默克尔细胞聚病毒(MCPyV)已与约80%的默克尔细胞癌(MCC)相关联，这是一种侵袭性的及越来越普遍的皮肤癌。宿主固有免疫、病毒载量控制和癌变之间的联系已被建立，但尚未充分表征。我们先前已经确定STING和NF-κB途径在宿主固有免疫对病毒感染的反应中的重要性。在这项研究中，我们进一步发现，MCPyV感染人体真皮成纤维细胞（HDFs）会诱导I型和III型干扰素（IFN）的表达，进而刺激IFN刺激基因（ISG）的强烈表达。使用IFN-β抗体、JAK抑制剂和CRISPR敲除受体来阻断I型IFN下游信号传导，可以显著抑制MCPyV感染引起的ISG表达，但并未显著恢复病毒复制活动。这些发现表明，对MCPyV感染的IFN介导的ISG诱导不是病毒控制所必需的。相反，我们发现，I型IFN通过抑制早期病毒转录，对MCPyV感染的后期起到更直接的作用。我们进一步证明，在受伤或紫外线辐射的人类皮肤中通常上调的生长因子可以显著刺激MCPyV基因的表达和复制。总之，这些数据表明，在健康人群中，对病毒活动诱导的IFN产生等宿主抗病毒反应可能通过限制病毒传播来降低MCPyV负担。同时，皮肤擦伤或紫外线照射引起的生长因子可能刺激感染的真皮成纤维细胞促进MCPyV扩散。这些相互对抗的因素的微妙平衡提供了一种支持持续MCPyV感染的机制。意义在于，默克尔细胞癌是一种对免疫系统受损个体特别致命的皮肤癌。虽然罕见，但MCC的发病率近年来显著增加。对于转移性疾病没有长期和有效的治疗方法，这凸显了需要额外的治疗和预防策略。通过研究宿主固有免疫系统如何与大多数这些癌症的病因体Merkel细胞聚病毒相互作用，我们的研究确定了控制病毒的关键因素以及支持病毒扩散的条件。这些研究为理解病毒如何平衡宿主免疫防御的影响和生长因子刺激的影响以实现持久感染提供了新的见解。由于病毒阳性MCC需要表达病毒致癌基因才能生存，我们观察到I型IFN可以抑制病毒致癌基因的转录，这表明这些细胞因子可以作为治疗病毒阳性MCC患者的可行治疗选择。

Merkel cell polyomavirus (MCPyV) has been associated with approximately 80% of Merkel cell carcinoma (MCC), an aggressive and increasingly incident skin cancer. The link between host innate immunity, viral load control, and carcinogenesis has been established but poorly characterized. We previously established the importance of the STING and NF-κB pathways in the host innate immune response to viral infection. In this study, we further discovered that MCPyV infection of human dermal fibroblasts (HDFs) induces the expression of type I and III interferons (IFNs), which in turn stimulate robust expression of IFN-stimulated genes (ISGs). Blocking type I IFN downstream signaling using an IFN-β antibody, JAK inhibitors, and CRISPR knockout of the receptor dramatically repressed MCPyV infection-induced ISG expression but did not significantly restore viral replication activities. These findings suggest that IFN-mediated induction of ISGs in response to MCPyV infection is not crucial to viral control. Instead, we found that type I IFN exerts a more direct effect on MCPyV infection postentry by repressing early viral transcription. We further demonstrated that growth factors normally upregulated in wounded or UV-irradiated human skin can significantly stimulate MCPyV gene expression and replication. Together, these data suggest that in healthy individuals, host antiviral responses, such as IFN production induced by viral activity, may restrict viral propagation to reduce MCPyV burden. Meanwhile, growth factors induced by skin abrasion or UV irradiation may stimulate infected dermal fibroblasts to promote MCPyV propagation. A delicate balance of these mutually antagonizing factors provides a mechanism to support persistent MCPyV infection. IMPORTANCE Merkel cell carcinoma is an aggressive skin cancer that is particularly lethal to immunocompromised individuals. Though rare, MCC incidence has increased significantly in recent years. There are no lasting and effective treatments for metastatic disease, highlighting the need for additional treatment and prevention strategies. By investigating how the host innate immune system interfaces with Merkel cell polyomavirus, the etiological agent of most of these cancers, our studies identified key factors necessary for viral control, as well as conditions that support viral propagation. These studies provide new insights for understanding how the virus balances the effects of the host immune defenses and of growth factor stimulation to achieve persistent infection. Since virus-positive MCC requires the expression of viral oncogenes to survive, our observation that type I IFN can repress viral oncogene transcription indicates that these cytokines could be explored as a viable therapeutic option for treating patients with virus-positive MCC.