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Jianxin You - One of the best experts on this subject based on the ideXlab platform.

  • merkel cell Polyomavirus Infection induces an antiviral innate immune response in human dermal fibroblasts
    Journal of Virology, 2021
    Co-Authors: Nathan A. Krump, Wei Liu, Ranran Wang, June F Yang, Jianxin You
    Abstract:

    Merkel cell Polyomavirus (MCPyV) infects most of the human population asymptomatically, but in rare cases it leads to a highly aggressive skin cancer called Merkel cell carcinoma (MCC). MCC incidence is much higher in aging and immunocompromised populations. The epidemiology of MCC suggests that dysbiosis between the host immune response and the MCPyV infectious cycle could contribute to the development of MCPyV-associated MCC. Insufficient restriction of MCPyV by normal cellular processes, for example, could promote the incidental oncogenic MCPyV integration events and/or entry into the original cell of MCC. Progress toward understanding MCPyV biology has been hindered by its narrow cellular tropism. Our discovery that primary human dermal fibroblasts (HDFs) support MCPyV Infection has made it possible to closely model cellular responses to different stages of the infectious cycle. The present study reveals that the onset of MCPyV replication and early gene expression induces an inflammatory cytokine and interferon-stimulated gene (ISG) response. The cGAS-STING pathway, in coordination with NF-κB, mediates induction of this innate immune gene expression program. Further, silencing of cGAS or NF-κB pathway factors led to elevated MCPyV replication. We also discovered that the PYHIN protein IFI16 localizes to MCPyV replication centers but does not contribute to the induction of ISGs. Instead, IFI16 upregulates inflammatory cytokines in response to MCPyV Infection by an alternative mechanism. The work described herein establishes a foundation for exploring how changes to the skin microenvironment induced by aging or immunodeficiency might alter the fate of MCPyV and its host cell to encourage carcinogenesis. IMPORTANCE MCC has a high rate of mortality and an increasing incidence. Immune-checkpoint therapies have improved the prognosis of patients with metastatic MCC. Still, a significant proportion of the patients fail to respond to immune-checkpoint therapies or have a medical need for iatrogenic immune-suppression. A greater understanding of MCPyV biology could inform targeted therapies for MCPyV-associated MCC. Moreover, cellular events preceding MCC oncogenesis remain largely unknown. The present study aims to explore how MCPyV interfaces with innate immunity during its infectious cycle. We describe how MCPyV replication and/or transcription elicit an innate immune response via cGAS-STING, NF-κB, and IFI16. We also explore the effects of this response on MCPyV replication. Our findings illustrate how healthy cellular conditions may allow low-level Infection that evades immune destruction until highly active replication is restricted by host responses. Conversely, pathological conditions could result in unbridled MCPyV replication that licenses MCC tumorigenesis.

  • merkel cell Polyomavirus Infection induces an antiviral innate immune response in human dermal fibroblasts
    Journal of Virology, 2021
    Co-Authors: Nathan A. Krump, Wei Liu, Ranran Wang, June F Yang, Jianxin You
    Abstract:

