Monkeypox virus, Interferon, and Necroptosis

我们所知道的关于痘病毒先天免疫逃避的大部分知识来自于对正痘病毒原型牛痘病毒(VACV)的研究。然而，越来越清楚的是，我们对VACV的了解并不总是适用于其他痘病毒。我们一直在研究的例子是猴痘病毒(MPXV)。VACV有一个E3L基因，无论是在培养细胞中还是在动物模型中，E3L基因对于抵抗干扰素都是必不可少的。尽管MPXV具有高致病性，但其E3同源物的N端缺少37个残基。因此，令人惊讶的是，尽管缺少E3先天免疫逃避蛋白的这一关键区域，MPXV却像它一样具有致病性。我们已经证明，虽然MPXV缺乏N末端的天然免疫逃避结构域，使病毒能够被宿主感知，但MPXV至少进化了两种明显独立的机制来克服在细胞中感知的影响。这项研究的目标是了解这种独特的人类病原体是如何在受感染的细胞中被感知的，以及它是如何进化来对抗感知的影响的。这种先天免疫逃避结构域的丧失使针对MPXV的疫苗接种成为问题。该项目的最终目标是开发一种能够安全地预防MPXV感染的疫苗。

Much of what we know about poxvirus innate immune evasion comes from work with the prototype orthopoxvirus, vaccinia virus (VACV). However, it is becoming clear that what we know for VACV is not always true for other poxviruses. The example we have been working on is monkeypox virus (MPXV). VACV has an E3L gene, which is essential for interferon-resistance, both in cells in culture and in the animal model. Despite being highly pathogenic, MPXV is missing 37 residues from the N-terminus of its E3 homologue. Thus, it is surprising that MPXV is as pathogenic as it is, despite missing this essential region of the E3 innate immune evasion protein. We have shown that while the lack of an N-terminal innate immune evasion domain in MPXV allows the virus to be sensed by the host, MPXV has evolved at least two apparently independent mechanisms to overcome the effects of being sensed in cells. The goals of this research are to understand how this unique human pathogen is sensed in infected cells and how it has evolved to counter the effects of sensing. Loss of this innate immune evasion domain makes vaccination against MPXV problematic. The final goal of this project is to develop a vaccine that can safely protect against MPXV infection.