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：
10.1038/88247
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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中最重要的机会性感染（1，2）。我们使用小鼠实验感染模型（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Cmv 1控制，Cmv 1是一个6号染色体基因座，可调节自然杀伤（NK）细胞对病毒感染靶标的活性（3-5）。在这里，我们使用的定位克隆策略，以分离在Cmv 1基因座突变的基因。Cmv 1在由标记D 608和D 60115定义的0.35-cM间隔内映射，其对应于1.6 Mb的物理距离（参考文献110）。（第6至8段）。该区域的转录本图谱鉴定出19个基因（8），包括杀伤细胞凝集素样受体家族a的成员（Klra，以前为Ly 49;参考文献10）。9-12），其编码与MHC I类分子相互作用的抑制性或活化性NK细胞受体（13-15）。Klra基因具有不同的拷贝数和基因组结构，并且在近交系中具有高度多态性，使得难以区分正常的等位基因变体和不同的Klra基因（15-17），或与Cmv 1相关的可能突变。重组近交系BXD-8/Ty（BXD-8;参考文献18）来源于Cmv 1（r）C57 BL/6（B6，抗性）和Cmv 1（s）DBA/2（易感），特别令人感兴趣，因为尽管Cmv 1处具有B6单倍型，但它对MCMV感染高度易感。我们确定BXD-8中的MCMV易感性与Klra 8（以前的Ly 49 h）缺失相关。
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).