    Merkel cell Polyomavirus (MCPyV) infects most of the human population asymptomatically, but in rare cases leads to a highly aggressive skin cancer called Merkel cell carcinoma (MCC). MCC incidence is much higher in aging and immunocompromised populations. The epidemiology of MCC suggests that dysbiosis between the host immune response and the MCPyV infectious cycle could contribute to the development of MCPyV-associated MCC. Insufficient restriction of MCPyV by normal cellular processes, for example, could promote the incidental oncogenic MCPyV integration events and/or entry into the original cell of MCC. Progress towards understanding MCPyV biology has been hindered by its narrow cellular tropism. Our discovery that primary human dermal fibroblasts (HDFs) support MCPyV Infection has made it possible to closely model cellular responses to different stages of the infectious cycle. The present study reveals that the onset of MCPyV replication and early gene expression induces an inflammatory cytokine and interferon stimulated gene (ISG) response. The cGAS-STING pathway, in coordination with NF-κB, mediates induction of this innate immune gene expression program. Further, silencing of cGAS or NF-κB pathway factors led to elevated MCPyV replication. We also discovered that the PYHIN protein IFI16 localizes to MCPyV replication centers, but does not contribute to the induction of ISGs. Instead, IFI16 upregulates inflammatory cytokines in response to MCPyV Infection by an alternative mechanism. The work described herein establishes a foundation for exploring how changes to the skin microenvironment induced by aging or immunodeficiency might alter the fate of MCPyV and its host cell to encourage carcinogenesis.ImportanceMCC has a high rate of mortality and an increasing incidence. Immune-checkpoint therapies have improved the prognosis of patients with metastatic MCC. Still, a significant proportion of the patients fail to respond to immune-checkpoint therapies or have a medical need for iatrogenic immune-suppression. A greater understanding of MCPyV biology could inform targeted therapies for MCPyV-associated MCC. Moreover, cellular events preceding MCC oncogenesis remain largely unknown. The present study aims to explore how MCPyV interfaces with innate immunity during its infectious cycle. We describe how MCPyV replication and/or transcription elicit an innate immune response via cGAS-STING, NF-κB, and IFI16. We also explore the impacts of this response on MCPyV replication. Our findings illustrate how healthy cellular conditions may allow low-level Infection that evades immune destruction until highly active replication is restricted by host responses. Conversely, pathologic conditions could result in unbridled MCPyV replication that licenses MCC tumorigenesis.

  • From Merkel Cell Polyomavirus Infection to Merkel Cell Carcinoma Oncogenesis
    'Frontiers Media SA', 2021
    Co-Authors: Nathan A. Krump, Jianxin You
    Abstract:

    Merkel cell Polyomavirus (MCPyV) Infection causes near-ubiquitous, asymptomatic Infection in the skin, but occasionally leads to an aggressive skin cancer called Merkel cell carcinoma (MCC). Epidemiological evidence suggests that poorly controlled MCPyV Infection may be a precursor to MCPyV-associated MCC. Clearer understanding of host responses that normally control MCPyV Infection could inform prophylactic measures in at-risk groups. Similarly, the presence of MCPyV in most MCCs could imbue them with vulnerabilities that-if better characterized-could yield targeted intervention solutions for metastatic MCC cases. In this review, we discuss recent developments in elucidating the interplay between host cells and MCPyV within the context of viral Infection and MCC oncogenesis. We also propose a model in which insufficient restriction of MCPyV Infection in aging and chronically UV-damaged skin causes unbridled viral replication that licenses MCC tumorigenesis

  • Merkel cell Polyomavirus Infection and Merkel cell carcinoma.
    Current opinion in virology, 2016
    Co-Authors: Wei Liu, Margo Macdonald, Jianxin You
    Abstract:

    Merkel cell Polyomavirus is the only Polyomavirus discovered to date that is associated with a human cancer. MCPyV Infection is highly prevalent in the general population. Nearly all healthy adults asymptomatically shed MCPyV from their skin. However, in elderly and immunosuppressed individuals, the Infection can lead to a lethal form of skin cancer, Merkel cell carcinoma. In the last few years, new findings have established links between MCPyV Infection, host immune response, and Merkel cell carcinoma development. This review discusses these recent discoveries on how MCPyV interacts with host cells to achieve persistent Infection and, in the immunocompromised population, contributes to MCC development.

  • identifying the target cells and mechanisms of merkel cell Polyomavirus Infection
    Cell Host & Microbe, 2016
    Co-Authors: Wei Liu, Christopher B Buck, Rachel M Schowalter, Megan E Spurgeon, Paul F Lambert, Ruifeng Yang, Aimee S Payne, Jianxin You
    Abstract:

    Summary Infection with Merkel cell Polyomavirus (MCPyV) can lead to Merkel cell carcinoma (MCC), a lethal form of skin cancer. However, the skin cell type productively infected by MCPyV remains a central question. We combined cell culture and ex vivo approaches to identify human dermal fibroblasts as natural host cells that support productive MCPyV Infection. Based on this, we established a cell culture model for MCPyV Infection, which will facilitate investigation of the oncogenic mechanisms for this DNA virus. Using this model, we discovered that induction of matrix metalloproteinase ( MMP ) genes by the WNT/β-catenin signaling pathway and other growth factors stimulates MCPyV Infection. This suggests that MCC risk factors such as UV radiation and aging, which are known to stimulate WNT signaling and MMP expression, may promote viral Infection and thus drive MCC. Our study also introduces the FDA-approved MEK antagonist trametinib as an effective inhibitor for controlling MCPyV Infection.

