ASO Author Reflections: The Evolving and Expanding Role of Merkel Cell Polyomavirus Antibody Titers

ABSTRACTSix new human polyomaviruses have been identified since 2008 (Merkel cell polyomavirus [MCPyV], human polyomavirus 6 [HPyV6], HPyV7, HPyV9, trichodysplasia spinulosa polyomavirus [TSPyV], and Malawi polyomavirus [MWPyV]). The presence of specific antibodies against MCPyV, HPyV6, HPyV7, HPyV9, and TSPyV in 828 Italian subjects aged 1 to 100 years was investigated by virus-like particle-based enzyme-linked immunosorbent assays (ELISAs). The findings indicate that all of these new polyomaviruses circulate widely in humans, with seroprevalences in adulthood ranging from 39.4% for HPyV9 to 87.1% for MCPyV, and that primary exposure is most intense in childhood, with the exception of HPyV7 and HPyV9, for which the seroprevalence increased throughout life. The proportion of subjects with high antibody titers was found to increase with age for MCPyV and to decrease with age for TSPyV.

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Significantly Low Levels of IgG Antibodies Against Oncogenic Merkel Cell Polyomavirus in Sera From Females Affected by Spontaneous Abortion

Frontiers in Microbiology ◽

10.3389/fmicb.2021.789991 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chiara Mazziotta ◽

Giulia Pellielo ◽

Mauro Tognon ◽

Fernanda Martini ◽

John Charles Rotondo

Keyword(s):

Antibody Response ◽

Spontaneous Abortion ◽

Viral Infections ◽

Merkel Cell Polyomavirus ◽

Enzyme Linked Immunosorbent Assay ◽

Merkel Cell ◽

Igg Antibodies ◽

Igg Antibody ◽

The Impact

Merkel cell polyomavirus (MCPyV) is a small DNA tumor virus ubiquitous in humans. MCPyV establishes a clinically asymptomatic lifelong infection in healthy immunocompetent individuals. Viral infections are considered to be risk factors for spontaneous abortion (SA), which is the most common adverse complication of pregnancy. The role of MCPyV in SA remains undetermined. Herein, the impact of MCPyV infection in females affected by SA was investigated. Specifically, an indirect enzyme-linked immunosorbent assay (ELISA) method with two linear synthetic peptides/mimotopes mimicking MCPyV antigens was used to investigate immunoglobulin G (IgG) antibodies against MCPyV in sera from 94 females affected by SA [mean ± standard deviation (SD) age 35 ± (6) years] and from 96 healthy females undergoing voluntary pregnancy interruption [VI, mean (±SD) age 32 ± (7) years]. MCPyV seroprevalence and serological profiles were analyzed. The overall prevalence of serum IgG antibodies against MCPyV was 35.1% (33/94) and 37.5% (36/96) in SA and VI females, respectively (p > 0.05). Notably, serological profile analyses indicated lower optical densities (ODs) in females with SA compared to those undergoing VI (p < 0.05), thus indicating a reduced IgG antibody response in SA females. Circulating IgGs were identified in sera from SA and VI females. Our immunological findings indicate that a relatively reduced fraction of pregnant females carry serum anti-MCPyV IgG antibodies, while SA females presented a more pronounced decrease in IgG antibody response to MCPyV. Although yet to be determined, this immunological decrease might prompt an increase in MCPyV multiplication events in females experiencing abortive events. The role of MCPyV in SA, if present, remains to be determined.

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Molecular Mechanisms of Merkel Cell Polyomavirus Transformation and Replication

Annual Review of Virology ◽

10.1146/annurev-virology-011720-121757 ◽

2020 ◽

Vol 7 (1) ◽

pp. 289-307 ◽

Cited By ~ 1

Author(s):

Wei Liu ◽

Jianxin You

Keyword(s):

