Identification of two cerebral malaria resistance loci using an inbred wild-derived mouse strain
Identification of two cerebral malaria resistance loci using an inbred wild-derived mouse strain
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DOI：
10.1073/pnas.152215199
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发表时间：
2002-07-23
影响因子：
11.1
通讯作者：
Holmberg, D
中科院分区：
文献类型：
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作者：
Bagot, S;Campino, S;Holmberg, D
疟疾是一种复杂的传染病，其中宿主/寄生虫相互作用受到宿主遗传因素的强烈影响。疟原虫感染的后果从无症状到严重并发症，如人类恶性疟原虫和啮齿动物伯氏疟原虫引起的神经系统综合征脑型疟疾。感染伯氏疟原虫ANKA的小鼠在疾病表现上表现出明显的差异，并且死于实验性脑型疟疾（ECM）或死于由高寄生虫血症（HIP）引起的溶血性贫血。迄今为止研究的大多数实验室小鼠品系对ECM易感;然而，许多野生来源的近交系表现出耐药性。为了评估这种差异的遗传基础，我们将一种独特的ECM抗性野生近交系（WLA）与ECM易感实验室品系（C57 BL/6 J）杂交。所有的（WLA X C57 BL/6 J）F-1和97%的F-2后代显示出与WLA菌株相似的ECM抗性。为了筛选有助于ECM抗性的基因座，我们分析了与C57 BL/6 J亲本品系回交的一组小鼠。该群组的全基因组筛选提供了ECM抗性与染色体1（chi（2）= 18.98，P = 1.3 × 10（-5））和染色体11（chi（2）= 16.51，P = 4.8 × 10（-5））上的两个遗传区域中的标记基因座的显著连锁，分别命名为Berr 1和Berr 2。这些数据提供了与鼠脑型疟疾抗性相关的基因座的第一个证据，这可能对寻找控制人类脑型疟疾的遗传因素具有重要意义。
Malaria is a complex infectious disease in which the host/parasite interaction is strongly influenced by host genetic factors. The consequences of plasmodial infections range from asymptomatic to severe complications like the neurological syndrome cerebral malaria induced by Plasmodium, falciparum in humans and Plasmodium, berghei ANKA in rodents. Mice infected with A berghei ANKA show marked differences in disease manifestation and either die from experimental cerebral malaria (ECM) or from hemolytic anemia caused by hyperparasitemia (HIP). A majority of laboratory mouse strains so far investigated are susceptible to ECM; however, a number of wild-derived inbred strains show resistance. To evaluate the genetic basis of this difference, we crossed a uniquely ECM-resistant, wild-derived inbred strain (WLA) with an ECM susceptible laboratory strain (C57BL/6J). All of the (WLA x C57BL/6J) F-1 and 97% of the F-2 progeny displayed ECM resistance similar to the WLA strain. To screen for loci contributing to ECM resistance, we analyzed a cohort of mice backcrossed to the C57BL/6J parental strain. A genome wide screening of this cohort provided significant linkage of ECM resistance to marker loci in two genetic regions on chromosome 1 (chi(2) = 18.98, P = 1.3 x 10(-5)) and on chromosome 11 (chi(2) = 16.51, P = 4.8 X 10(-5)), being designated Berr1 and Berr2, respectively. These data provide the first evidence of loci associated with resistance to murine cerebral malaria, which may have important implications for the search for genetic factors controlling cerebral malaria in humans.