Suppression of Lysine-specific Demethylase 1 Activity Reduces Herpes Simplex Virus Infection in Mice

• Main Authors: Pin-HungLin, 林品宏
• Other Authors: Shun-Hua Chen
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/79855432445487051020

碩士 === 國立成功大學 === 微生物及免疫學研究所 === 100 === Herpes simplex virus (HSV) infection causes stromal keratitis (HSK) and fatal encephalitis (HSE). Acyclovir is used to treat patients, but the emergence of acyclovir-resistant virus frequently occurs, especially in immunocompromised patients who are highly susceptible to HSV infection. During infection, HSV can facilitate viral replication by recruiting lysine-specific demethylase-1 (LSD1) to demethylate histones bound on promoters of viral immediate-early genes. Inhibition of LSD1 has been shown to suppress HSV replication in vitro. However, it remains unclear whether inhibition of LSD1 could reduce HSV infection and diseases in vivo. To address this issue, we used in vitro studies and more importantly, murine infection models. Our in vitro results showed that treatment with a LSD1 inhibitor, tranylcypromine (TCP), reduced the replication of wild type and acyclovir-resistant HSV-1 in both mouse and human cell lines. In addition, in vivo results revealed that in the mouse eye infected with acyclovir-resistant HSV-1, treatment of TCP before or after infection reduced viral titers. In mice with HSE, TCP treatment significantly decreased the death rate by 45% and viral loads in the eye, trigeminal ganglion, and brain. In mice with HSK, TCP treatment diminished the corneal disease and angiogenesis as well as the eye viral titer. In addition, in latently infected mice subjected to hyperthermia to induce viral reactivation, TCP treatment suppressed HSV-1 reactivation from the mouse trigeminal ganglion. Collectively, these results show that inhibition of LSD1 reduces HSV infection and diseases in mice and suggest that the LSD1 inhibitor could be used as an alternative therapy, especially for acyclovir-resistant HSV-1 in patients.