High accumulation of Mx2 renders limited multiplication of oncolytic herpes simplex virus-1 in human tumor cells

• Published in: Scientific reports 2021-10, Vol.11 (1), p.21227-21227, Article 21227
• Main Authors: Ren, Yong, Chen, Meiling, Wu, Guangxian, Ji, Dongmei, Zhou, Grace Guoying, Ren, Pei-Gen, Fu, Wenmin
• Format: Article
• Language: English
• Subjects: 631/250/262; 631/326/596/1296; 631/67/1858; Brain Neoplasms - metabolism; Brain Neoplasms - virology; Cell Line, Tumor; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Glioblastoma; Glioblastoma - metabolism; Glioblastoma - virology; Herpes simplex; Herpesvirus 1, Human - pathogenicity; Herpesvirus 1, Human - physiology; Humanities and Social Sciences; Humans; Immunity, Innate; Interferon regulatory factor 3; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - metabolism; Interferon-alpha - genetics; Interferon-alpha - metabolism; mRNA; multidisciplinary; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Myxovirus resistance proteins; Myxovirus Resistance Proteins - genetics; Myxovirus Resistance Proteins - metabolism; NF-κB protein; Nuclear transport; Oncolysis; Science; Science (multidisciplinary); Translocation; Tumor cell lines; Tumor cells; Tumors; Virus Replication; Viruses; α-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-00691-y

Increasing studies demonstrated that oncolytic activities of oHSV-1 are limited to the capacity of virus replicating in tumors. In order to potentiate the oHSV-1 oncolytic activity and expand the application of oHSV-1 treatment in multiple types of tumors, it is critical to explore the potential factors or mechanisms mediating tumor resistance to oHSV-1 infection. Here we evaluated the levels of oHSV-1 multiplication in various tumor cell lines and showed that glioblastoma cell line A172 had the lowest virus yields but intrinsically accumulated the highest levels of Mx2 protein. Subsequently we demonstrated that genetic depletion of Mx2 specifically enhanced oHSV-1 productive replication in A172 cells through promoting the nuclear translocation of uncoated viral genomic DNA and down-regulating innate antiviral response. In the further investigation, we found that Mx2 knockdown could alter the intrinsic mRNA accumulation of diverse sets innate immune genes in A172 cells, in particular DHX36 and MyD88. Mx2 depletion led to a decrease in mRNA levels of MyD88 and DHX36 in A172 cells and MyD88/DHX36 knockdown increased virus yield in A172 cells and decreased the production of IFNα, activation of IRF3 activity and NF-κB signaling in A172 cells. This shed new lights on understanding the roles of some intrinsic antiviral genes in oHSV-1 resistance, facilitating to offer potential targets to improve oHSV-1 oncolytic efficacy and develop candidates of biomarkers to predict the efficiency of oHSV-1 multiplication in tumors.