Heikki Joensuu - One of the best experts on this subject based on the ideXlab platform.

  • association of merkel cell Polyomavirus Infection with tumor p53 kit stem cell factor pdgfr alpha and survival in merkel cell carcinoma
    International Journal of Cancer, 2011
    Co-Authors: Marika Waltari, Heli Kukko, Risto Sankila, Tom Böhling, Virve Koljonen, Heikki Joensuu, Harri Sihto
    Abstract:

    Most Merkel cell carcinomas (MCCs) contain Merkel cell Polyomavirus (MCPyV) DNA, and the virus likely has a pivotal role in tumor pathogenesis. p53 and the KIT receptor tyrosine kinase have also been implicated in MCC pathogenesis, but little is known about their association with MCPyV Infection. We identified 207 patients diagnosed with MCC in Finland in 1979-2004 and reviewed the histological diagnoses. Adequate clinical information, tumor tissue and DNA were available from 87 confirmed MCC cases. Presence of MCPyV DNA was assessed using quantitative PCR; p53, KIT, phospho-KIT, stem cell factor (SCF) and PDGFRα expression using immunohistochemistry and presence of mutations in KIT exons 9, 11, 13 and 17 and PDGFRA exons 10, 12, 14 and 18 using DNA sequencing. Most (77.0%) of the 87 tumors contained MCPyV DNA and 37 (42.5%) expressed KIT, whereas PDGFRα, p53, SCF and pKIT expression was less common (31.9, 22.8, 8.6 and 4.8%, respectively). No KIT or PFGFRA mutations were detected, but 10 (12.5%) of the 80 tumors studied harbored common PDGFRA exon 10 S478P substitution. Tumor p53 and KIT expression were associated with absence of MCPyV DNA (p = 0.01 and 0.009, respectively). Tumor p53 expression was associated with unfavorable MCC-specific survival (p = 0.021) and overall survival (p = 0.046), but tumor KIT expression only when stratified by presence of MCPyV DNA. The results suggest that p53 and KIT expression are associated with absence of MCPyV DNA in MCC, and that the molecular pathogenesis of MCC is multifactorial.

  • merkel cell Polyomavirus Infection large t antigen retinoblastoma protein and outcome in merkel cell carcinoma
    Clinical Cancer Research, 2011
    Co-Authors: Harri Sihto, Heli Kukko, Risto Sankila, Tom Böhling, Virve Koljonen, Heikki Joensuu
    Abstract:

    Purpose: Merkel cell carcinoma (MCC) is rare skin cancer that is often associated with Merkel cell Polyomavirus (MCPyV) Infection. Polyomaviruses repress tumor suppressor proteins, thus influencing cell-cycle progression, but the effect of MCPyV on the key cell-cycle regulating proteins is poorly understood. Experimental Design: We evaluated expression of the MCPyV large T-antigen (LTA), Ki-67, and the key putative tumor suppressor proteins, the retinoblastoma protein (RB and phospho-RB) and p53, and their regulatory proteins (cyclin D1, cyclin E, p16, p21, p27, and MDM2) by using immunohistochemistry from tumors of 91 MCC patients identified from a population-based nationwide cohort. Tumor MCPyV DNA was measured by using quantitative PCR, and TP53 mutations were identified with sequencing. Results: MCPyV LTA expression was strongly associated with presence of MCPyV DNA in tumor, and it was almost invariably associated with tumor RB expression ( P P ≤ 0.01 for all four analyses). Presence of MCPyV LTA was also associated with the female gender, the intermediate type of tumor histology, location of the tumor in a limb, cell proliferation rate, and absence of p53 expression. TP53 mutations were detected only in MCPyV DNA–negative tumors. Conclusions: MCPyV DNA–positive MCC has several clinical and molecular features that differ from MCPyV DNA-negative cancers. MCPyV-associated MCCs express RB, but may not harbor TP53 mutations. These findings provide further support that MCPyV causes the majority of MCCs. Clin Cancer Res; 17(14); 4806–13. ©2011 AACR .

