skin spicules. This virus may play a role in respiratory illness.