Selective antibody neutralization prevents neuropathogenic lactate dehydrogenase-elevating virus from causing paralytic disease in immunocompetent mice
Selective antibody neutralization prevents neuropathogenic lactate dehydrogenase-elevating virus from causing paralytic disease in immunocompetent mice
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DOI：
10.3109/13550289909022003
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发表时间：
1999-04-01
影响因子：
3.2
通讯作者：
Plagemann, PGW
中科院分区：
文献类型：
--
作者：
Chen, ZY;Li, K;Plagemann, PGW
神经致病性乳酸脱氢酶升高病毒（LDV）通过与内源性鼠逆转录病毒相互作用在C58和AKR小鼠中细胞内感染前角神经元，导致麻痹性疾病;年龄依赖性脊髓灰质炎（ADPM）。ADPM的诱导需要由于年老、遗传缺陷（如裸鼠）或任何免疫抑制治疗而抑制的宿主免疫系统。以前的结果表明，感染前角神经元的神经致病性LDV分离株和ADPM的后续发展是防止抗LDV抗体在感染过程中主动诱导或被动管理时。然而，保护机制尚不清楚，因为中和和非中和多克隆抗体似乎都具有保护性，而只有中和单克隆抗体具有保护性。此外，运动神经元免受感染的保护发生在对LDV复制没有任何明显影响的情况下，已知巨噬细胞亚群是主要的容许宿主细胞。这些矛盾现在已经得到解决。我们最近报道了神经致病性LDV分离株包含神经致病性和非神经致病性准种，其建立高病毒血症持续感染的能力不同。使用神经致病性和非神经致病性准种的生物克隆;我们现在证明了两者都在相同的容许巨噬细胞亚群中复制，但是神经致病性准种比非神经致病性准种对体外抗体中和的敏感性高约100倍，抗体能中和神经致病性的而不能中和非神经致病性的在FVB、BALB/c、C57 BL/6和C58小鼠中，神经致病性LDV感染后7天即产生神经致病性准种，并选择性抑制神经致病性LDV的体内复制。先前观察到的早期多克隆抗LDV抗体中和作用的缺乏和LDV在巨噬细胞中复制的明显无效的抗体控制是由于非神经致病性准种的生长，所述准种也存在于神经致病性LDV接种物中并且对抗体中和具有高度抗性。使用克隆的神经致病性LDV准种，我们证明了一个明确的关系，在发展中的中和抗体，复制抑制的神经致病性LDV和预防ADPM在C58小鼠。因此，我们的研究结果建立了一个不可分割的关系，神经元保护作用的抗体和其中和的神经致病性LDV准种，并解释为什么神经致病性LDVs只在免疫抑制小鼠引起麻痹性疾病。
Neuropathogenic lactate dehydrogenase-elevating viruses (LDV) cytocidally infect anterior horn neurons in C58 and AKR mice via interaction with endogenous murine retroviruses to cause a paralytic disease; age-dependent poliomyelitis (ADPM). The induction of ADPM requires a suppressed host immune system as a result of old age, genetic defects (such as nude mice) or any immunosuppressive treatment. Previous results have shown that the infection of anterior horn neurons by neuropathogenic LDV isolates and the subsequent development of ADPM are prevented by anti-LDV antibodies either induced actively during infection or when passively administered. However, the mechanism of protection was unclear since both neutralizing and nonneutralizing polyclonal antibodies seemed protective, whereas only neutralizing monoclonal antibodies were protective. Furthermore, the protection of motor neurons from infection occurred in the absence of any apparent effect on LDV replication in a subpopulation of macrophages known to be the primary permissive host cells. These paradoxes have now been resolved. We have recently reported that the neuropathogenic LDV isolates contain both neuropathogenic and non-neuropathogenic quasispecies that differ in their ability to establish a high viremia persistent infection. Using biological clones of both neuropathogenic and non-neuropathogenic quasispecies; we now demonstrate that both replicate in the same subpopulation of permissive macrophages, but that the neuropathogenic quasispecies are about 100 times more susceptible to in vitro antibody neutralization than the non-neuropathogenic ones, and that antibodies that neutralize the neuropathogenic but not the non-neuropathogenic quasispecies develop as soon as 7 days after infection with neuropathogenic LDVs and selectively suppress the replication of the neuropathogenic LDVs in vivo in FVB, BALB/c, C57 BL/6 and C58 mice. The previously observed lack of neutralizing effect of early polyclonal anti-LDV antibodies and the apparent ineffective antibody control of LDV replication in macrophages were due to outgrowth of the non-neuropathogenic quasispecies that are also present in the neuropathogenic LDV inoculum and are highly resistant to antibody neutralization. Using cloned neuropathogenic LDV quasispecies, we demonstrate a clear relationship in the development of neutralizing antibodies, replication suppression of the neuropathogenic LDVs and the prevention of ADPM in C58 mice. Our results therefore establish an inseparable relationship between the neuron-protective effect of an antibody and its neutralization of the neuropathogenic LDV quasispecies and explain why neuropathogenic LDVs cause paralytic disease only in immunosuppressed mice.