Protection from Severe Influenza Virus Infections in Mice Carrying the Mx1 Influenza Virus Resistance Gene Strongly Depends on Genetic Background.
Protection from Severe Influenza Virus Infections in Mice Carrying the Mx1 Influenza Virus Resistance Gene Strongly Depends on Genetic Background.
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DOI：
10.1128/jvi.01305-15
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发表时间：
2015-10
影响因子：
5.4
通讯作者：
Schughart K
中科院分区：
文献类型：
--
作者：
Shin DL;Hatesuer B;Bergmann S;Nedelko T;Schughart K
流感病毒感染对人类健康构成严重威胁。外在因素和内在因素都决定了流感的严重程度。MX动力蛋白样GTCR 1（Mx 1）基因已被证明在小鼠中赋予对甲型流感病毒感染的强大抵抗力。大多数实验室小鼠品系，包括C57 BL/6 J，在Mx 1中携带无义或缺失突变，因此是无功能等位基因，而野生型小鼠品系携带野生型Mx 1等位基因。表达来自A2 G小鼠品系的野生型等位基因的同类C57 BL/6 J（B6-Mx 1 r/r）小鼠对甲型流感病毒感染（单碱基和多碱基亚型）具有高度抗性。此外，在基因图谱研究中，Mx 1被确定为对流感病毒感染具有抗性的主要位点。在这里，我们研究了Mx 1的保护功能是否受到遗传背景的影响。为此，我们在DBA/2 J背景下产生了携带A2 G野生型Mx 1抗性等位基因的同源小鼠品系（D2-Mx 1 r/r）。最值得注意的是，表达功能性Mx 1野生型等位基因的同类D2-Mx 1 r/r小鼠仍然对H1N1病毒高度易感。然而，用α干扰素预处理D2-Mx 1 r/r小鼠可以保护它们免受致命感染。我们的研究结果首次表明，来自A2 G的Mx 1野生型等位基因的存在并不能完全保护小鼠免受致命的甲型流感病毒感染。这些观察结果也与人类对流感病毒感染的易感性高度相关。 重要性甲型流感病毒是对人类健康的主要威胁。季节性流感流行每年造成很高的经济损失、发病率和死亡率。宿主的遗传因素强烈影响对病毒感染的易感性和抵抗力。Mx 1（MX动力蛋白样GTCR 1）基因已被描述为小鼠和人类的主要抗性基因。大多数近交系实验室小鼠品系缺乏Mx 1，但携带来自A2 G小鼠品系的野生型Mx 1基因的同源B6-Mx 1 r/r小鼠具有高度抗性。在这里，我们非常意外地发现，携带来自A2 G株的野生型Mx 1基因的同类D2-Mx 1 r/r小鼠不能完全免受致命流感病毒感染。这些观察结果表明，遗传背景是非常重要的Mx 1抗性基因的保护功能。我们的研究结果也与了解人类流感病毒感染的遗传易感性高度相关。
Influenza virus infections represent a serious threat to human health. Both extrinsic and intrinsic factors determine the severity of influenza. The MX dynamin-like GTPase 1 (Mx1) gene has been shown to confer strong resistance to influenza A virus infections in mice. Most laboratory mouse strains, including C57BL/6J, carry nonsense or deletion mutations in Mx1 and thus a nonfunctional allele, whereas wild-derived mouse strains carry a wild-type Mx1 allele. Congenic C57BL/6J (B6-Mx1r/r) mice expressing a wild-type allele from the A2G mouse strain are highly resistant to influenza A virus infections, to both mono- and polybasic subtypes. Furthermore, in genetic mapping studies, Mx1 was identified as the major locus of resistance to influenza virus infections. Here, we investigated whether the Mx1 protective function is influenced by the genetic background. For this, we generated a congenic mouse strain carrying the A2G wild-type Mx1 resistance allele on a DBA/2J background (D2-Mx1r/r). Most remarkably, congenic D2-Mx1r/r mice expressing a functional Mx1 wild-type allele are still highly susceptible to H1N1 virus. However, pretreatment of D2-Mx1r/r mice with alpha interferon protected them from lethal infections. Our results showed, for the first time, that the presence of an Mx1 wild-type allele from A2G as such does not fully protect mice from lethal influenza A virus infections. These observations are also highly relevant for susceptibility to influenza virus infections in humans. IMPORTANCE Influenza A virus represents a major health threat to humans. Seasonal influenza epidemics cause high economic loss, morbidity, and deaths each year. Genetic factors of the host strongly influence susceptibility and resistance to virus infections. The Mx1 (MX dynamin-like GTPase 1) gene has been described as a major resistance gene in mice and humans. Most inbred laboratory mouse strains are deficient in Mx1, but congenic B6-Mx1r/r mice that carry the wild-type Mx1 gene from the A2G mouse strain are highly resistant. Here, we show that, very unexpectedly, congenic D2-Mx1r/r mice carrying the wild-type Mx1 gene from the A2G strain are not fully protected against lethal influenza virus infections. These observations demonstrate that the genetic background is very important for the protective function of the Mx1 resistance gene. Our results are also highly relevant for understanding genetic susceptibility to influenza virus infections in humans.