Monkeypox virus, Interferon, and Necroptosis

猴痘病毒、干扰素和坏死性凋亡

• 批准号: 10455608
• 负责人: Bertram L. Jacobs
• 金额: $ 54.12万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-24 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10455608
• 关键词: Africa; Animal Model; Animals; Attenuated; Binding; Caspase; Cell Death; Cells; Cessation of life; Data; Disease Outbreaks; E3L gene; Exposure to; Failure; Funding; Genetic Recombination; Goals; Homologous Gene; Human; Immune Evasion; In Vitro; Infection; Interferons; Lead; Molecular; Monkeypox virus; Mus; N-terminal; Nucleic Acid Binding; Orthopoxvirus; Pathogenesis; Pathogenicity; Pattern; Pattern recognition receptor; Persons; Phosphorylation; Phosphotransferases; Poxviridae; Prairie Dog; Proteins; RIPK3 gene; Regimen; Research; Resistance; Smallpox; Vaccination; Vaccinia virus; Viral Pathogenesis; Virulence; Virus; Virus Diseases; Work; World Health Organization; Zoonoses; canine model; human pathogen; in vivo; inhibitor; loss of function mutation; mortality; mutant; pathogen; prevent; prototype; repaired; vaccine development

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.

我们对痘病毒先天性免疫逃避的了解大多来自于对痘病毒原型——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。我们一直在研究猴痘病毒（MPXV）的例子。在培养细胞和动物模型中，VACV具有E3L基因，该基因对干扰素耐药性至关重要。尽管具有高致病性，但MPXV在其E3同源物的n端缺失37个残基。因此，令人惊讶的是，尽管MPXV缺失了E3先天免疫逃避蛋白的这一重要区域，但它仍然具有致病性。我们已经证明，虽然MPXV中缺乏n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被感知的影响。这项研究的目的是了解这种独特的人类病原体是如何在感染细胞中被感知的，以及它是如何进化以对抗感知的影响的。这种先天免疫逃避结构域的缺失使得针对MPXV的疫苗接种存在问题。该项目的最终目标是开发一种可以安全地预防MPXV感染的疫苗。