Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily
Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily
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DOI：
10.1038/ng0501-42
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发表时间：
2001-05-01
期刊：
影响因子：
30.8
通讯作者：
Vidal, SM
中科院分区：
文献类型：
--
作者：
Lee, SH;Girard, S;Vidal, SM
巨细胞病毒是先天性病毒性疾病的主要原因，也是免疫功能低下患者最重要的机会性感染(1，2)。我们使用小鼠实验性感染模型(MCMV)来研究宿主/病毒相互作用的遗传参数。对MCMV感染的易感性由Cmv1控制，Cmv1是一个6号染色体基因座，调节自然杀伤(NK)细胞对病毒感染目标的活动(3-5)。在这里，我们使用定位克隆策略来分离在Cmv1基因座突变的基因。由标记D6Ott8和D6Ott115定义的0.35厘米间隔内的Cmv1地图，对应于1.6Mb的物理距离。6-8)。该区域的转录图谱鉴定了19个基因(8)，包括杀伤细胞凝集素样受体家族a的成员(Klra，前Ly49；参考文献。9-12)，编码抑制性或激活性NK细胞受体，与MHC I类分子相互作用(13-15)。Klra基因具有不同的拷贝数和基因组结构，并且在近交系之间具有高度的多态，这使得很难区分正常的等位变异和不同的Klra基因(15-17)，或者与Cmv1相关的可能的突变。重组近交系菌株BXD-8/Ty(BXD-8；参18)来自Cmv1(R)C57BL/6(B6，抗性)和Cmv1(S)Dba/2(易感)，特别令人感兴趣，因为尽管Cmv1具有B6单倍型，但它对MCMV感染高度敏感。我们确定BXD-8对MCMV的敏感性与Klra8(以前的Ly49h)缺失有关。
Cytomegalovirus is the leading cause of congenital viral disease and the most important opportunistic infection in immunocompromised patients(1,2). We have used a mouse experimental infection model (MCMV) to study the genetic parameters of host/virus interaction. Susceptibility to infection with MCMV is controlled by Cmv1, a chromosome 6 locus that regulates natural killer (NK) cell activity against virally infected targets(3-5). Here, we use a positional cloning strategy to isolate the gene mutated at the Cmv1 locus. Cmv1 maps within a 0.35-cM interval defined by markers D6Ott8 and D6Ott115, which corresponds to a physical distance of 1.6 Mb (refs. 6-8). A transcript map of the region identified 19 genes(8), including members of the killer cell lectin-like receptor family a (Klra, formerly Ly49; refs. 9-12), which encode inhibitory or activating NK cell receptors that interact with MHC class I molecules(13-15). Klra genes have different copy numbers and genomic organization, and are highly polymorphic among inbred strains, making it difficult to distinguish between normal allelic variants and distinct Klra genes(15-17), or possible mutations associated with Cmv1. The recombinant inbred strain BXD-8/Ty (BXD-8; ref. 18), derived from Cmv1(r) C57BL/6 (B6, resistant) and Cmv1(s) DBA/2 (susceptible), is of particular interest because it is highly susceptible to MCMV infection despite having a B6 haplotype at Cmv1, We determined that MCMV susceptibility in BXD-8 is associated with the deletion of Klra8 (formerly Ly49h).