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Identifying the Target Cells and Mechanisms of Merkel Cell Polyomavirus Infection.

ABSTRACT: 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/?-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.

SUBMITTER: Liu W

PROVIDER: S-EPMC4900903 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Identifying the Target Cells and Mechanisms of Merkel Cell Polyomavirus Infection.

Liu Wei W Yang Ruifeng R Payne Aimee S AS Schowalter Rachel M RM Spurgeon Megan E ME Lambert Paul F PF Xu Xiaowei X Buck Christopher B CB You Jianxin J

Cell host & microbe 20160519 6

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 D ...[more]

PMID: 27212661

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Project description:Merkel cell polyomavirus (MCPyV) is the first polyomavirus to be associated with human cancer. Mechanistic studies attempting to fully elucidate MCPyV's oncogenic mechanisms have been hampered by the lack of animal models for MCPyV infection. In this study, we examined the ability of MCPyV-GFP pseudovirus (containing a green fluorescent protein [GFP] reporter construct), MCPyV recombinant virions, and several MCPyV chimeric viruses to infect dermal fibroblasts isolated from various model animals, including mouse (Mus musculus), rabbit (Oryctolagus cuniculus), rat (Rattus norvegicus), chimpanzee (Pan troglodytes), rhesus macaque (Macaca mulatta), patas monkey (Erythrocebus patas), common woolly monkey (Lagothrix lagotricha), red-chested mustached tamarin (Saguinus labiatus), and tree shrew (Tupaia belangeri). We found that MCPyV-GFP pseudovirus was able to enter the dermal fibroblasts of all species tested. Chimpanzee dermal fibroblasts were the only type that supported vigorous MCPyV gene expression and viral replication, and they did so to a level beyond that of human dermal fibroblasts. We further demonstrated that both human and chimpanzee dermal fibroblasts produce infectious MCPyV virions that can successfully infect new cells. In addition, rat dermal fibroblasts supported robust MCPyV large T antigen expression after infection with an MCPyV chimeric virus in which the entire enhancer region of the MCPyV early promoter has been replaced with the simian virus 40 (SV40) analog. Our results suggest that viral transcription and/or replication events represent the major hurdle for MCPyV cross-species transmission. The capacity of rat dermal fibroblasts to support MCPyV early gene expression suggests that the rat is a candidate model organism for studying viral oncogene function during Merkel cell carcinoma (MCC) oncogenic progression.IMPORTANCE MCPyV plays an important role in the development of a highly aggressive form of skin cancer, Merkel cell carcinoma (MCC). With the increasing number of MCC diagnoses, there is a need to better understand the virus and its oncogenic potential. However, studies attempting to fully elucidate MCPyV's oncogenic mechanisms have been hampered by the lack of animal models for MCPyV infection. To pinpoint the best candidate for developing an MCPyV infection animal model, we examined MCPyV's ability to infect dermal fibroblasts isolated from various established model animals. Of the animal cell types we tested, chimpanzee dermal fibroblasts were the only isolates that supported the full MCPyV infectious cycle. To overcome the infection blockade in the other model animals, we constructed chimeric viruses that achieved robust MCPyV entry and oncogene expression in rat fibroblasts. Our results suggest that the rat may serve as an in vivo model to study MCV oncogenesis.

Dataset Information

Identifying the Target Cells and Mechanisms of Merkel Cell Polyomavirus Infection.

Publications

Identifying the Target Cells and Mechanisms of Merkel Cell Polyomavirus Infection.

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