Natural Killer Cell Deficiencies in Aging Mice

描述(由申请人提供)：众所周知，老龄化的后果是感染相关疾病和死亡的风险增加。然而，到目前为止，大多数关于衰老和对病毒疾病抵抗力的工作是相关的，因为它不能再现自然致病原发感染后对病毒疾病易感性增加的情况。 病毒。我们先前已经证明，在感染小鼠病原体ECTV(ECTV)期间，年轻的C57BL/6(B6)小鼠在感染后存活下来，没有全身疾病的症状，因为它们的自然杀伤细胞(NKC)迁移到引流淋巴结(D-LN)并抑制病毒传播。相反，老年B6小鼠死于感染，因为它们的NKC不能迁移到D-LN，病毒迅速传播到重要器官。此外，我们发现NKC缺乏迁移是NKC固有的，因为过继转移的NKC不会在年轻宿主的D-LN中积聚，而年轻小鼠的NKC会在老年宿主的D-LN中积聚，从而保护它们免受死亡。因此，我们建立了老年人NKC的移行缺陷与对感染抵抗力下降之间的直接联系。最近，我们确定了衰老小鼠的NKC是由于其在骨髓中的不成熟而缺乏的。我们现在将按照两个具体目标来跟进这些观察结果。在目标1中，我们将确定NKC迁移受损的原因，确定NKC在老年小鼠中的其他缺陷，并确定我们的发现的普遍性。在目标2中，我们将研究为什么老年小鼠的NKC不能在骨髓中正常成熟。由于人类中的许多传染病通过LNS系统传播，NKC缺陷患者显著增加了病毒感染的发生率，NKC成熟蛋白和迁移缺陷也可能导致老年人对至少某些病毒的易感性增加。我们的小鼠模型为研究NKC功能障碍提供了一个独特的途径，具有很强的潜力来促进我们对病毒疾病易感性增加的原因的了解，我们认为这些病毒疾病应该是人类可以遗传的。

DESCRIPTION (provided by applicant): It is well established that a consequence of aging is an increased risk of infection related diseases and death. However, most work to date on aging and resistance to viral disease is correlative, because it does not reproduce the condition of increased susceptibility to a viral disease following a primary infection with naturally pathogenic viruses. We have previously shown that during infection with the mouse pathogen ectromelia virus (ECTV), young C57BL/6 (B6) mice survive the infection without symptoms of systemic disease because their natural killer cells (NKC) migrate to the draining lymph node (D-LN) and curb viral dissemination. Conversely, aged B6 mice succumb to the infection because their NKC fail to migrate to the D-LN and the virus spreads rapidly to vital organs. Further, we showed that the lack of NKC migration is intrinsic to the NKC, because adoptively transferred NKC from aged mice did not accumulate in the D-LN of young hosts, while NKC from young mice accumulated in the D-LN of aged hosts, protecting them from lethality. Thus, we established a direct link between migration defects of NKC in the aged and decreased resistance to an infection. More recently, we determined that the NKC in aged mice are deficient due to their improper maturation in the bone marrow. We will now follow up these observations in two Specific Aims. In Aim 1, we will determine why the migration of NKC is impaired, identify other defects of NKC in aged mice and determine the generality of our findings. In Aim 2, we will investigate why NKC in aged mice fail to properly mature in the bone marrow. Because many infectious diseases in humans spread systemically via LNs and NKC-deficient patients have significantly increased incidence of viral infections, it is possible that a defective NKC maturatin and migration also contributes to the increased susceptibility of older people to at least some viruses. Our mouse model provides a unique avenue to investigate NKC dysfunctions with strong potential to advance our knowledge on causes of increased susceptibility to viral disease that we believe should be translatable to humans.