  • clinical factors associated with merkel cell Polyomavirus Infection in merkel cell carcinoma
    Journal of the National Cancer Institute, 2009
    Co-Authors: Harri Sihto, Heli Kukko, Risto Sankila, Tom Böhling, Virve Koljonen, Heikki Joensuu
    Abstract:

    BACKGROUND: Merkel cell carcinoma is a rare malignancy of the skin. Integration of Merkel cell Polyomavirus (MCPyV) DNA to the tumor genome is frequent in these cancers. The clinical consequences of MCPyV Infection are unknown. METHODS: We analyzed formalin-fixed paraffin-embedded Merkel cell carcinoma tissue samples from 114 of 207 patients diagnosed with Merkel cell carcinoma in Finland from 1979 to 2004 for the presence of MCPyV DNA with the use of polymerase chain reaction (PCR), quantitative PCR, and DNA sequencing and examined associations between tumor MCPyV DNA status and histopathologic factors and survival. The median follow-up time after Merkel cell carcinoma diagnosis for subjects who were alive was 9.9 years (range = 4.9-21.9 years). All P values are two-sided. RESULTS: MCPyV DNA was present in 91 carcinomas (79.8%). Compared with MCPyV DNA-negative cancers, MCPyV DNA-positive cancers were more often located in a limb (40.7% vs 8.7%, P = .015) and less frequent in patients who had regional nodal metastases at diagnosis (6.6% vs 21.7%, P = .043). Patients with MCPyV DNA-positive tumors had better overall survival than those with MCPyV DNA-negative tumors (5-year survival: 45.0% vs 13.0%, respectively; P < .001, two-sided log-rank test). CONCLUSIONS: MCPyV Infection is associated with clinical outcomes in patients with Merkel cell carcinoma. These findings lend support to the hypothesis that viral Infection is frequently associated with the pathogenesis of Merkel cell carcinoma.

Renzo Boldorini - One of the best experts on this subject based on the ideXlab platform.

Yanis L. Tolstov - One of the best experts on this subject based on the ideXlab platform.

  • asymptomatic primary merkel cell Polyomavirus Infection among adults
    Emerging Infectious Diseases, 2011
    Co-Authors: Yanis L. Tolstov, Alycia V Knauer, Jian Guo Chen, Thomas W Kensler, Lawrence A Kingsley
    Abstract:

    Merkel cell Polyomavirus (MCV) is a recently discovered virus that causes 80% of Merkel cell carcinomas. We examined data for 564 gay/bisexual male participants >18 years of age in the Multicenter AIDS Cohort Study in Pittsburgh, Pennsylvania, USA, and found that 447 (79.3%) were MCV-antibody positive at initial enrollment. Of the 117 MCV-seronegative men, 31 subsequently seroconverted over a 4-year follow-up period, corresponding to a 6.6% annual conversion rate. MCV immunoglobulin G levels remained detectable up to 25 years after exposure. No signs, symptoms, or routine diagnostic test results were associated with MCV Infection, and no correlation between HIV Infection or AIDS progression and MCV Infection was noted. An initial correlation between chronic hepatitis B virus Infection and MCV prevalence could not be confi rmed among MCV seroconverters or in studies of a second hepatitis B virus–hyperendemic cohort from Qidong, China. In adults, MCV is typically an asymptomatic, common, and commensal viral Infection that initiates rare cancers after virus (rather than host cell) mutations.

  • Human Merkel cell Polyomavirus Infection II. MCV is a common human Infection that can be detected by conformational capsid epitope immunoassays.
    International Journal of Cancer, 2009
    Co-Authors: Yanis L. Tolstov, Huichen Feng, Frank J. Jenkins, Diana V Pastrana, Christopher B Buck, J. Becker, Yuan Chang, Stergios J Moschos, Patrick S. Moore
    Abstract:

