A Polymorphic Residue That Attenuates the Antiviral Potential of Interferon Lambda 4 in Hominid Lineages
A Polymorphic Residue That Attenuates the Antiviral Potential of Interferon Lambda 4 in Hominid Lineages
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减弱干扰素 Lambda 4 在原始人类谱系中的抗病毒潜力的多态性残基
DOI：
10.1101/214825
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Bamford C
中科院分区：
文献类型：
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作者：
Bamford C
作为抗菌信号分子，III型干扰素或波长干扰素(λS)对于抵御细菌、真菌和病毒等各种病原体的感染至关重要。与直觉相反的是，家族成员干扰素λ4的表达与丙型肝炎病毒在人类群体中的清除减少有关；相比之下，自然移码突变取消干扰素λ4的产生提高了丙型肝炎病毒的清除。为了进一步了解物种间和物种内的遗传差异如何影响干扰素λ4的功能，我们筛选了一组已知的人干扰素λ4的编码变体的抗病毒活性，并确定了三个对活性有显著影响的基因：P70S、L79F和K154E。最显著的变异是K154E，它是在非洲刚果热带雨林的俾格米人狩猎采集者中发现的。K154E在一系列抗病毒(丙型肝炎病毒、寨卡病毒、流感病毒和脑心肌炎病毒)和基因表达分析中显著增强了体外活性。值得注意的是，E154是哺乳动物干扰素λ4S的祖先残基，保存得非常好，但K154在包括尼安德特人在内的原始人基因组的进化过程中一直是固定的。与黑猩猩干扰素λ4相比，人类同源基因由于氨基酸K154而活性降低。对已发表的人类和黑猩猩基因表达数据的比较表明，K154和E154在干扰素λ4中活性的差异与丙型肝炎病毒感染期间体内抗病毒基因表达的差异有关。从机制上讲，我们的数据显示，人类特有的K154通过一种新的方式通过减少其分泌和效力来负面影响干扰素λ4的活性。因此，我们证明干扰素λ4的减弱活性在人类中是保守的，并假设不同物种之间干扰素λ4活性的差异有助于宿主对感染的不同特异性反应和结果，例如丙型肝炎病毒感染。人类干扰素λ4抗病毒活性降低的原因尚不清楚，但可能发生在600万至36万年前的非洲。
As antimicrobial signalling molecules, type III or lambda interferons (IFNλs) are critical for defence against infection by diverse pathogens, including bacteria, fungi and viruses. Counter-intuitively, expression of one member of the family, IFNλ4, is associated with decreased clearance of hepatitis C virus (HCV) in the human population; by contrast, a natural frameshift mutation that abrogates IFNλ4 production improves HCV clearance. To further understand how genetic variation between and within species affects IFNλ4 function, we screened a panel of all known extant coding variants of human IFNλ4 for their antiviral potential and identify three that substantially affect activity: P70S, L79F and K154E. The most notable variant was K154E, which was found in African Congo rainforest ‘Pygmy’ hunter-gatherers. K154E greatly enhancedin vitroactivity in a range of antiviral (HCV, Zika virus, influenza virus and encephalomyocarditis virus) and gene expression assays. Remarkably, E154 is the ancestral residue in mammalian IFNλ4s and is extremely well conserved, yet K154 has been fixed throughout evolution of the hominid genusHomo, including Neanderthals. Compared to chimpanzee IFNλ4, the human orthologue had reduced activity due to amino acid K154. Comparison of published gene expression data from humans and chimpanzees showed that this difference in activity between K154 and E154 in IFNλ4 correlates with differences in antiviral gene expressionin vivoduring HCV infection. Mechanistically, our data show that the human-specific K154 negatively affects IFNλ4 activity through a novel means by reducing its secretion and potency. We thus demonstrate that attenuated activity of IFNλ4 is conserved among humans and postulate that differences in IFNλ4 activity between species contribute to distinct host-specific responses to—and outcomes of—infection, such as HCV infection. The driver of reduced IFNλ4 antiviral activity in humans remains unknown but likely arose between 6 million and 360,000 years ago in Africa.