Department of Molecular and Biomedical Sciences, University of Maine, Orono, ME 04469, USA.
Graduate School in Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA.
Viruses. 2021 Sep 14;13(9):1834. doi: 10.3390/v13091834.
JC polyomavirus (JCPyV) is a neuroinvasive pathogen causing a fatal, demyelinating disease of the central nervous system (CNS) known as progressive multifocal leukoencephalopathy (PML). Within the CNS, JCPyV predominately targets two cell types: oligodendrocytes and astrocytes. The underlying mechanisms of astrocytic infection are poorly understood, yet recent findings suggest critical differences in JCPyV infection of primary astrocytes compared to a widely studied immortalized cell model. RNA sequencing was performed in primary normal human astrocytes (NHAs) to analyze the transcriptomic profile that emerges during JCPyV infection. Through a comparative analysis, it was validated that JCPyV requires the mitogen-activated protein kinase, extracellular signal-regulated kinase (MAPK/ERK) pathway, and additionally requires the expression of dual-specificity phosphatases (DUSPs). Specifically, the expression of DUSP1 is needed to establish a successful infection in NHAs, yet this was not observed in an immortalized cell model of JCPyV infection. Additional analyses demonstrated immune activation uniquely observed in NHAs. These results support the hypothesis that DUSPs within the MAPK/ERK pathway impact viral infection and influence potential downstream targets and cellular pathways. Collectively, this research implicates DUSP1 in JCPyV infection of primary human astrocytes, and most importantly, further resolves the signaling events that lead to successful JCPyV infection in the CNS.
JC 多瘤病毒（JCPyV）是一种神经侵袭性病原体，可导致中枢神经系统（CNS）致命的脱髓鞘疾病，即进行性多灶性白质脑病（PML）。在 CNS 中，JCPyV 主要靶向两种细胞类型：少突胶质细胞和星形胶质细胞。星形胶质细胞感染的潜在机制尚不清楚，但最近的发现表明，与广泛研究的永生化细胞模型相比，JCPyV 对原代星形胶质细胞的感染存在关键差异。对原代正常人星形胶质细胞（NHAs）进行 RNA 测序，以分析 JCPyV 感染过程中出现的转录组谱。通过比较分析，验证了 JCPyV 需要丝裂原活化蛋白激酶，细胞外信号调节激酶（MAPK/ERK）途径，并且还需要双特异性磷酸酶（DUSPs）的表达。具体而言，DUSP1 的表达对于 NHAs 中成功的感染是必需的，但在 JCPyV 感染的永生化细胞模型中未观察到。进一步的分析表明，仅在 NHAs 中观察到免疫激活。这些结果支持这样的假设，即 MAPK/ERK 途径中的 DUSPs 影响病毒感染，并影响潜在的下游靶标和细胞途径。总的来说，这项研究表明 DUSP1 参与了 JCPyV 对原代人星形胶质细胞的感染，最重要的是，进一步阐明了导致 CNS 中 JCPyV 成功感染的信号事件。
