Monkeypox virus, Interferon, and Necroptosis

我们对痘病毒先天免疫逃避的了解大部分来自于对原型正痘病毒--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具有E3 L基因，该基因在培养的细胞和动物模型中对于干扰素抗性是必需的。尽管具有高致病性，但MPXV在其E3同源物的N-末端缺少37个残基。因此，令人惊讶的是，MPXV是致病性的，因为它是，尽管缺少E3先天免疫逃避蛋白的这一必要区域。我们已经表明，虽然MPXV中缺乏N-末端先天免疫逃避结构域允许病毒被宿主感知，但MPXV已经进化出至少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如何在受感染的细胞中被感知，以及它如何进化以对抗感知的影响。这种先天免疫逃避结构域的丧失使得针对MPXV的疫苗接种成为问题。该项目的最终目标是开发一种可以安全预防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.