Molecular Mechanisms ◽

Human Tumor ◽

Merkel Cell Polyomavirus ◽

Merkel Cell ◽

Virus Family ◽

The Past ◽

Molecular Events ◽

Cellular Tropism ◽

Novel Virus

Viral infection underlies a significant share of the global cancer burden. Merkel cell polyomavirus (MCPyV) is the newest member of the human oncogenic virus family. Its discovery over a decade ago marked the beginning of an exciting era in human tumor virology. Since then, significant evidence has emerged to support the etiologic role of MCPyV in Merkel cell carcinoma (MCC), an extremely lethal form of skin cancer. MCPyV infection is widespread in the general population. MCC diagnoses have tripled over the past 20 years, but effective treatments are currently lacking. In this review, we highlight recent discoveries that have shaped our understanding of MCPyV oncogenic mechanism and host cellular tropism, as well as the molecular events occurring in the viral infectious life cycle. These insights will guide future efforts in developing novel virus-targeted therapeutic strategies for treating the devastating human cancers associated with this new tumorigenic virus.

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Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells

Cancers ◽

10.3390/cancers12071989 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1989

Author(s):

Thibault Kervarrec ◽

Mahtab Samimi ◽

Sonja Hesbacher ◽

Patricia Berthon ◽

Marion Wobser ◽

...

Keyword(s):

Transcription Factor ◽

Epithelial Cells ◽

Human Keratinocytes ◽

Merkel Cell Polyomavirus ◽

Bhlh Transcription Factor ◽

Merkel Cell ◽

T Antigens ◽

Differentiation Potential ◽

Transcription Factor 1

Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by the Merkel cell polyomavirus (MCPyV). It is still under discussion, in which cells viral integration and MCC development occurs. Recently, we demonstrated that a virus-positive MCC derived from a trichoblastoma, an epithelial neoplasia bearing Merkel cell (MC) differentiation potential. Accordingly, we hypothesized that MC progenitors may represent an origin of MCPyV-positive MCC. To sustain this hypothesis, phenotypic comparison of trichoblastomas and physiologic human MC progenitors was conducted revealing GLI family zinc finger 1 (GLI1), Keratin 17 (KRT 17), and SRY-box transcription factor 9 (SOX9) expressions in both subsets. Furthermore, GLI1 expression in keratinocytes induced transcription of the MC marker SOX2 supporting a role of GLI1 in human MC differentiation. To assess a possible contribution of the MCPyV T antigens (TA) to the development of an MC-like phenotype, human keratinocytes were transduced with TA. While this led only to induction of KRT8, an early MC marker, combined GLI1 and TA expression gave rise to a more advanced MC phenotype with SOX2, KRT8, and KRT20 expression. Finally, we demonstrated MCPyV-large T antigens’ capacity to inhibit the degradation of the MC master regulator Atonal bHLH transcription factor 1 (ATOH1). In conclusion, our report suggests that MCPyV TA contribute to the acquisition of an MC-like phenotype in epithelial cells.

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The Role of Merkel Cell Polyomavirus and Other Human Polyomaviruses in Emerging Hallmarks of Cancer

Viruses ◽

10.3390/v7041871 ◽

2015 ◽

Vol 7 (4) ◽

pp. 1871-1901 ◽

Cited By ~ 29

Author(s):

Ugo Moens ◽

Kashif Rasheed ◽

Ibrahim Abdulsalam ◽

Baldur Sveinbjørnsson

Keyword(s):

Merkel Cell Polyomavirus ◽

Merkel Cell ◽

Hallmarks Of Cancer ◽

Human Polyomaviruses

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No evidence for a causal role of Merkel cell polyomavirus in keratoacanthoma

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2011.07.026 ◽

2012 ◽

Vol 67 (1) ◽

pp. 41-46 ◽

Cited By ~ 14

Author(s):

Ulrike Wieland ◽

Nina Scola ◽

Benjamin Stolte ◽

Markus Stücker ◽

Steffi Silling ◽

...

Keyword(s):

Merkel Cell Polyomavirus ◽

Causal Role ◽

Merkel Cell

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DNA Sequences of Small DNA Tumor Viruses, Merkel Cell Polyomavirus and Human Papillomavirus, in Spontaneous Abortion Specimens

10.20944/preprints201811.0366.v1 ◽

2018 ◽

Author(s):

Andrea Tagliapietra ◽

John Rotondo ◽

Ilaria Bononi ◽

Elisa Mazzoni ◽

Federica Magagnoli ◽

...

