# Merkel cell polyomavirus infection, host response, and viral oncogenic mechanism

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $362,492

## Abstract

Project Summary
Merkel cell polyomavirus (MCPyV), the most recently discovered tumor virus, can cause a highly
aggressive form of skin cancer called Merkel cell carcinoma (MCC). While the incidence of MCC has
tripled over the past twenty years, there is no effective therapy for metastatic MCCs, highlighting the
need to better understand MCPyV oncogenic mechanism in order to develop more successful
therapies. MCPyV asymptomatically infects most of the human population, but tends to cause MCC in
the elderly and immunocompromised individuals. These observations suggest that host immunity
plays a critical role in controlling MCPyV-induced tumorigenesis. However, very little is known about
the innate immune response elicited by MCPyV. Neither is it clear how a dysregulated immune
system contributes to MCC tumorigenesis. This is largely because MCPyV tropism was previously
unknown and there was a lack of biologically relevant culture system for MCPyV. Recently, we
discovered that human dermal fibroblasts (HDFs) support productive MCPyV infection and
established the first in vitro as well as ex vivo infection models for MCPyV. Using these systems, we
demonstrated that MCPyV infection activates STING-mediated innate immune responses, which in
turn restrict viral amplification and spread. In addition, we discovered that STING is silenced in
MCPyV(+) MCC tumors, revealing that loss of STING function is needed to drive MCC tumorigenesis.
Our studies suggest that disruption of STING function may cause pathologic rampant replication of
MCPyV to promote viral genome integration into the host genome, which is a key event in MCPyV-
driven tumorigenesis. In addition, loss of STING function may allow MCPyV-induced pre-cancerous
cells to circumvent its tumor suppressive effects, thus stimulating cell proliferation and tumorigenesis.
Building on these observations, we hypothesize that STING functions not only as a key antiviral
immune mediator for controlling MCPyV infection but also a prime tumor suppressor that blocks
MCPyV-driven tumorigenesis. To test this hypothesis, we will combine the in vitro and ex vivo MCPyV
infection models with 3D “artificial human skin” reconstructed in mice to examine the impact of STING
innate immune sensing pathways on MCPyV infection (Aim 1) and to determine how disruption of
STING signaling impacts MCPyV-driven MCC tumorigenesis (Aim 2). Through revealing the largely
unknown interplay between MCPyV and the innate immune system, our ultimate goal is to understand
how poorly controlled MCPyV infection leads to MCC development. Identification of immune effectors
that normally restrict MCPyV propagation could also unveil novel strategies for preventing and treating
the devastating MCC cancers.

## Key facts

- **NIH application ID:** 10741777
- **Project number:** 5R01CA187718-08
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jianxin You
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $362,492
- **Award type:** 5
- **Project period:** 2015-04-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10741777

## Citation

> US National Institutes of Health, RePORTER application 10741777, Merkel cell polyomavirus infection, host response, and viral oncogenic mechanism (5R01CA187718-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10741777. Licensed CC0.

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