    Merkel cell Polyomavirus (MCV) is a newly-discovered human tumor virus found in ∼80% of Merkel cell carcinoma (MCC). The rate of MCV Infection among persons without MCC is unknown. We developed a MCV virus-like particle (VLP) enzyme-linked immunoassay (EIA) that does not cross-react with human BK or murine Polyomaviruses. Peptide mapping of the MCV VP1 gene and immunoblotting with denatured MCV VLP are less sensitive than the MCV EIA in detecting MCV antibodies suggesting antibody reactivity in this assay primarily targets conformational but not linear epitopes. Among MCC patients, all 21 (100%) patients tested with MCV-positive tumors had high serum MCV IgG but not high MCV IgM levels. Only 3 of 6 (50%) MCC patients with MCV-negative tumors were positive for MCV antibodies. Sera from most adults, including 107 of 166 (64%) blood donors, 63 of 100 (63%) commercial donors and 37 of 50 (74%) systemic lupus erythematosus patients, show evidence for prior MCV exposure. Age-specific MCV prevalence was determined by examining a cross-sectional distribution of 150 Langerhans cell histiocytosis (an unrelated neoplasm) patient sera. MCV prevalence increases from 50% among children age 15 years or younger to 80% among persons older than 50 years. We did not find evidence for vertical transmission among infants. Although past exposure to MCV is common among all adult groups, MCC patients have a markedly elevated MCV IgG response compared with control patients. Our study demonstrates that MCV is a widespread but previously unrecognized human Infection.

  • human merkel cell Polyomavirus Infection i mcv t antigen expression in merkel cell carcinoma lymphoid tissues and lymphoid tumors
    International Journal of Cancer, 2009
    Co-Authors: Masahiro Shuda, Yanis L. Tolstov, Huichen Feng, Reety Arora, Hyun Jin Kwun, Ronit Sarid, Maria Teresa Fernandezfigueras, Ole Gjoerup, Mahesh Mansukhani, Steven H Swerdlow
    Abstract:

    Merkel cell Polyomavirus (MCV) is a recently discovered human virus closely related to African green monkey lymphotropic Polyomavirus. MCV DNA is integrated in approximately 80% of Merkel cell carcinomas (MCC), a neuroendocrine skin cancer linked to lymphoid malignancies such as chronic lymphocytic leukemia (CLL). To assess MCV Infection and its association with human diseases, we developed a monoclonal antibody that specifically recognizes endogenous and transfected MCV large T (LT) antigen. We show expression of MCV LT protein localized to nuclei of tumor cells from MCC having PCR quantified MCV genome at an average of 5.2 (range 0.8-14.3) T antigen DNA copies per cell. Expression of this putative viral oncoprotein in tumor cells provides the mechanistic underpinning supporting the notion that MCV causes a subset of MCC. In contrast, although 2.2% of 325 hematolymphoid malignancies surveyed also showed evidence for MCV Infection by DNA PCR, none were positive at high viral copy numbers, and none of 173 lymphoid malignancies examined on tissue microarrays expressed MCV LT protein in tumor cells. As with some of the other human Polyomaviruses, lymphocytes may serve as a tissue reservoir for MCV Infection, but hematolymphoid malignancies associated with MCC are unlikely to be caused by MCV.

  • human merkel cell Polyomavirus Infection i mcv t antigen expression in merkel cell carcinoma lymphoid tissues and lymphoid tumors
    International Journal of Cancer, 2009
    Co-Authors: Masahiro Shuda, Yanis L. Tolstov, Huichen Feng, Reety Arora, Hyun Jin Kwun, Ronit Sarid, Maria Teresa Fernandezfigueras, Ole Gjoerup, Mahesh Mansukhani, Steven H Swerdlow
    Abstract:

    Merkel cell Polyomavirus (MCV) is a recently discovered human virus closely related to African green monkey lymphotropic Polyomavirus. MCV DNA is integrated in �80% of Merkel cell carcinomas (MCC), a neuroendocrine skin cancer linked to lymphoid malignancies such as chronic lymphocytic leukemia (CLL). To assess MCV Infection and its association with human diseases, we developed a monoclonal antibody that specifically recognizes endogenous and transfected MCV large T (LT) antigen. We show expression of MCV LT protein localized to nuclei of tumor cells from MCC having PCR quantified MCV genome at an average of 5.2 (range 0.8‐14.3) T antigen DNA copies per cell. Expression of this putative viral oncoprotein in tumor cells provides the mechanistic underpinning supporting the notion that MCV causes a subset of MCC. In contrast, although 2.2% of 325 hematolymphoid malignancies surveyed also showed evidence for MCV Infection by DNA PCR, none were positive at high viral copy numbers, and none of 173 lymphoid malignancies examined on tissue microarrays expressed MCV LT protein in tumor cells. As with some of the other human Polyomaviruses, lymphocytes may serve as a tissue reservoir for MCV Infection, but hematolymphoid malignancies associated with MCC are unlikely to be caused by MCV. ' 2009 UICC

