Department of Microbiology, Institute for Immunology, and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Microbiology, Institute for Immunology, and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
J Virol. 2014 Jul;88(14):7703-14. doi: 10.1128/JVI.00050-14. Epub 2014 Apr 23.
Successful adaptive immunity to virus infection often depends on the initial innate response. Previously, we demonstrated that Junín virus, the etiological agent responsible for Argentine hemorrhagic fever (AHF), activates an early innate immune response via an interaction between the viral glycoprotein and Toll-like receptor 2 (TLR2). Here we show that TLR2/6 but not TLR1/2 heterodimers sense Junín virus glycoprotein and induce a cytokine response, which in turn upregulates the expression of the RNA helicases RIG-I and MDA5. NF-κB and Erk1/2 were important in the cytokine response, since both proteins were phosphorylated as a result of the interaction of virus with TLR2, and treatment with an Erk1/2-specific inhibitor blocked cytokine production. We show that the Junín virus glycoprotein activates cytokine production in a human macrophage cell line as well. Moreover, we show that TLR2-mediated immune response plays a role in viral clearance because wild-type mice cleared Candid 1 (JUNV C1), the vaccine strain of Junín virus, more rapidly than did TLR2 knockout mice. This clearance correlated with the generation of Junín virus-specific CD8(+) T cells. However, infected wild-type and TLR2 knockout mice developed TLR2-independent blocking antibody responses with similar kinetics. We also show that microglia and astrocytes but not neurons are susceptible to infection with JUNV C1. Although JUNV C1 infection of the brain also triggered a TLR2-dependent cytokine response, virus levels were equivalent in wild-type and TLR2 knockout mice. Importance: Junín virus is transmitted by rodents native to Argentina and is associated with both systemic disease and, in some patients, neurological symptoms. Humans become infected when they inhale aerosolized Junín virus. AHF has a 15 to 30% mortality rate, and patients who clear the infection develop a strong antibody response to Junín virus. Here we investigated what factors determine the immune response to Junín virus. We show that a strong initial innate immune response to JUNV C1 determines how quickly mice can clear systemic infection and that this depended on the cellular immune response. In contrast, induction of an innate immune response in the brain had no effect on virus infection levels. These findings may explain how the initial immune response to Junín virus infection could determine different outcomes in humans.
成功的病毒感染适应性免疫通常依赖于初始的先天免疫反应。先前，我们证明了 Junín 病毒，即阿根廷出血热（AHF）的致病因子，通过病毒糖蛋白与 Toll 样受体 2（TLR2）之间的相互作用激活早期先天免疫反应。在这里，我们表明 TLR2/6 而不是 TLR1/2 异二聚体感知 Junín 病毒糖蛋白并诱导细胞因子反应，这反过来又上调 RNA 解旋酶 RIG-I 和 MDA5 的表达。NF-κB 和 Erk1/2 在细胞因子反应中很重要，因为这两种蛋白由于病毒与 TLR2 的相互作用而被磷酸化，并且使用 Erk1/2 特异性抑制剂阻断细胞因子的产生。我们还表明 Junín 病毒糖蛋白在人巨噬细胞系中也能激活细胞因子的产生。此外，我们表明 TLR2 介导的免疫反应在病毒清除中起作用，因为野生型小鼠比 TLR2 敲除小鼠更快地清除 Candid 1（JUNV C1），即 Junín 病毒的疫苗株。这种清除与 Junín 病毒特异性 CD8(+)T 细胞的产生有关。然而，感染的野生型和 TLR2 敲除小鼠产生了具有相似动力学的 TLR2 非依赖性阻断抗体反应。我们还表明，小胶质细胞和星形胶质细胞而不是神经元容易感染 JUNV C1。尽管 JUNV C1 感染大脑也触发了 TLR2 依赖性细胞因子反应，但野生型和 TLR2 敲除小鼠中的病毒水平相等。重要性：Junín 病毒由阿根廷本土的啮齿动物传播，与全身疾病有关，在一些患者中还与神经症状有关。当人类吸入气溶胶化的 Junín 病毒时就会被感染。AHF 的死亡率为 15%至 30%，清除感染的患者会对 Junín 病毒产生强烈的抗体反应。在这里，我们研究了是什么因素决定了对 Junín 病毒的免疫反应。我们表明，对 JUNV C1 的强烈初始先天免疫反应决定了小鼠清除全身感染的速度，这取决于细胞免疫反应。相比之下，在大脑中诱导先天免疫反应对病毒感染水平没有影响。这些发现可能解释了为什么对 Junín 病毒感染的初始免疫反应可以决定人类的不同结果。
