Ahmed Chulbul M, Dabelic Rea, Waiboci Lilian W, Jager Lindsey D, Heron Linda L, Johnson Howard M
Department of Microbiology and Cell Science, University of Florida, P.O. Box 110700, Gainesville, FL 32611-0700, USA.
J Virol. 2009 Feb;83(3):1402-15. doi: 10.1128/JVI.01138-08. Epub 2008 Nov 19.
The suppressor of cytokine signaling 1 (SOCS-1) protein modulates cytokine signaling by binding to and inhibiting the function of Janus kinases (JAKs), ErbB, and other tyrosine kinases. We have developed a small tyrosine kinase inhibitor peptide (Tkip) that binds to the autophosphorylation site of tyrosine kinases and inhibits activation of STAT transcription factors. We have also shown that a peptide corresponding to the kinase-inhibitory region of SOCS-1, SOCS1-KIR, similarly interacts with the activation loop of JAK2 and blocks STAT activation. Poxviruses activate cellular tyrosine kinases, such as ErbB-1 and JAK2, in the infection of cells. We used the pathogenesis of vaccinia virus in C57BL/6 mice to determine the ability of the SOCS-1 mimetics to protect mice against lethal vaccinia virus infection. Injection of mice intraperitoneally with Tkip or SOCS1-KIR containing a palmitate for cell penetration, before and at the time of intranasal challenge with 2 x 10(6) PFU of vaccinia virus, resulted in complete protection at 100 microg. Initiation of treatment 1 day postinfection resulted in 80% survival. Administration of SOCS-1 mimetics by the oral route also protected mice against lethal effects of the virus. Both SOCS1-KIR and Tkip inhibited vaccinia virus transcription and replication at early and possibly later stages of infection. Vaccinia virus-induced phosphorylation of ErbB-1 and JAK2 was inhibited by the mimetics. Protected mice mounted a strong humoral and cellular response to vaccinia virus. The use of SOCS-1 mimetics in the treatment of poxvirus infections reveals an endogenous regulatory system that previously was not known to have an antiviral function.
细胞因子信号转导抑制因子1（SOCS-1）蛋白通过结合并抑制Janus激酶（JAKs）、表皮生长因子受体（ErbB）及其他酪氨酸激酶的功能来调节细胞因子信号转导。我们研发了一种小的酪氨酸激酶抑制剂肽（Tkip），它能结合酪氨酸激酶的自磷酸化位点并抑制信号转导和转录激活因子（STAT）转录因子的激活。我们还发现，一段与SOCS-1的激酶抑制区域相对应的肽段，即SOCS1-KIR，同样能与JAK2的激活环相互作用并阻断STAT激活。痘病毒在感染细胞时会激活细胞酪氨酸激酶，如ErbB-1和JAK2。我们利用痘苗病毒在C57BL/6小鼠中的致病机制来确定SOCS-1模拟物保护小鼠免受致死性痘苗病毒感染的能力。在用2×10⁶空斑形成单位（PFU）的痘苗病毒进行鼻内攻击之前及同时，给小鼠腹腔注射含有用于细胞穿透的棕榈酸酯的Tkip或SOCS1-KIR，在剂量为100微克时可实现完全保护。感染后1天开始治疗，存活率为80%。通过口服途径给予SOCS-1模拟物也能保护小鼠免受病毒的致死作用。SOCS1-KIR和Tkip在感染的早期及可能的后期阶段均抑制痘苗病毒的转录和复制。模拟物可抑制痘苗病毒诱导的ErbB-1和JAK2的磷酸化。受到保护的小鼠对痘苗病毒产生了强烈的体液和细胞免疫反应。使用SOCS-1模拟物治疗痘病毒感染揭示了一个以前未知具有抗病毒功能的内源性调节系统。
