[转移贴]-Nature：基因差异可影响人类抗流感能力

rojjer

原帖由ipsvirus发表于27/3/2012 15:14

根据这篇3月25日在线发表于《Nature》杂志网站上的文章，人体内一个基因的“版本”不同影响了人们抵抗流感的能力。该基因名为IFITM3，它会指导合成与它同名的蛋白质。最开始研究人员发现这种蛋白质能在试管中抑制流感病毒的复制，于是通过动物实验进行验证。

结果发现，那些这一基因被技术性剔除的实验鼠，由于缺少相关蛋白质，即使只感染低致病性的流感病毒，也会出现较严重的症状，但如果重新引入这个基因，则症状会随之减轻。

研究人员分析了人类所携带的这个基因后发现，人体的这个基因存在两个版本。本次研究报告作者之一、英国桑格研究所的薛雅丽博士说，虽然两个版本的基因只有一处小小的不同，但它们指导合成的蛋白质在功能上却大不相同，其结果就是感染同样的流感病毒，有的人病情会特别严重，有的人却只有轻微症状。

对流感患者的分析也显示，无论是甲型H1N1流感，还是普通的季节性流感，那些病情较重的患者往往都携带了对病毒抵抗力较弱的那个基因版本。

薛雅丽说，这项研究成果对防治流感来说有重要意义，如果再出现大规模流感疫情，医疗卫生部门可以通过基因检测手段，预先筛查出那些对流感病毒抵抗力较弱的人群，有针对性地注射疫苗或采取其他防护措施，降低死亡率。此外从长远看，这项研究结果也有助开发新的流感药物和治疗手段。

转自http://www.bioon.com/biology/biomed/520297.shtml



IFITM3 restricts the morbidity and mortality associated with influenza

Aaron R. Everitt, Simon Clare, Thomas Pertel, Sinu P. John, Rachael S. Wash, Sarah E. Smith, Christopher R. Chin, Eric M. Feeley, Jennifer S. Sims, David J. Adams, Helen M. Wise, Leanne Kane, David Goulding, Paul Digard, Verneri Anttila, J. Kenneth Baillie, Tim S. Walsh, David A. Hume, Aarno Palotie, Yali Xue, Vincenza Colonna, Chris Tyler-Smith, Jake Dunning, Stephen B. Gordon, The GenISIS Investigators, The MOSAIC Investigators, Rosalind L. Smyth, Peter J. Openshaw, Gordon Dougan,        Abraham L. Brass & Paul Kellam

The 2009 H1N1 influenza pandemic showed the speed with which a novel respiratory virus can spread and the ability of a generally mild infection to induce severe morbidity and mortality in a subset of the population. Recent in vitro studies show that the interferon-inducible transmembrane (IFITM) protein family members potently restrict the replication of multiple pathogenic viruses1, 2, 3, 4, 5, 6, 7. Both the magnitude and breadth of the IFITM proteins’ in vitro effects suggest that they are critical for intrinsic resistance to such viruses, including influenza viruses. Using a knockout mouse model8, we now test this hypothesis directly and find that IFITM3 is essential for defending the host against influenza A virus in vivo. Mice lacking Ifitm3 display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 ‘Spanish’ influenza9, 10. Similar increased viral replication is seen in vitro, with protection rescued by the re-introduction of Ifitm3. To test the role of IFITM3 in human influenza virus infection, we assessed the IFITM3 alleles of individuals hospitalized with seasonal or pandemic influenza H1N1/09 viruses. We find that a statistically significant number of hospitalized subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.

原文链接http://www.nature.com/nature/jou ... ll/nature10921.html

rojjer

ipsvirus ：
本帖最后由 ipsvirus 于 2012-3-27 19:12 编辑

而关于IFITM3能抑制流感病毒也是本文作者Abraham L. Brass发现的，其研究发表在09年Cell上：The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus。

在流感病毒感染细胞后，会劫持细胞系统来实现扩增。反过来，宿主细胞也会表达一些抗病毒因子来抵抗病毒感染。在这项研究中，研究人员利用一种功能性基因组扫描方法，鉴定出H1N1流感病毒感染细胞过程中有约120多个基因表达发生改变。其中一个重要的发现就是干扰素诱导跨膜蛋白（IFITM），研究发现IFITM家族的3个成员IFITM1，IFITM2，IFITM3，都能抑制流感病毒感染的早期过程。当IFITM3被中断后，H1N1的复制速度要比一般条件下要快5～10倍。此外，研究人员还利用不同的H1N1株系测试了不同的细胞类型的IFITM3功能，如人类和老鼠的肺部细胞等，所得结果相似。

另外一个发现就是IFITM不仅能抑制流感病毒，而且对黄病毒属也具有一定的抑制效果，比如登革热病毒和西尼罗河病毒。但是对HCV却没什么效果。

这项发现或许有助于开发更有效的抗病毒药物以及减缓流感传播的预防性药物。

作者对IFITM的抑制作用机制的假说如图所示

rojjer

ipsvirus:
The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus

Abraham L. Brass, I-Chueh Huang, Yair Benita, Sinu P. John, Manoj N. Krishnan, Eric M. Feeley, Bethany J. Ryan, Jessica L. Weyer, Louise van der Weyden, Erol Fikrig, David J. Adams, Ramnik J. Xavier, Michael Farzan, and Stephen J. Elledge

Influenza viruses exploit host cell machinery to replicate, resulting in epidemics of respiratory illness. In turn, the host expresses antiviral restriction factors to defend against infection. To find host cell modifiers of influenza A H1N1 viral infection, we used a functional genomic screen and identified over 120 influenza A virus-dependency factors with roles in endosomal acidification, vesicular trafficking, mitochondrial metabolism, and RNA splicing. We discovered that the interferon-inducible transmembrane proteins IFITM1, 2, and 3 restrict an early step in influenza A viral replication. The IFITM proteins confer basal resistance to influenza A virus but are also inducible by interferons type I and II and are critical for interferon's virustatic actions. Further characterization revealed that the IFITM proteins inhibit the early replication of flaviviruses, including dengue virus and West Nile virus. Collectively this work identifies a family of antiviral restriction factors that mediate cellular innate immunity to at least three major human pathogens.

原文链接http://www.cell.com/abstract/S0092-8674(09)01564-5

rojjer

yy7200:
学习了，这种基因的差异是与生具有，还是后天环境影响的？

ipsvirus:
5# yy7200

这种应该是天生的，Nature这篇文章关键就是发现了这个IFITM基因在人群中的多样性，而且这与抗流感病毒感染直接关联。这对开发针对性疫苗和药物还是有作用的。  


zzx219:
前段时间还看到一个关于拉马克获得性遗传的报告，到时候能不能让这些抗流感特性也给遗传下来了。  

rojjer

杨子~ :
学习学习，这种天生的抗性不知道和血型又没有关系

hxq78316:
好像和血型没关系！


yangcao:
好东西，再一次证明了基因的结构决定其功能。