Keyword(s):

Human Papillomavirus ◽

Spontaneous Abortion ◽

Dna Sequences ◽

Mononuclear Cells ◽

Merkel Cell Polyomavirus ◽

Merkel Cell ◽

Peripheral Blood Mononuclear ◽

Chorionic Villi ◽

Tumor Viruses

Background. The role of viruses in spontaneous abortion (SA) in not completely known. Methods. Merkel cell polyomavirus (MCPyV) and Human papillomavirus (HPV), two small DNA tumor viruses, were investigated in SA. MCPyV/HPV DNAs were investigated by PCR and droplet-digital/quantitative PCRs (ddPCR/qPCR) in chorionic villi and peripheral blood mononuclear cells (PBMCs) from SA females (n=100), the cases, and voluntary interruption (VI, n=100) of pregnancy females, the controls. Results. MCPyV DNAs were detected in 4% and 5% of SA and VI chorionic villi, respectively, with a mean DNA load of 1.99 copy/104 cells in SA and 3.02 copy/10,000 cells in VI (p>0.05). HPV DNAs were detected in 2% of VI chorionic villi, with a mean DNA load of 7.12 copy/cell. Two cases in the VI samples were HPV-45 positive. In PBMCs, MCPyV DNA was detected in 9% and 14% of SA and VI samples, with a mean viral DNA load of 2.09 and 4.70 copy/10,000 cells in SA and VI samples, respectively (p>0.05). None of PBMCs samples tested HPV-positive. Conclusions. MCPyV and HPV DNAs were quantified, for the first time, by ddPCR/qPCR in SA and VI chorionic villi and PBMCs. Data of the present study may help to better understand the role of MCPyV/HPV in SA.

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Merkel cell polyomavirus in gastrointestinal neuroendocrine tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.4120 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 4120-4120

Author(s):

Salvatore Lorenzo Renne ◽

Caterina Fumagalli ◽

Nicola Fazio ◽

Giuseppe Viale ◽

Massimo Barberis

Keyword(s):

Neuroendocrine Tumors ◽

Cell Biology ◽

Stop Codon ◽

Premature Stop Codon ◽

Genetic Alterations ◽

Merkel Cell Polyomavirus ◽

Helicase Domain ◽

Merkel Cell ◽

Viral Dna

4120 Background: Cutaneous Merkel cell carcinoma (MCC) is a high grade neuroendocrine carcinoma potentially induced by Merkel Cell Polyomavirus (MCPyV), a clonally integrated host in the tumor cell genome. Integration of viral DNA and truncating mutations in the helicase domain of the large T (LT) antigen, a protein implicated in the viral life cycle, have been detected in all MCPyV associated MCCs. These results suggest a role of the virus in tumor pathogenesis according to a two step model: a necessary but not sufficient integration of viral DNA followed by LT antigen premature truncations. Gastrointestinal neuroendocrine tumors (GI-NETs) share common phenotypical features with MCCs, therefore we evaluated whether MCPyVs may be present in GI-NET. Methods: Formalin–fixed and paraffin-embedded samples from 14 cases of liver metastases of G2 GI-NETs, 9 small cell lung cancer (SCLCs) and 4 MCCs of the skin were screened for MCPyV-DNA positivity using two PCR primer sets mapping the LT antigen gene. Then to confirm the putative pathogenetic role of the virus, we seeked for premature truncation of LT antigen by sequencing the helicase portion using seven amplicons mapping 1356-2210 region of the MCPyV complete genome (RefSeq: NC_010277.1). Results: Viral DNA was detected in 7/14 GI-NETs, in 0/9 SCLCs and in 4/4 MCCs. We found a premature stop codon truncating the helicase domain in two GI-NETs. Both the patients had a rapid disease progression. We also found previously not reported alterations in MCCs: a single aminoacid deletion in 3 cases and a point mutation causing a single aminoacid substitution in another case. Conclusions: For the first time the potential tumorigenic signature of MCPyV has been detected in GI-NETs, suggesting a possible role in pathogenesis. The study is ongoing to confirm these observations that could support new diagnostic and therapeutical perspectives of a subset of GI NETs. Moreover we have shown that the clonal integration of MCPyV in MCCs produces different genetic alterations with unknown effects on cell biology.

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