Steven H Swerdlow - One of the best experts on this subject based on the ideXlab platform.

  • human merkel cell Polyomavirus Infection i mcv t antigen expression in merkel cell carcinoma lymphoid tissues and lymphoid tumors
    International Journal of Cancer, 2009
    Co-Authors: Masahiro Shuda, Yanis L. Tolstov, Huichen Feng, Reety Arora, Hyun Jin Kwun, Ronit Sarid, Maria Teresa Fernandezfigueras, Ole Gjoerup, Mahesh Mansukhani, Steven H Swerdlow
    Abstract:

    Merkel cell Polyomavirus (MCV) is a recently discovered human virus closely related to African green monkey lymphotropic Polyomavirus. MCV DNA is integrated in approximately 80% of Merkel cell carcinomas (MCC), a neuroendocrine skin cancer linked to lymphoid malignancies such as chronic lymphocytic leukemia (CLL). To assess MCV Infection and its association with human diseases, we developed a monoclonal antibody that specifically recognizes endogenous and transfected MCV large T (LT) antigen. We show expression of MCV LT protein localized to nuclei of tumor cells from MCC having PCR quantified MCV genome at an average of 5.2 (range 0.8-14.3) T antigen DNA copies per cell. Expression of this putative viral oncoprotein in tumor cells provides the mechanistic underpinning supporting the notion that MCV causes a subset of MCC. In contrast, although 2.2% of 325 hematolymphoid malignancies surveyed also showed evidence for MCV Infection by DNA PCR, none were positive at high viral copy numbers, and none of 173 lymphoid malignancies examined on tissue microarrays expressed MCV LT protein in tumor cells. As with some of the other human Polyomaviruses, lymphocytes may serve as a tissue reservoir for MCV Infection, but hematolymphoid malignancies associated with MCC are unlikely to be caused by MCV.

  • human merkel cell Polyomavirus Infection i mcv t antigen expression in merkel cell carcinoma lymphoid tissues and lymphoid tumors
    International Journal of Cancer, 2009
    Co-Authors: Masahiro Shuda, Yanis L. Tolstov, Huichen Feng, Reety Arora, Hyun Jin Kwun, Ronit Sarid, Maria Teresa Fernandezfigueras, Ole Gjoerup, Mahesh Mansukhani, Steven H Swerdlow
    Abstract:

    Merkel cell Polyomavirus (MCV) is a recently discovered human virus closely related to African green monkey lymphotropic Polyomavirus. MCV DNA is integrated in �80% of Merkel cell carcinomas (MCC), a neuroendocrine skin cancer linked to lymphoid malignancies such as chronic lymphocytic leukemia (CLL). To assess MCV Infection and its association with human diseases, we developed a monoclonal antibody that specifically recognizes endogenous and transfected MCV large T (LT) antigen. We show expression of MCV LT protein localized to nuclei of tumor cells from MCC having PCR quantified MCV genome at an average of 5.2 (range 0.8‐14.3) T antigen DNA copies per cell. Expression of this putative viral oncoprotein in tumor cells provides the mechanistic underpinning supporting the notion that MCV causes a subset of MCC. In contrast, although 2.2% of 325 hematolymphoid malignancies surveyed also showed evidence for MCV Infection by DNA PCR, none were positive at high viral copy numbers, and none of 173 lymphoid malignancies examined on tissue microarrays expressed MCV LT protein in tumor cells. As with some of the other human Polyomaviruses, lymphocytes may serve as a tissue reservoir for MCV Infection, but hematolymphoid malignancies associated with MCC are unlikely to be caused by MCV. ' 2009 UICC